Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma
Abstract
:1. Introduction
2. The Tumor Microenvironment in Lymphoma
2.1. Overview of the Tumor Microenvironment
2.2. Inflamed and Noninflamed Lymphomas
2.3. Requisites for an Adequate Antitumor Immune Response
3. Mechanisms of Immune Evasion
3.1. Loss of Major Histocompatibility Complexes
3.2. Expression of Immunosuppressive Ligands
3.3. Recruitment and Expansion of Immunosuppressive Cell Populations
3.4. Secretion of Exhaustive and Suppressive Cytokines
3.5. Low Tumor Mutational Burden
3.6. Innate Immune Dysfunction
4. Engaging the Antitumor Immune Response
4.1. Immune Checkpoint Inhibitors
4.1.1. Non-Hodgkin Lymphomas
4.1.2. Hodgkin Lymphoma
4.1.3. T-Cell Lymphomas
4.1.4. Peritransplant Setting
4.1.5. Checkpoint Inhibitors under Investigation
4.2. Checkpoint Inhibitors of the Innate Immune System
4.3. Immune Checkpoint Stimulators
4.4. Polyspecific Engagers
4.4.1. T-Cell-Engaging Formats
4.4.2. NK-Cell-Engaging Formats
5. Remaining Hurdles and Future Directions
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Leach, D.R.; Krummel, M.F.; Allison, J.P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271, 1734–1736. [Google Scholar] [CrossRef] [Green Version]
- Hellmann, M.D.; Paz-Ares, L.; Bernabe Caro, R.; Zurawski, B.; Kim, S.-W.; Carcereny Costa, E.; Park, K.; Alexandru, A.; Lupinacci, L.; de la Mora Jimenez, E.; et al. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer. N. Engl. J. Med. 2019, 381, 2020–2031. [Google Scholar] [CrossRef]
- Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.-J.; Rutkowski, P.; Lao, C.D.; Cowey, C.L.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 2019, 381, 1535–1546. [Google Scholar] [CrossRef] [Green Version]
- André, T.; Shiu, K.-K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer. N. Engl. J. Med. 2020, 383, 2207–2218. [Google Scholar] [CrossRef] [PubMed]
- Ansell, S.; Gutierrez, M.E.; Shipp, M.A.; Gladstone, D.; Moskowitz, A.; Borello, I.; Popa-Mckiver, M.; Farsaci, B.; Zhu, L.; Lesokhin, A.M.; et al. A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039). Blood 2016, 128, 183. [Google Scholar] [CrossRef]
- Scott, D.W.; Gascoyne, R.D. The tumour microenvironment in B cell lymphomas. Nat. Rev. Cancer 2014, 14, 517–534. [Google Scholar] [CrossRef] [PubMed]
- Joshi, M.; Ansell, S.M. Activating the Antitumor Immune Response in Non-Hodgkin Lymphoma Using Immune Checkpoint Inhibitors. J. Immunol. Res. 2020, 2020, 8820377. [Google Scholar] [CrossRef] [PubMed]
- Calabretta, E.; d’Amore, F.; Carlo-Stella, C. Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma. Int. J. Mol. Sci. 2019, 20, 5503. [Google Scholar] [CrossRef] [Green Version]
- Mulder, T.A.; Wahlin, B.E.; Österborg, A.; Palma, M. Targeting the Immune Microenvironment in Lymphomas of B-Cell Origin: From Biology to Clinical Application. Cancers 2019, 11, 915. [Google Scholar] [CrossRef] [Green Version]
- Ansell, S.M. Fundamentals of immunology for understanding immunotherapy for lymphoma. Blood Adv. 2020, 4, 5863–5867. [Google Scholar] [CrossRef]
- Younes, A.; Ansell, S.; Fowler, N.; Wilson, W.; de Vos, S.; Seymour, J.; Advani, R.; Forero, A.; Morschhauser, F.; Kersten, M.J.; et al. The landscape of new drugs in lymphoma. Nat. Rev. Clin. Oncol. 2017, 14, 335–346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roemer, M.G.; Advani, R.H.; Ligon, A.H.; Natkunam, Y.; Redd, R.A.; Homer, H.; Connelly, C.F.; Sun, H.H.; Daadi, S.E.; Freeman, G.J.; et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J. Clin. Oncol. 2016, 34, 2690–2697. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wein, F.; Küppers, R. The role of T cells in the microenvironment of Hodgkin lymphoma. J. Leukoc. Biol. 2016, 99, 45–50. [Google Scholar] [CrossRef] [Green Version]
- Aldinucci, D.; Gloghini, A.; Pinto, A.; Colombatti, A.; Carbone, A. The role of CD40/CD40L and interferon regulatory factor 4 in Hodgkin lymphoma microenvironment. Leuk. Lymphoma 2012, 53, 195–201. [Google Scholar] [CrossRef]
- Craig, V.J.; Cogliatti, S.B.; Arnold, I.; Gerke, C.; Balandat, J.E.; Wündisch, T.; Müller, A. B-cell receptor signaling and CD40 ligand-independent T cell help cooperate in Helicobacter-induced MALT lymphomagenesis. Leukemia 2010, 24, 1186–1196. [Google Scholar] [CrossRef] [Green Version]
- Steidl, C.; Connors, J.M.; Gascoyne, R.D. Molecular pathogenesis of Hodgkin’s lymphoma: Increasing evidence of the importance of the microenvironment. J. Clin. Oncol. 2011, 29, 1812–1826. [Google Scholar] [CrossRef]
- Goodman, A.; Patel, S.P.; Kurzrock, R. PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat. Rev. Clin. Oncol. 2017, 14, 203–220. [Google Scholar] [CrossRef]
- Chiu, J.; Ernst, D.M.; Keating, A. Acquired Natural Killer Cell Dysfunction in the Tumor Microenvironment of Classic Hodgkin Lymphoma. Front. Immunol. 2018, 9, 267. [Google Scholar] [CrossRef]
- Huergo-Zapico, L.; Acebes-Huerta, A.; Gonzalez-Rodriguez, A.P.; Contesti, J.; Gonzalez-García, E.; Payer, A.R.; Villa-Alvarez, M.; Fernández-Guizán, A.; López-Soto, A.; Gonzalez, S. Expansion of NK cells and reduction of NKG2D expression in chronic lymphocytic leukemia. Correlation with progressive disease. PLoS ONE 2014, 9, e108326. [Google Scholar] [CrossRef]
- MacFarlane, A.W.t.; Jillab, M.; Smith, M.R.; Alpaugh, R.K.; Cole, M.E.; Litwin, S.; Millenson, M.M.; Al-Saleem, T.; Cohen, A.D.; Campbell, K.S. NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors. Oncoimmunology 2017, 6, e1330235. [Google Scholar] [CrossRef] [PubMed]
- Komohara, Y.; Niino, D.; Ohnishi, K.; Ohshima, K.; Takeya, M. Role of tumor-associated macrophages in hematological malignancies. Pathol. Int. 2015, 65, 170–176. [Google Scholar] [CrossRef]
- Qian, B.Z.; Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 2010, 141, 39–51. [Google Scholar] [CrossRef] [Green Version]
- Vari, F.; Arpon, D.; Keane, C.; Hertzberg, M.S.; Talaulikar, D.; Jain, S.; Cui, Q.; Han, E.; Tobin, J.; Bird, R.; et al. Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 2018, 131, 1809–1819. [Google Scholar] [CrossRef] [Green Version]
- Xiu, B.; Lin, Y.; Grote, D.M.; Ziesmer, S.C.; Gustafson, M.P.; Maas, M.L.; Zhang, Z.; Dietz, A.B.; Porrata, L.F.; Novak, A.J.; et al. IL-10 induces the development of immunosuppressive CD14(+)HLA-DR(low/-) monocytes in B-cell non-Hodgkin lymphoma. Blood Cancer J. 2015, 5, e328. [Google Scholar] [CrossRef] [Green Version]
- Lin, Y.; Gustafson, M.P.; Bulur, P.A.; Gastineau, D.A.; Witzig, T.E.; Dietz, A.B. Immunosuppressive CD14+HLA-DR(low)/- monocytes in B-cell non-Hodgkin lymphoma. Blood 2011, 117, 872–881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Steidl, C.; Lee, T.; Shah, S.P.; Farinha, P.; Han, G.; Nayar, T.; Delaney, A.; Jones, S.J.; Iqbal, J.; Weisenburger, D.D.; et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N. Engl. J. Med. 2010, 362, 875–885. [Google Scholar] [CrossRef] [Green Version]
- Carey, C.D.; Gusenleitner, D.; Lipschitz, M.; Roemer, M.G.M.; Stack, E.C.; Gjini, E.; Hu, X.; Redd, R.; Freeman, G.J.; Neuberg, D.; et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 2017, 130, 2420–2430. [Google Scholar] [CrossRef] [PubMed]
- Guo, B.; Cen, H.; Tan, X.; Ke, Q. Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med. 2016, 14, 159. [Google Scholar] [CrossRef] [Green Version]
- Dumitru, C.A.; Moses, K.; Trellakis, S.; Lang, S.; Brandau, S. Neutrophils and granulocytic myeloid-derived suppressor cells: Immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol. Immunother. 2012, 61, 1155–1167. [Google Scholar] [CrossRef]
- Dardalhon, V.; Anderson, A.C.; Karman, J.; Apetoh, L.; Chandwaskar, R.; Lee, D.H.; Cornejo, M.; Nishi, N.; Yamauchi, A.; Quintana, F.J.; et al. Tim-3/galectin-9 pathway: Regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J. Immunol. 2010, 185, 1383–1392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Limagne, E.; Richard, C.; Thibaudin, M.; Fumet, J.D.; Truntzer, C.; Lagrange, A.; Favier, L.; Coudert, B.; Ghiringhelli, F. Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients. Oncoimmunology 2019, 8, e1564505. [Google Scholar] [CrossRef]
- Azzaoui, I.; Uhel, F.; Rossille, D.; Pangault, C.; Dulong, J.; Le Priol, J.; Lamy, T.; Houot, R.; Le Gouill, S.; Cartron, G.; et al. T-cell defect in diffuse large B-cell lymphomas involves expansion of myeloid-derived suppressor cells. Blood 2016, 128, 1081–1092. [Google Scholar] [CrossRef] [PubMed]
- Marini, O.; Spina, C.; Mimiola, E.; Cassaro, A.; Malerba, G.; Todeschini, G.; Perbellini, O.; Scupoli, M.; Carli, G.; Facchinelli, D.; et al. Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients. Oncotarget 2016, 7, 27676–27688. [Google Scholar] [CrossRef] [Green Version]
- Chen, B.J.; Dashnamoorthy, R.; Galera, P.; Makarenko, V.; Chang, H.; Ghosh, S.; Evens, A.M. The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget 2019, 10, 2030–2040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Von Wasielewski, R.; Seth, S.; Franklin, J.; Fischer, R.; Hübner, K.; Hansmann, M.L.; Diehl, V.; Georgii, A. Tissue eosinophilia correlates strongly with poor prognosis in nodular sclerosing Hodgkin’s disease, allowing for known prognostic factors. Blood 2000, 95, 1207–1213. [Google Scholar] [CrossRef]
- Andersen, M.D.; Kamper, P.; Nielsen, P.S.; Bendix, K.; Riber-Hansen, R.; Steiniche, T.; Hamilton-Dutoit, S.; Clausen, M.; d’Amore, F. Tumour-associated mast cells in classical Hodgkin’s lymphoma: Correlation with histological subtype, other tumour-infiltrating inflammatory cell subsets and outcome. Eur. J. Haematol. 2016, 96, 252–259. [Google Scholar] [CrossRef]
- Küppers, R. The biology of Hodgkin’s lymphoma. Nat. Rev. Cancer 2009, 9, 15–27. [Google Scholar] [CrossRef]
- Aldinucci, D.; Lorenzon, D.; Olivo, K.; Rapanà, B.; Gattei, V. Interactions between tissue fibroblasts in lymph nodes and Hodgkin/Reed-Sternberg cells. Leuk. Lymphoma 2004, 45, 1731–1739. [Google Scholar] [CrossRef] [PubMed]
- Dörsam, B.; Bösl, T.; Reiners, K.S.; Barnert, S.; Schubert, R.; Shatnyeva, O.; Zigrino, P.; Engert, A.; Hansen, H.P.; von Strandmann, E.P. Hodgkin Lymphoma-Derived Extracellular Vesicles Change the Secretome of Fibroblasts Toward a CAF Phenotype. Front. Immunol. 2018, 9, 1358. [Google Scholar] [CrossRef]
- Pandey, S.; Mourcin, F.; Marchand, T.; Nayar, S.; Guirriec, M.; Pangault, C.; Monvoisin, C.; Amé-Thomas, P.; Guilloton, F.; Dulong, J.; et al. IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma. Blood 2017, 129, 2507–2518. [Google Scholar] [CrossRef] [Green Version]
- Epron, G.; Ame-Thomas, P.; Le Priol, J.; Pangault, C.; Dulong, J.; Lamy, T.; Fest, T.; Tarte, K. Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: Role of IL-15 and CD40L signaling. Leukemia 2012, 26, 139–148. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hussell, T.; Isaacson, P.G.; Crabtree, J.E.; Spencer, J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 1993, 342, 571–574. [Google Scholar] [CrossRef]
- Hussell, T.; Isaacson, P.G.; Crabtree, J.E.; Spencer, J. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J. Pathol. 1996, 178, 122–127. [Google Scholar] [CrossRef]
- Medina, D.J.; Goodell, L.; Glod, J.; Gélinas, C.; Rabson, A.B.; Strair, R.K. Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways. Haematologica 2012, 97, 1255–1263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kline, J.; Godfrey, J.; Ansell, S.M. The immune landscape and response to immune checkpoint blockade therapy in lymphoma. Blood 2020, 135, 523–533. [Google Scholar] [CrossRef] [PubMed]
- Thorsson, V.; Gibbs, D.L.; Brown, S.D.; Wolf, D.; Bortone, D.S.; Ou Yang, T.H.; Porta-Pardo, E.; Gao, G.F.; Plaisier, C.L.; Eddy, J.A.; et al. The Immune Landscape of Cancer. Immunity 2018, 48, 812–830. [Google Scholar] [CrossRef] [Green Version]
- Gajewski, T.F.; Corrales, L.; Williams, J.; Horton, B.; Sivan, A.; Spranger, S. Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment. Adv. Exp. Med. Biol. 2017, 1036, 19–31. [Google Scholar] [CrossRef] [PubMed]
- Godfrey, J.; Tumuluru, S.; Bao, R.; Leukam, M.; Venkataraman, G.; Phillip, J.; Fitzpatrick, C.; McElherne, J.; MacNabb, B.W.; Orlowski, R.; et al. PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype. Blood 2019, 133, 2279–2290. [Google Scholar] [CrossRef]
- Ayers, M.; Lunceford, J.; Nebozhyn, M.; Murphy, E.; Loboda, A.; Kaufman, D.R.; Albright, A.; Cheng, J.D.; Kang, S.P.; Shankaran, V.; et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 2017, 127, 2930–2940. [Google Scholar] [CrossRef] [PubMed]
- Georgiou, K.; Chen, L.; Berglund, M.; Ren, W.; de Miranda, N.F.; Lisboa, S.; Fangazio, M.; Zhu, S.; Hou, Y.; Wu, K.; et al. Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. Blood 2016, 127, 3026–3034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chong, L.C.; Twa, D.D.; Mottok, A.; Ben-Neriah, S.; Woolcock, B.W.; Zhao, Y.; Savage, K.J.; Marra, M.A.; Scott, D.W.; Gascoyne, R.D.; et al. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood 2016, 128, 1206–1213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Twa, D.D.; Chan, F.C.; Ben-Neriah, S.; Woolcock, B.W.; Mottok, A.; Tan, K.L.; Slack, G.W.; Gunawardana, J.; Lim, R.S.; McPherson, A.W.; et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 2014, 123, 2062–2065. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spina, V.; Bruscaggin, A.; Cuccaro, A.; Martini, M.; Di Trani, M.; Forestieri, G.; Manzoni, M.; Condoluci, A.; Arribas, A.; Terzi-Di-Bergamo, L.; et al. Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 2018, 131, 2413–2425. [Google Scholar] [CrossRef] [Green Version]
- Chapuy, B.; Stewart, C.; Dunford, A.J.; Kim, J.; Kamburov, A.; Redd, R.A.; Lawrence, M.S.; Roemer, M.G.M.; Li, A.J.; Ziepert, M.; et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat. Med. 2018, 24, 679–690. [Google Scholar] [CrossRef] [PubMed]
- Rooney, M.S.; Shukla, S.A.; Wu, C.J.; Getz, G.; Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 2015, 160, 48–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sharma, P.; Allison, J.P. The future of immune checkpoint therapy. Science 2015, 348, 56–61. [Google Scholar] [CrossRef] [PubMed]
- Kapp, U.; Wolf, J.; Hummel, M.; Pawlita, M.; von Kalle, C.; Dallenbach, F.; Schwonzen, M.; Krueger, G.R.; Müller-Lantzsch, N.; Fonatsch, C.; et al. Hodgkin’s lymphoma-derived tissue serially transplanted into severe combined immunodeficient mice. Blood 1993, 82, 1247–1256. [Google Scholar] [CrossRef]
- Morris, C.S.; Stuart, A.E. Reed-Sternberg/lymphocyte rosette: Lymphocyte subpopulations as defined by monoclonal antibodies. J. Clin. Pathol. 1984, 37, 767–771. [Google Scholar] [CrossRef] [Green Version]
- Biggar, R.J.; Jaffe, E.S.; Goedert, J.J.; Chaturvedi, A.; Pfeiffer, R.; Engels, E.A. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006, 108, 3786–3791. [Google Scholar] [CrossRef]
- Liu, Y.; Abdul Razak, F.R.; Terpstra, M.; Chan, F.C.; Saber, A.; Nijland, M.; van Imhoff, G.; Visser, L.; Gascoyne, R.; Steidl, C.; et al. The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia 2014, 28, 2248–2251. [Google Scholar] [CrossRef]
- Liu, W.R.; Shipp, M.A. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma. Blood 2017, 130, 2265–2270. [Google Scholar] [CrossRef] [Green Version]
- Steidl, C.; Telenius, A.; Shah, S.P.; Farinha, P.; Barclay, L.; Boyle, M.; Connors, J.M.; Horsman, D.E.; Gascoyne, R.D. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 2010, 116, 418–427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cader, F.Z.; Schackmann, R.C.J.; Hu, X.; Wienand, K.; Redd, R.; Chapuy, B.; Ouyang, J.; Paul, N.; Gjini, E.; Lipschitz, M.; et al. Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment. Blood 2018, 132, 825–836. [Google Scholar] [CrossRef]
- Greaves, P.; Clear, A.; Owen, A.; Iqbal, S.; Lee, A.; Matthews, J.; Wilson, A.; Calaminici, M.; Gribben, J.G. Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood 2013, 122, 2856–2863. [Google Scholar] [CrossRef] [PubMed]
- Marshall, N.A.; Christie, L.E.; Munro, L.R.; Culligan, D.J.; Johnston, P.W.; Barker, R.N.; Vickers, M.A. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004, 103, 1755–1762. [Google Scholar] [CrossRef] [Green Version]
- Ansell, S.M.; Lesokhin, A.M.; Borrello, I.; Halwani, A.; Scott, E.C.; Gutierrez, M.; Schuster, S.J.; Millenson, M.M.; Cattry, D.; Freeman, G.J.; et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med. 2015, 372, 311–319. [Google Scholar] [CrossRef] [Green Version]
- Armand, P.; Engert, A.; Younes, A.; Fanale, M.; Santoro, A.; Zinzani, P.L.; Timmerman, J.M.; Collins, G.P.; Ramchandren, R.; Cohen, J.B.; et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J. Clin. Oncol. 2018, 36, 1428–1439. [Google Scholar] [CrossRef]
- Horton, B.L.; Williams, J.B.; Cabanov, A.; Spranger, S.; Gajewski, T.F. Intratumoral CD8(+) T-cell Apoptosis Is a Major Component of T-cell Dysfunction and Impedes Antitumor Immunity. Cancer Immunol. Res. 2018, 6, 14–24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wei, S.C.; Levine, J.H.; Cogdill, A.P.; Zhao, Y.; Anang, N.A.S.; Andrews, M.C.; Sharma, P.; Wang, J.; Wargo, J.A.; Pe’er, D.; et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell 2017, 170, 1120–1133. [Google Scholar] [CrossRef] [Green Version]
- Armand, P.; Rodig, S.; Melnichenko, V.; Thieblemont, C.; Bouabdallah, K.; Tumyan, G.; Özcan, M.; Portino, S.; Fogliatto, L.; Caballero, M.D.; et al. Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma. J. Clin. Oncol. 2019, 37, 3291–3299. [Google Scholar] [CrossRef]
- Zinzani, P.L.; Ribrag, V.; Moskowitz, C.H.; Michot, J.M.; Kuruvilla, J.; Balakumaran, A.; Zhang, Y.; Chlosta, S.; Shipp, M.A.; Armand, P. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood 2017, 130, 267–270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nayak, L.; Iwamoto, F.M.; LaCasce, A.; Mukundan, S.; Roemer, M.G.M.; Chapuy, B.; Armand, P.; Rodig, S.J.; Shipp, M.A. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 2017, 129, 3071–3073. [Google Scholar] [CrossRef] [Green Version]
- Eberle, F.C.; Salaverria, I.; Steidl, C.; Summers, T.A., Jr.; Pittaluga, S.; Neriah, S.B.; Rodriguez-Canales, J.; Xi, L.; Ylaya, K.; Liewehr, D.; et al. Gray zone lymphoma: Chromosomal aberrations with immunophenotypic and clinical correlations. Mod. Pathol. 2011, 24, 1586–1597. [Google Scholar] [CrossRef]
- Shi, M.; Roemer, M.G.; Chapuy, B.; Liao, X.; Sun, H.; Pinkus, G.S.; Shipp, M.A.; Freeman, G.J.; Rodig, S.J. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am. J. Surg. Pathol. 2014, 38, 1715–1723. [Google Scholar] [CrossRef]
- Chapuy, B.; Roemer, M.G.; Stewart, C.; Tan, Y.; Abo, R.P.; Zhang, L.; Dunford, A.J.; Meredith, D.M.; Thorner, A.R.; Jordanova, E.S.; et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 2016, 127, 869–881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ennishi, D.; Jiang, A.; Boyle, M.; Collinge, B.; Grande, B.M.; Ben-Neriah, S.; Rushton, C.; Tang, J.; Thomas, N.; Slack, G.W.; et al. Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2019, 37, 190–201. [Google Scholar] [CrossRef] [PubMed]
- Ennishi, D.; Takata, K.; Béguelin, W.; Duns, G.; Mottok, A.; Farinha, P.; Bashashati, A.; Saberi, S.; Boyle, M.; Meissner, B.; et al. Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition. Cancer Discov. 2019, 9, 546–563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pangault, C.; Amé-Thomas, P.; Ruminy, P.; Rossille, D.; Caron, G.; Baia, M.; De Vos, J.; Roussel, M.; Monvoisin, C.; Lamy, T.; et al. Follicular lymphoma cell niche: Identification of a preeminent IL-4-dependent T(FH)-B cell axis. Leukemia 2010, 24, 2080–2089. [Google Scholar] [CrossRef]
- Calvo, K.R.; Dabir, B.; Kovach, A.; Devor, C.; Bandle, R.; Bond, A.; Shih, J.H.; Jaffe, E.S. IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma. Blood 2008, 112, 3818–3826. [Google Scholar] [CrossRef]
- Schmitz, R.; Young, R.M.; Ceribelli, M.; Jhavar, S.; Xiao, W.; Zhang, M.; Wright, G.; Shaffer, A.L.; Hodson, D.J.; Buras, E.; et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012, 490, 116–120. [Google Scholar] [CrossRef] [PubMed]
- Burr, M.L.; Sparbier, C.E.; Chan, K.L.; Chan, Y.C.; Kersbergen, A.; Lam, E.Y.N.; Azidis-Yates, E.; Vassiliadis, D.; Bell, C.C.; Gilan, O.; et al. An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer Cell 2019, 36, 385–401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ansell, S.M.; Hurvitz, S.A.; Koenig, P.A.; LaPlant, B.R.; Kabat, B.F.; Fernando, D.; Habermann, T.M.; Inwards, D.J.; Verma, M.; Yamada, R.; et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin. Cancer Res. 2009, 15, 6446–6453. [Google Scholar] [CrossRef] [Green Version]
- Ansell, S.M.; Minnema, M.C.; Johnson, P.; Timmerman, J.M.; Armand, P.; Shipp, M.A.; Rodig, S.J.; Ligon, A.H.; Roemer, M.G.M.; Reddy, N.; et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J. Clin. Oncol. 2019, 37, 481–489. [Google Scholar] [CrossRef]
- Küppers, R.; Stevenson, F.K. Critical influences on the pathogenesis of follicular lymphoma. Blood 2018, 131, 2297–2306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Coelho, V.; Krysov, S.; Ghaemmaghami, A.M.; Emara, M.; Potter, K.N.; Johnson, P.; Packham, G.; Martinez-Pomares, L.; Stevenson, F.K. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc. Natl. Acad. Sci. USA 2010, 107, 18587–18592. [Google Scholar] [CrossRef] [Green Version]
- Zhu, D.; McCarthy, H.; Ottensmeier, C.H.; Johnson, P.; Hamblin, T.J.; Stevenson, F.K. Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood 2002, 99, 2562–2568. [Google Scholar] [CrossRef]
- Carreras, J.; Lopez-Guillermo, A.; Roncador, G.; Villamor, N.; Colomo, L.; Martinez, A.; Hamoudi, R.; Howat, W.J.; Montserrat, E.; Campo, E. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J. Clin. Oncol. 2009, 27, 1470–1476. [Google Scholar] [CrossRef] [PubMed]
- Yang, Z.Z.; Grote, D.M.; Ziesmer, S.C.; Xiu, B.; Novak, A.J.; Ansell, S.M. PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival. Blood Cancer J. 2015, 5, e281. [Google Scholar] [CrossRef] [Green Version]
- Smeltzer, J.P.; Jones, J.M.; Ziesmer, S.C.; Grote, D.M.; Xiu, B.; Ristow, K.M.; Yang, Z.Z.; Nowakowski, G.S.; Feldman, A.L.; Cerhan, J.R.; et al. Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma. Clin. Cancer Res. 2014, 20, 2862–2872. [Google Scholar] [CrossRef] [Green Version]
- Lesokhin, A.M.; Ansell, S.M.; Armand, P.; Scott, E.C.; Halwani, A.; Gutierrez, M.; Millenson, M.M.; Cohen, A.D.; Schuster, S.J.; Lebovic, D.; et al. Nivolumab in Patients with Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J. Clin. Oncol. 2016, 34, 2698–2704. [Google Scholar] [CrossRef] [Green Version]
- Nijland, M.; Veenstra, R.N.; Visser, L.; Xu, C.; Kushekhar, K.; van Imhoff, G.W.; Kluin, P.M.; van den Berg, A.; Diepstra, A. HLA dependent immune escape mechanisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy? Oncoimmunology 2017, 6, e1295202. [Google Scholar] [CrossRef] [Green Version]
- Chan, T.A.; Yarchoan, M.; Jaffee, E.; Swanton, C.; Quezada, S.A.; Stenzinger, A.; Peters, S. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann. Oncol. 2019, 30, 44–56. [Google Scholar] [CrossRef]
- Courtney, A.H.; Lo, W.L.; Weiss, A. TCR Signaling: Mechanisms of Initiation and Propagation. Trends Biochem. Sci. 2018, 43, 108–123. [Google Scholar] [CrossRef]
- Batlevi, C.L.; Matsuki, E.; Brentjens, R.J.; Younes, A. Novel immunotherapies in lymphoid malignancies. Nat. Rev. Clin. Oncol. 2016, 13, 25–40. [Google Scholar] [CrossRef] [Green Version]
- Greaves, P.; Gribben, J.G. The role of B7 family molecules in hematologic malignancy. Blood 2013, 121, 734–744. [Google Scholar] [CrossRef] [PubMed]
- Chen, L.; Flies, D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013, 13, 227–242. [Google Scholar] [CrossRef] [PubMed]
- Van Bruggen, J.A.C.; Martens, A.W.J.; Tonino, S.H.; Kater, A.P. Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma. Cancers 2020, 12, 3837. [Google Scholar] [CrossRef]
- Brudno, J.N.; Kochenderfer, J.N. Chimeric antigen receptor T-cell therapies for lymphoma. Nat. Rev. Clin. Oncol. 2018, 15, 31–46. [Google Scholar] [CrossRef] [PubMed]
- Mueller, S.N.; Mackay, L.K. Tissue-resident memory T cells: Local specialists in immune defence. Nat. Rev. Immunol. 2016, 16, 79–89. [Google Scholar] [CrossRef]
- Jameson, S.C.; Masopust, D. Understanding Subset Diversity in T Cell Memory. Immunity 2018, 48, 214–226. [Google Scholar] [CrossRef] [Green Version]
- Roemer, M.G.; Advani, R.H.; Redd, R.A.; Pinkus, G.S.; Natkunam, Y.; Ligon, A.H.; Connelly, C.F.; Pak, C.J.; Carey, C.D.; Daadi, S.E.; et al. Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status. Cancer Immunol. Res. 2016, 4, 910–916. [Google Scholar] [CrossRef] [Green Version]
- Rimsza, L.M.; Roberts, R.A.; Miller, T.P.; Unger, J.M.; LeBlanc, M.; Braziel, R.M.; Weisenberger, D.D.; Chan, W.C.; Muller-Hermelink, H.K.; Jaffe, E.S.; et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: A follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 2004, 103, 4251–4258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roberts, R.A.; Wright, G.; Rosenwald, A.R.; Jaramillo, M.A.; Grogan, T.M.; Miller, T.P.; Frutiger, Y.; Chan, W.C.; Gascoyne, R.D.; Ott, G.; et al. Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival. Blood 2006, 108, 311–318. [Google Scholar] [CrossRef] [Green Version]
- Challa-Malladi, M.; Lieu, Y.K.; Califano, O.; Holmes, A.B.; Bhagat, G.; Murty, V.V.; Dominguez-Sola, D.; Pasqualucci, L.; Dalla-Favera, R. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 2011, 20, 728–740. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Reichel, J.; Chadburn, A.; Rubinstein, P.G.; Giulino-Roth, L.; Tam, W.; Liu, Y.; Gaiolla, R.; Eng, K.; Brody, J.; Inghirami, G.; et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 2015, 125, 1061–1072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cycon, K.A.; Rimsza, L.M.; Murphy, S.P. Alterations in CIITA constitute a common mechanism accounting for downregulation of MHC class II expression in diffuse large B-cell lymphoma (DLBCL). Exp. Hematol. 2009, 37, 184–194. [Google Scholar] [CrossRef] [PubMed]
- Steidl, C.; Shah, S.P.; Woolcock, B.W.; Rui, L.; Kawahara, M.; Farinha, P.; Johnson, N.A.; Zhao, Y.; Telenius, A.; Neriah, S.B.; et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011, 471, 377–381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Riemersma, S.A.; Jordanova, E.S.; Schop, R.F.; Philippo, K.; Looijenga, L.H.; Schuuring, E.; Kluin, P.M. Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood 2000, 96, 3569–3577. [Google Scholar] [CrossRef] [PubMed]
- Ansell, S.M. Immunotherapy in Hodgkin Lymphoma: The Road Ahead. Trends Immunol. 2019, 40, 380–386. [Google Scholar] [CrossRef]
- Green, M.R.; Monti, S.; Rodig, S.J.; Juszczynski, P.; Currie, T.; O’Donnell, E.; Chapuy, B.; Takeyama, K.; Neuberg, D.; Golub, T.R.; et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010, 116, 3268–3277. [Google Scholar] [CrossRef] [Green Version]
- Kiyasu, J.; Miyoshi, H.; Hirata, A.; Arakawa, F.; Ichikawa, A.; Niino, D.; Sugita, Y.; Yufu, Y.; Choi, I.; Abe, Y.; et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 2015, 126, 2193–2201. [Google Scholar] [CrossRef] [PubMed]
- Green, M.R.; Rodig, S.; Juszczynski, P.; Ouyang, J.; Sinha, P.; O’Donnell, E.; Neuberg, D.; Shipp, M.A. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: Implications for targeted therapy. Clin. Cancer Res. 2012, 18, 1611–1618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carreras, J.; Kikuti, Y.Y.; Miyaoka, M.; Hiraiwa, S.; Tomita, S.; Ikoma, H.; Kondo, Y.; Ito, A.; Nakamura, N.; Hamoudi, R. A Combination of Multilayer Perceptron, Radial Basis Function Artificial Neural Networks and Machine Learning Image Segmentation for the Dimension Reduction and the Prognosis Assessment of Diffuse Large B-Cell Lymphoma. AI 2021, 2, 106–134. [Google Scholar] [CrossRef]
- Wing, K.; Onishi, Y.; Prieto-Martin, P.; Yamaguchi, T.; Miyara, M.; Fehervari, Z.; Nomura, T.; Sakaguchi, S. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008, 322, 271–275. [Google Scholar] [CrossRef] [PubMed]
- Monney, L.; Sabatos, C.A.; Gaglia, J.L.; Ryu, A.; Waldner, H.; Chernova, T.; Manning, S.; Greenfield, E.A.; Coyle, A.J.; Sobel, R.A.; et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002, 415, 536–541. [Google Scholar] [CrossRef]
- Joller, N.; Kuchroo, V.K. Tim-3, Lag-3, and TIGIT. Curr. Top. Microbiol. Immunol. 2017, 410, 127–156. [Google Scholar] [CrossRef] [Green Version]
- Rangachari, M.; Zhu, C.; Sakuishi, K.; Xiao, S.; Karman, J.; Chen, A.; Angin, M.; Wakeham, A.; Greenfield, E.A.; Sobel, R.A.; et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion. Nat. Med. 2012, 18, 1394–1400. [Google Scholar] [CrossRef] [Green Version]
- Zhang, T.; Ren, T.; Song, Z.; Zhao, J.; Jiao, L.; Zhang, Z.; He, J.; Liu, X.; Qiu, L.; Li, L.; et al. Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3(+) CD8(+) T Cells and Survival in Diffuse Large B Cell Lymphoma. J. Immunol. Res. 2020, 2020, 6968595. [Google Scholar] [CrossRef]
- Huang, C.T.; Workman, C.J.; Flies, D.; Pan, X.; Marson, A.L.; Zhou, G.; Hipkiss, E.L.; Ravi, S.; Kowalski, J.; Levitsky, H.I.; et al. Role of LAG-3 in regulatory T cells. Immunity 2004, 21, 503–513. [Google Scholar] [CrossRef] [Green Version]
- Gagliani, N.; Magnani, C.F.; Huber, S.; Gianolini, M.E.; Pala, M.; Licona-Limon, P.; Guo, B.; Herbert, D.R.; Bulfone, A.; Trentini, F.; et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 2013, 19, 739–746. [Google Scholar] [CrossRef]
- Huard, B.; Prigent, P.; Tournier, M.; Bruniquel, D.; Triebel, F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur. J. Immunol. 1995, 25, 2718–2721. [Google Scholar] [CrossRef]
- Kouo, T.; Huang, L.; Pucsek, A.B.; Cao, M.; Solt, S.; Armstrong, T.; Jaffee, E. Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer Immunol. Res. 2015, 3, 412–423. [Google Scholar] [CrossRef] [Green Version]
- Xu, F.; Liu, J.; Liu, D.; Liu, B.; Wang, M.; Hu, Z.; Du, X.; Tang, L.; He, F. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014, 74, 3418–3428. [Google Scholar] [CrossRef] [Green Version]
- Workman, C.J.; Cauley, L.S.; Kim, I.J.; Blackman, M.A.; Woodland, D.L.; Vignali, D.A. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 2004, 172, 5450–5455. [Google Scholar] [CrossRef]
- Burton, B.R.; Britton, G.J.; Fang, H.; Verhagen, J.; Smithers, B.; Sabatos-Peyton, C.A.; Carney, L.J.; Gough, J.; Strobel, S.; Wraith, D.C. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat. Commun 2014, 5, 4741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Josefsson, S.E.; Huse, K.; Kolstad, A.; Beiske, K.; Pende, D.; Steen, C.B.; Inderberg, E.M.; Lingjærde, O.C.; Østenstad, B.; Smeland, E.B.; et al. T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling. Clin. Cancer Res. 2018, 24, 870–881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Levin, S.D.; Taft, D.W.; Brandt, C.S.; Bucher, C.; Howard, E.D.; Chadwick, E.M.; Johnston, J.; Hammond, A.; Bontadelli, K.; Ardourel, D.; et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur. J. Immunol. 2011, 41, 902–915. [Google Scholar] [CrossRef]
- Wang, S.C.; Li, Y.H.; Piao, H.L.; Hong, X.W.; Zhang, D.; Xu, Y.Y.; Tao, Y.; Wang, Y.; Yuan, M.M.; Li, D.J.; et al. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy. Cell Death Dis. 2015, 6, e1738. [Google Scholar] [CrossRef] [Green Version]
- Sarhan, D.; Cichocki, F.; Zhang, B.; Yingst, A.; Spellman, S.R.; Cooley, S.; Verneris, M.R.; Blazar, B.R.; Miller, J.S. Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res. 2016, 76, 5696–5706. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Inozume, T.; Yaguchi, T.; Furuta, J.; Harada, K.; Kawakami, Y.; Shimada, S. Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase. J. Investig. Dermatol. 2016, 136, 255–263. [Google Scholar] [CrossRef] [Green Version]
- Joller, N.; Lozano, E.; Burkett, P.R.; Patel, B.; Xiao, S.; Zhu, C.; Xia, J.; Tan, T.G.; Sefik, E.; Yajnik, V.; et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 2014, 40, 569–581. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, Z.Z.; Grote, D.M.; Ziesmer, S.C.; Xiu, B.; Yates, N.R.; Secreto, F.J.; Hodge, L.S.; Witzig, T.E.; Novak, A.J.; Ansell, S.M. Soluble and membrane-bound TGF-β-mediated regulation of intratumoral T cell differentiation and function in B-cell non-Hodgkin lymphoma. PLoS ONE 2013, 8, e59456. [Google Scholar] [CrossRef] [Green Version]
- Gabrilovich, D.I.; Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009, 9, 162–174. [Google Scholar] [CrossRef]
- Jaiswal, S.; Chao, M.P.; Majeti, R.; Weissman, I.L. Macrophages as mediators of tumor immunosurveillance. Trends Immunol. 2010, 31, 212–219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsai, R.K.; Discher, D.E. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 2008, 180, 989–1003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chao, M.P.; Alizadeh, A.A.; Tang, C.; Myklebust, J.H.; Varghese, B.; Gill, S.; Jan, M.; Cha, A.C.; Chan, C.K.; Tan, B.T.; et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 2010, 142, 699–713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Advani, R.; Flinn, I.; Popplewell, L.; Forero, A.; Bartlett, N.L.; Ghosh, N.; Kline, J.; Roschewski, M.; LaCasce, A.; Collins, G.P.; et al. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma. N. Engl. J. Med. 2018, 379, 1711–1721. [Google Scholar] [CrossRef]
- Caron, G.; Le Gallou, S.; Lamy, T.; Tarte, K.; Fest, T. CXCR4 expression functionally discriminates centroblasts versus centrocytes within human germinal center B cells. J. Immunol. 2009, 182, 7595–7602. [Google Scholar] [CrossRef] [Green Version]
- Yang, Z.Z.; Grote, D.M.; Ziesmer, S.C.; Niki, T.; Hirashima, M.; Novak, A.J.; Witzig, T.E.; Ansell, S.M. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Investig. 2012, 122, 1271–1282. [Google Scholar] [CrossRef] [PubMed]
- Rossille, D.; Gressier, M.; Damotte, D.; Maucort-Boulch, D.; Pangault, C.; Semana, G.; Le Gouill, S.; Haioun, C.; Tarte, K.; Lamy, T.; et al. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: Results from a French multicenter clinical trial. Leukemia 2014, 28, 2367–2375. [Google Scholar] [CrossRef]
- Fei, Y.; Yu, J.; Li, Y.; Li, L.; Zhou, S.; Zhang, T.; Li, L.; Qiu, L.; Meng, B.; Pan, Y.; et al. Plasma soluble PD-L1 and STAT3 predict the prognosis in diffuse large B cell lymphoma patients. J. Cancer 2020, 11, 7001–7008. [Google Scholar] [CrossRef]
- Samstein, R.M.; Lee, C.H.; Shoushtari, A.N.; Hellmann, M.D.; Shen, R.; Janjigian, Y.Y.; Barron, D.A.; Zehir, A.; Jordan, E.J.; Omuro, A.; et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 2019, 51, 202–206. [Google Scholar] [CrossRef]
- Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Børresen-Dale, A.L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421. [Google Scholar] [CrossRef] [Green Version]
- Chapuy, B.; Stewart, C.; Dunford, A.J.; Kim, J.; Wienand, K.; Kamburov, A.; Griffin, G.K.; Chen, P.H.; Lako, A.; Redd, R.A.; et al. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood 2019, 134, 2369–2382. [Google Scholar] [CrossRef] [PubMed]
- Wienand, K.; Chapuy, B.; Stewart, C.; Dunford, A.J.; Wu, D.; Kim, J.; Kamburov, A.; Wood, T.R.; Cader, F.Z.; Ducar, M.D.; et al. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion. Blood Adv. 2019, 3, 4065–4080. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Keane, C.; Gould, C.; Jones, K.; Hamm, D.; Talaulikar, D.; Ellis, J.; Vari, F.; Birch, S.; Han, E.; Wood, P.; et al. The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma. Clin. Cancer Res. 2017, 23, 1820–1828. [Google Scholar] [CrossRef] [Green Version]
- Zocchi, M.R.; Catellani, S.; Canevali, P.; Tavella, S.; Garuti, A.; Villaggio, B.; Zunino, A.; Gobbi, M.; Fraternali-Orcioni, G.; Kunkl, A.; et al. High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 2012, 119, 1479–1489. [Google Scholar] [CrossRef]
- Kaiser, B.K.; Yim, D.; Chow, I.T.; Gonzalez, S.; Dai, Z.; Mann, H.H.; Strong, R.K.; Groh, V.; Spies, T. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 2007, 447, 482–486. [Google Scholar] [CrossRef] [PubMed]
- Wilson, E.B.; El-Jawhari, J.J.; Neilson, A.L.; Hall, G.D.; Melcher, A.A.; Meade, J.L.; Cook, G.P. Human tumour immune evasion via TGF-β blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity. PLoS ONE 2011, 6, e22842. [Google Scholar] [CrossRef] [Green Version]
- Belting, L.; Hömberg, N.; Przewoznik, M.; Brenner, C.; Riedel, T.; Flatley, A.; Polić, B.; Busch, D.H.; Röcken, M.; Mocikat, R. Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma. Eur. J. Immunol. 2015, 45, 2593–2601. [Google Scholar] [CrossRef]
- Purdy, A.K.; Campbell, K.S. Natural killer cells and cancer: Regulation by the killer cell Ig-like receptors (KIR). Cancer Biol. Ther. 2009, 8, 2211–2220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schwaller, J.; Schneider, P.; Mhawech-Fauceglia, P.; McKee, T.; Myit, S.; Matthes, T.; Tschopp, J.; Donze, O.; Le Gal, F.A.; Huard, B. Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness. Blood 2007, 109, 331–338. [Google Scholar] [CrossRef] [Green Version]
- Schwaller, J.; Went, P.; Matthes, T.; Dirnhofer, S.; Donze, O.; Mhawech-Fauceglia, P.; Myit, S.; Huard, B. Paracrine promotion of tumor development by the TNF ligand APRIL in Hodgkin’s Disease. Leukemia 2007, 21, 1324–1327. [Google Scholar] [CrossRef]
- Rosenbaum, C.A.; Jung, S.H.; Pitcher, B.; Bartlett, N.L.; Smith, S.M.; Hsi, E.; Wagner-Johnston, N.; Thomas, S.P.; Leonard, J.P.; Cheson, B.D. Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance). Br. J. Haematol. 2019, 185, 53–64. [Google Scholar] [CrossRef] [PubMed]
- Robak, T.; Warzocha, K.; Govind Babu, K.; Kulyaba, Y.; Kuliczkowski, K.; Abdulkadyrov, K.; Loscertales, J.; Kryachok, I.; Kłoczko, J.; Rekhtman, G.; et al. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: Results from the COMPLEMENT 2 trial. Leuk. Lymphoma 2017, 58, 1084–1093. [Google Scholar] [CrossRef] [PubMed]
- Van Oers, M.H.; Kuliczkowski, K.; Smolej, L.; Petrini, M.; Offner, F.; Grosicki, S.; Levin, M.D.; Gupta, I.; Phillips, J.; Williams, V.; et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): An open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015, 16, 1370–1379. [Google Scholar] [CrossRef]
- Herrera, A.F. Noncellular Immune Therapies for Non-Hodgkin Lymphoma. Hematol. Oncol. Clin. N. Am. 2019, 33, 707–725. [Google Scholar] [CrossRef]
- Cassaday, R.D.; Press, O.W.; Pagel, J.M.; Rajendran, J.G.; Gooley, T.A.; Fisher, D.R.; Holmberg, L.A.; Miyaoka, R.S.; Sandmaier, B.M.; Green, D.J.; et al. Phase I Study of a CD45-Targeted Antibody-Radionuclide Conjugate for High-Risk Lymphoma. Clin. Cancer Res. 2019, 25, 6932–6938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jurczak, W.; Gruszka, A.M.; Sowa Staszczak, A.; Dlugosz-Danecka, M.; Szostek, M.; Zimowska-Curylo, D.; Giza, A.; Krawczyk, K.; Jakobczyk, M.; Hubalewska-Dydejczyk, A.; et al. Consolidation with (90)Y ibritumomab tiuxetan radioimmunotherapy in mantle cell lymphoma patients ineligible for high dose therapy: Results of the phase II multicentre Polish Lymphoma Research Group trial, after 8-year long follow-up. Leuk. Lymphoma 2019, 60, 2689–2696. [Google Scholar] [CrossRef]
- Metzger, M.L.; Mauz-Körholz, C. Epidemiology, outcome, targeted agents and immunotherapy in adolescent and young adult non-Hodgkin and Hodgkin lymphoma. Br. J. Haematol. 2019, 185, 1142–1157. [Google Scholar] [CrossRef] [PubMed]
- Chu, Y.; Gardenswartz, A.; Termuhlen, A.M.; Cairo, M.S. Advances in cellular and humoral immunotherapy—Implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma. Br. J. Haematol. 2019, 185, 1055–1070. [Google Scholar] [CrossRef] [PubMed]
- O’Mahony, D.; Morris, J.C.; Quinn, C.; Gao, W.; Wilson, W.H.; Gause, B.; Pittaluga, S.; Neelapu, S.; Brown, M.; Fleisher, T.A.; et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin. Cancer Res. 2007, 13, 958–964. [Google Scholar] [CrossRef] [Green Version]
- Berger, R.; Rotem-Yehudar, R.; Slama, G.; Landes, S.; Kneller, A.; Leiba, M.; Koren-Michowitz, M.; Shimoni, A.; Nagler, A. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 2008, 14, 3044–3051. [Google Scholar] [CrossRef] [Green Version]
- Armand, P.; Janssens, A.; Gritti, G.; Radford, J.; Timmerman, J.; Pinto, A.; Mercadal Vilchez, S.; Johnson, P.; Cunningham, D.; Leonard, J.P.; et al. Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma. Blood 2021, 137, 637–645. [Google Scholar] [CrossRef] [PubMed]
- Ding, W.; LaPlant, B.R.; Call, T.G.; Parikh, S.A.; Leis, J.F.; He, R.; Shanafelt, T.D.; Sinha, S.; Le-Rademacher, J.; Feldman, A.L.; et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 2017, 129, 3419–3427. [Google Scholar] [CrossRef]
- Westin, J.R.; Chu, F.; Zhang, M.; Fayad, L.E.; Kwak, L.W.; Fowler, N.; Romaguera, J.; Hagemeister, F.; Fanale, M.; Samaniego, F.; et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: A single group, open-label, phase 2 trial. Lancet Oncol. 2014, 15, 69–77. [Google Scholar] [CrossRef] [Green Version]
- Palomba, M.L.; Till, B.G.; Park, S.I.; Morschhauser, F.; Cartron, G.; Marks, R.; Penuel, E.; Chitra, S.; Kuhn, M.; Popplewell, L. A Phase Ib Study Evaluating the Safety and Clinical Activity of Atezolizumab Combined with Obinutuzumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma (NHL). Hematol. Oncol. 2017, 35, 137–138. [Google Scholar] [CrossRef]
- Nastoupil, L.J.; Westin, J.R.; Fowler, N.H.; Fanale, M.A.; Samaniego, F.; Oki, Y.; Obi, C.; Cao, J.; Cheng, X.; Ma, M.C.J.; et al. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study. J. Clin. Oncol. 2017, 35, 7519. [Google Scholar] [CrossRef]
- Tuscano, J.M.; Maverakis, E.; Groshen, S.; Tsao-Wei, D.; Luxardi, G.; Merleev, A.A.; Beaven, A.; DiPersio, J.F.; Popplewell, L.; Chen, R.; et al. A Phase I Study of the Combination of Rituximab and Ipilimumab in Patients with Relapsed/Refractory B-Cell Lymphoma. Clin. Cancer Res. 2019, 25, 7004–7013. [Google Scholar] [CrossRef] [Green Version]
- Younes, A.; John, B.M.; Diefenbach, C.S.; Ferrari, S.; Kahn, C.; Sharman, J.P.; Tani, M.; Ujjani, C.S.; Vitolo, U.; Yuen, S.; et al. Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab and Bendamustine in Patients with Previously Untreated Follicular Lymphoma: An Interim Analysis. Blood 2017, 130, 481. [Google Scholar] [CrossRef]
- Younes, A.; Burke, J.M.; Cheson, B.; Diefenbach, C.; Ferrari, S.; Hahn, U.; Hawkes, E.; Khan, C.; Lossos, I.S.; Musuraka, G.; et al. Safety and Efficacy of Atezolizumab in Combination with Rituximab Plus CHOP in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Primary Analysis of a Phase I/II Study. Blood 2018, 132, 2969. [Google Scholar] [CrossRef]
- Smith, S.D.; Till, B.G.; Shadman, M.S.; Lynch, R.C.; Cowan, A.J.; Wu, Q.V.; Voutsinas, J.; Rasmussen, H.A.; Blue, K.; Ujjani, C.S.; et al. Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: Potential for biomarker driven therapy. Br. J. Haematol. 2020, 189, 1119–1126. [Google Scholar] [CrossRef] [PubMed]
- Younes, A.; Santoro, A.; Shipp, M.; Zinzani, P.L.; Timmerman, J.M.; Ansell, S.; Armand, P.; Fanale, M.; Ratanatharathorn, V.; Kuruvilla, J.; et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016, 17, 1283–1294. [Google Scholar] [CrossRef] [Green Version]
- Herrera, A.F.; Goy, A.; Mehta, A.; Ramchandren, R.; Pagel, J.M.; Svoboda, J.; Guan, S.; Hill, J.S.; Kwei, K.; Liu, E.A.; et al. Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma. Am. J. Hematol. 2020, 95, 18–27. [Google Scholar] [CrossRef] [Green Version]
- Casulo, C.; Santoro, A.; Ando, K.; Le Gouill, S.; Ruan, J.; Radford, J.; Arcaini, L.; Pinto, A.; Bouabdallah, R.; Izutsu, K.; et al. Durvalumab (Anti PD-L1) As Monotherapy or in Combination Therapy for Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL): A Subgroup Analysis from the Phase 1/2 Fusion NHL-001 Global Multicenter Trial. Blood 2019, 134, 5320. [Google Scholar] [CrossRef]
- Zinzani, P.L.; Santoro, A.; Gritti, G.; Brice, P.; Barr, P.M.; Kuruvilla, J.; Cunningham, D.; Kline, J.; Johnson, N.A.; Mehta-Shah, N.; et al. Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study. J. Clin. Oncol. 2019, 37, 3081–3089. [Google Scholar] [CrossRef]
- Maruyama, D.; Hatake, K.; Kinoshita, T.; Fukuhara, N.; Choi, I.; Taniwaki, M.; Ando, K.; Terui, Y.; Higuchi, Y.; Onishi, Y.; et al. Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Cancer Sci. 2017, 108, 1007–1012. [Google Scholar] [CrossRef] [PubMed]
- Maruyama, D.; Terui, Y.; Yamamoto, K.; Fukuhara, N.; Choi, I.; Kuroda, J.; Ando, K.; Hattori, A.; Tobinai, K. Final results of a phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Jpn. J. Clin. Oncol. 2020, 50, 1265–1273. [Google Scholar] [CrossRef]
- Ramchandren, R.; Domingo-Domènech, E.; Rueda, A.; Trněný, M.; Feldman, T.A.; Lee, H.J.; Provencio, M.; Sillaber, C.; Cohen, J.B.; Savage, K.J.; et al. Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. J. Clin. Oncol. 2019, 37, 1997–2007. [Google Scholar] [CrossRef]
- Armand, P.; Shipp, M.A.; Ribrag, V.; Michot, J.M.; Zinzani, P.L.; Kuruvilla, J.; Snyder, E.S.; Ricart, A.D.; Balakumaran, A.; Rose, S.; et al. Programmed Death-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J. Clin. Oncol. 2016, 34, 3733–3739. [Google Scholar] [CrossRef]
- Chen, R.; Zinzani, P.L.; Fanale, M.A.; Armand, P.; Johnson, N.A.; Brice, P.; Radford, J.; Ribrag, V.; Molin, D.; Vassilakopoulos, T.P.; et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J. Clin. Oncol. 2017, 35, 2125–2132. [Google Scholar] [CrossRef] [PubMed]
- Chen, R.; Zinzani, P.L.; Lee, H.J.; Armand, P.; Johnson, N.A.; Brice, P.; Radford, J.; Ribrag, V.; Molin, D.; Vassilakopoulos, T.P.; et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood 2019, 134, 1144–1153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Song, Y.; Gao, Q.; Zhang, H.; Fan, L.; Zhou, J.; Zou, D.; Li, W.; Yang, H.; Liu, T.; Wang, Q.; et al. Treatment of relapsed or refractory classical Hodgkin lymphoma with the anti-PD-1, tislelizumab: Results of a phase 2, single-arm, multicenter study. Leukemia 2020, 34, 533–542. [Google Scholar] [CrossRef] [Green Version]
- Shi, Y.; Su, H.; Song, Y.; Jiang, W.; Sun, X.; Qian, W.; Zhang, W.; Gao, Y.; Jin, Z.; Zhou, J.; et al. Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): A multicentre, single-arm, phase 2 trial. Lancet Haematol. 2019, 6, e12–e19. [Google Scholar] [CrossRef]
- Song, Y.; Wu, J.; Chen, X.; Lin, T.; Cao, J.; Liu, Y.; Zhao, Y.; Jin, J.; Huang, H.; Hu, J.; et al. A Single-Arm, Multicenter, Phase II Study of Camrelizumab in Relapsed or Refractory Classical Hodgkin Lymphoma. Clin. Cancer Res. 2019, 25, 7363–7369. [Google Scholar] [CrossRef] [Green Version]
- Davis, K.L.; Fox, E.; Merchant, M.S.; Reid, J.M.; Kudgus, R.A.; Liu, X.; Minard, C.G.; Voss, S.; Berg, S.L.; Weigel, B.J.; et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): A multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020, 21, 541–550. [Google Scholar] [CrossRef]
- Geoerger, B.; Zwaan, C.M.; Marshall, L.V.; Michon, J.; Bourdeaut, F.; Casanova, M.; Corradini, N.; Rossato, G.; Farid-Kapadia, M.; Shemesh, C.S.; et al. Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): A multicentre phase 1-2 study. Lancet Oncol. 2020, 21, 134–144. [Google Scholar] [CrossRef]
- Geoerger, B.; Kang, H.J.; Yalon-Oren, M.; Marshall, L.V.; Vezina, C.; Pappo, A.; Laetsch, T.W.; Petrilli, A.S.; Ebinger, M.; Toporski, J.; et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): Interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020, 21, 121–133. [Google Scholar] [CrossRef]
- Herrera, A.F.; Moskowitz, A.J.; Bartlett, N.L.; Vose, J.M.; Ramchandren, R.; Feldman, T.A.; LaCasce, A.S.; Ansell, S.M.; Moskowitz, C.H.; Fenton, K.; et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2018, 131, 1183–1194. [Google Scholar] [CrossRef]
- Cheson, B.D.; Bartlett, N.L.; LaPlant, B.; Lee, H.J.; Advani, R.J.; Christian, B.; Diefenbach, C.S.; Feldman, T.A.; Ansell, S.M. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): A multicentre, single-arm, phase 2 trial. Lancet Haematol. 2020, 7, e808–e815. [Google Scholar] [CrossRef]
- Bröckelmann, P.J.; Goergen, H.; Keller, U.; Meissner, J.; Ordemann, R.; Halbsguth, T.V.; Sasse, S.; Sökler, M.; Kerkhoff, A.; Mathas, S.; et al. Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma: The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial. JAMA Oncol. 2020, 6, 872–880. [Google Scholar] [CrossRef]
- Diefenbach, C.S.; Hong, F.; Ambinder, R.F.; Cohen, J.B.; Robertson, M.J.; David, K.A.; Advani, R.H.; Fenske, T.S.; Barta, S.K.; Palmisiano, N.D.; et al. Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: Phase 1 results of an open-label, multicentre, phase 1/2 trial. Lancet Haematol. 2020, 7, e660–e670. [Google Scholar] [CrossRef]
- Wilcox, R.A.; Feldman, A.L.; Wada, D.A.; Yang, Z.Z.; Comfere, N.I.; Dong, H.; Kwon, E.D.; Novak, A.J.; Markovic, S.N.; Pittelkow, M.R.; et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 2009, 114, 2149–2158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Poggio, T.; Duyster, J.; Illert, A.L. Current Immunotherapeutic Approaches in T Cell Non-Hodgkin Lymphomas. Cancers 2018, 10, 339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Atsaves, V.; Tsesmetzis, N.; Chioureas, D.; Kis, L.; Leventaki, V.; Drakos, E.; Panaretakis, T.; Grander, D.; Medeiros, L.J.; Young, K.H.; et al. PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. Leukemia 2017, 31, 1633–1637. [Google Scholar] [CrossRef] [PubMed]
- Bi, X.W.; Wang, H.; Zhang, W.W.; Wang, J.H.; Liu, W.J.; Xia, Z.J.; Huang, H.Q.; Jiang, W.Q.; Zhang, Y.J.; Wang, L. PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J. Hematol. Oncol. 2016, 9, 109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, B.J.; Chapuy, B.; Ouyang, J.; Sun, H.H.; Roemer, M.G.; Xu, M.L.; Yu, H.; Fletcher, C.D.; Freeman, G.J.; Shipp, M.A.; et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 2013, 19, 3462–3473. [Google Scholar] [CrossRef] [Green Version]
- Kantekure, K.; Yang, Y.; Raghunath, P.; Schaffer, A.; Woetmann, A.; Zhang, Q.; Odum, N.; Wasik, M. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am. J. Dermatopathol. 2012, 34, 126–128. [Google Scholar] [CrossRef] [Green Version]
- Kwong, Y.L.; Chan, T.S.Y.; Tan, D.; Kim, S.J.; Poon, L.M.; Mow, B.; Khong, P.L.; Loong, F.; Au-Yeung, R.; Iqbal, J.; et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 2017, 129, 2437–2442. [Google Scholar] [CrossRef] [Green Version]
- Li, X.; Cheng, Y.; Zhang, M.; Yan, J.; Li, L.; Fu, X.; Zhang, X.; Chang, Y.; Sun, Z.; Yu, H.; et al. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J. Hematol. Oncol. 2018, 11, 15. [Google Scholar] [CrossRef] [Green Version]
- Barta, S.K.; Zain, J.; MacFarlane, A.W.t.; Smith, S.M.; Ruan, J.; Fung, H.C.; Tan, C.R.; Yang, Y.; Alpaugh, R.K.; Dulaimi, E.; et al. Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma. Clin. Lymphoma Myeloma Leuk. 2019, 19, 356–364. [Google Scholar] [CrossRef] [PubMed]
- Bennani, N.N.; Pederson, L.D.; Atherton, P.; Micallef, I.; Colgan, J.P.; Thanarajasingam, G.; Nowakowski, G.; Witzig, T.E.; Feldman, A.L.; Ansell, S.M. A Phase II Study of Nivolumab in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma. Blood 2019, 134, 467. [Google Scholar] [CrossRef]
- Khodadoust, M.S.; Rook, A.H.; Porcu, P.; Foss, F.; Moskowitz, A.J.; Shustov, A.; Shanbhag, S.; Sokol, L.; Fling, S.P.; Ramchurren, N.; et al. Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study. J. Clin. Oncol. 2020, 38, 20–28. [Google Scholar] [CrossRef] [PubMed]
- Ratner, L.; Waldmann, T.A.; Janakiram, M.; Brammer, J.E. Rapid Progression of Adult T-Cell Leukemia-Lymphoma after PD-1 Inhibitor Therapy. N. Engl. J. Med. 2018, 378, 1947–1948. [Google Scholar] [CrossRef] [PubMed]
- Rauch, D.A.; Conlon, K.C.; Janakiram, M.; Brammer, J.E.; Harding, J.C.; Ye, B.H.; Zang, X.; Ren, X.; Olson, S.; Cheng, X.; et al. Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade. Blood 2019, 134, 1406–1414. [Google Scholar] [CrossRef]
- Bashey, A.; Medina, B.; Corringham, S.; Pasek, M.; Carrier, E.; Vrooman, L.; Lowy, I.; Solomon, S.R.; Morris, L.E.; Holland, H.K.; et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 2009, 113, 1581–1588. [Google Scholar] [CrossRef]
- Davids, M.S.; Kim, H.T.; Bachireddy, P.; Costello, C.; Liguori, R.; Savell, A.; Lukez, A.P.; Avigan, D.; Chen, Y.B.; McSweeney, P.; et al. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N. Engl. J. Med. 2016, 375, 143–153. [Google Scholar] [CrossRef]
- Khouri, I.F.; Fernandez Curbelo, I.; Turturro, F.; Jabbour, E.J.; Milton, D.R.; Bassett, R.L., Jr.; Vence, L.M.; Allison, J.P.; Gulbis, A.M.; Sharma, P. Ipilimumab plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies. Clin. Cancer Res. 2018, 24, 1011–1018. [Google Scholar] [CrossRef] [Green Version]
- Armand, P.; Nagler, A.; Weller, E.A.; Devine, S.M.; Avigan, D.E.; Chen, Y.B.; Kaminski, M.S.; Holland, H.K.; Winter, J.N.; Mason, J.R.; et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: Results of an international phase II trial. J. Clin. Oncol. 2013, 31, 4199–4206. [Google Scholar] [CrossRef] [Green Version]
- Frigault, M.J.; Armand, P.; Redd, R.A.; Jeter, E.; Merryman, R.W.; Coleman, K.C.; Herrera, A.F.; Dahi, P.; Nieto, Y.; LaCasce, A.S.; et al. PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation. Blood Adv. 2020, 4, 122–126. [Google Scholar] [CrossRef]
- Stenner, F.; Renner, C. Cancer Immunotherapy and the Immune Response in Follicular Lymphoma. Front. Oncol. 2018, 8, 219. [Google Scholar] [CrossRef] [PubMed]
- Yang, Z.Z.; Kim, H.J.; Villasboas, J.C.; Chen, Y.P.; Price-Troska, T.; Jalali, S.; Wilson, M.; Novak, A.J.; Ansell, S.M. Expression of LAG-3 defines exhaustion of intratumoral PD-1(+) T cells and correlates with poor outcome in follicular lymphoma. Oncotarget 2017, 8, 61425–61439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El Halabi, L.; Adam, J.; Gravelle, P.; Marty, V.; Danu, A.; Lazarovici, J.; Ribrag, V.; Bosq, J.; Camara-Clayette, V.; Laurent, C.; et al. Expression of the Immune Checkpoint Regulators LAG-3 and TIM-3 in Classical Hodgkin Lymphoma. Clin. Lymphoma Myeloma Leuk. 2020. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Du, H.; Xiao, T.W.; Liu, J.Z.; Liu, G.Z.; Wang, J.X.; Li, G.Y.; Wang, L.X. Prognostic value of PD-1 and TIM-3 on CD3+ T cells from diffuse large B-cell lymphoma. Biomed. Pharmacother. 2015, 75, 83–87. [Google Scholar] [CrossRef]
- Burova, E.; Hermann, A.; Dai, J.; Ullman, E.; Halasz, G.; Potocky, T.; Hong, S.; Liu, M.; Allbritton, O.; Woodruff, A.; et al. Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3-Knockin Mice. Mol. Cancer Ther. 2019, 18, 2051–2062. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, Z.Z.; Kim, H.J.; Wu, H.; Jalali, S.; Tang, X.; Krull, J.E.; Ding, W.; Novak, A.J.; Ansell, S.M. TIGIT Expression Is Associated with T-cell Suppression and Exhaustion and Predicts Clinical Outcome and Anti-PD-1 Response in Follicular Lymphoma. Clin. Cancer Res. 2020, 26, 5217–5231. [Google Scholar] [CrossRef]
- Li, W.; Blessin, N.C.; Simon, R.; Kluth, M.; Fischer, K.; Hube-Magg, C.; Makrypidi-Fraune, G.; Wellge, B.; Mandelkow, T.; Debatin, N.F.; et al. Expression of the immune checkpoint receptor TIGIT in Hodgkin’s lymphoma. BMC Cancer 2018, 18, 1209. [Google Scholar] [CrossRef]
- Josefsson, S.E.; Beiske, K.; Blaker, Y.N.; Førsund, M.S.; Holte, H.; Østenstad, B.; Kimby, E.; Köksal, H.; Wälchli, S.; Bai, B.; et al. TIGIT and PD-1 Mark Intratumoral T Cells with Reduced Effector Function in B-cell Non-Hodgkin Lymphoma. Cancer Immunol. Res. 2019, 7, 355–362. [Google Scholar] [CrossRef]
- Liu, J.; Wang, L.; Zhao, F.; Tseng, S.; Narayanan, C.; Shura, L.; Willingham, S.; Howard, M.; Prohaska, S.; Volkmer, J.; et al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS ONE 2015, 10, e0137345. [Google Scholar] [CrossRef] [Green Version]
- Petrova, P.S.; Viller, N.N.; Wong, M.; Pang, X.; Lin, G.H.; Dodge, K.; Chai, V.; Chen, H.; Lee, V.; House, V.; et al. TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding. Clin. Cancer Res. 2017, 23, 1068–1079. [Google Scholar] [CrossRef] [Green Version]
- Lin, G.H.Y.; Chai, V.; Lee, V.; Dodge, K.; Truong, T.; Wong, M.; Johnson, L.D.; Linderoth, E.; Pang, X.; Winston, J.; et al. TTI-621 (SIRPαFc), a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by multiple polarized macrophage subsets. PLoS ONE 2017, 12, e0187262. [Google Scholar] [CrossRef] [Green Version]
- Johnson, L.D.S.; Banerjee, S.; Kruglov, O.; Viller, N.N.; Horwitz, S.M.; Lesokhin, A.; Zain, J.; Querfeld, C.; Chen, R.; Okada, C.; et al. Targeting CD47 in Sézary syndrome with SIRPαFc. Blood Adv. 2019, 3, 1145–1153. [Google Scholar] [CrossRef] [Green Version]
- Ansell, S.M.; Maris, M.; Lesokhin, A.M.; Chen, R.; Flinn, I.W.; Sawas, A.; Minden, M.D.; Villa, D.; Percival, M.M.; Advani, A.S.; et al. Phase 1 Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies. Clin. Cancer Res. 2021. [Google Scholar] [CrossRef] [PubMed]
- Patel, K.; Ramchandren, R.; Maris, M.; Lesokhin, A.M.; von Keudell, G.R.; Cheson, B.D.; Zonder, J.; Seymour, E.K.; Catalano, T.; Lin, G.H.Y.; et al. Investigational CD47-Blocker TTI-622 Shows Single-Agent Activity in Patients with Advanced Relapsed or Refractory Lymphoma: Update from the Ongoing First-in-Human Dose Escalation Study. Blood 2020, 136, 46–47. [Google Scholar] [CrossRef]
- Abrisqueta, P.; Sancho, J.-M.; Cordoba, R.; Persky, D.O.; Andreadis, C.; Huntington, S.F.; Carpio, C.; Morillo Giles, D.; Wei, X.; Li, Y.F.; et al. Anti-CD47 Antibody, CC-90002, in Combination with Rituximab in Subjects with Relapsed and/or Refractory Non-Hodgkin Lymphoma (R/R NHL). Blood 2019, 134, 4089. [Google Scholar] [CrossRef]
- Vey, N.; Karlin, L.; Sadot-Lebouvier, S.; Broussais, F.; Berton-Rigaud, D.; Rey, J.; Charbonnier, A.; Marie, D.; André, P.; Paturel, C.; et al. A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. Oncotarget 2018, 9, 17675–17688. [Google Scholar] [CrossRef] [Green Version]
- Armand, P.; Lesokhin, A.; Borrello, I.; Timmerman, J.; Gutierrez, M.; Zhu, L.; Popa McKiver, M.; Ansell, S.M. A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Leukemia 2020. [Google Scholar] [CrossRef]
- Fisher, T.S.; Kamperschroer, C.; Oliphant, T.; Love, V.A.; Lira, P.D.; Doyonnas, R.; Bergqvist, S.; Baxi, S.M.; Rohner, A.; Shen, A.C.; et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol. Immunother. 2012, 61, 1721–1733. [Google Scholar] [CrossRef]
- Reithofer, M.; Rosskopf, S.; Leitner, J.; Battin, C.; Bohle, B.; Steinberger, P.; Jahn-Schmid, B. 4-1BB costimulation promotes bystander activation of human CD8 T cells. Eur. J. Immunol. 2020. [Google Scholar] [CrossRef] [PubMed]
- Turaj, A.H.; Hussain, K.; Cox, K.L.; Rose-Zerilli, M.J.J.; Testa, J.; Dahal, L.N.; Chan, H.T.C.; James, S.; Field, V.L.; Carter, M.J.; et al. Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment. Cancer Cell 2017, 32, 777–791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Buchan, S.L.; Fallatah, M.; Thirdborough, S.M.; Taraban, V.Y.; Rogel, A.; Thomas, L.J.; Penfold, C.A.; He, L.Z.; Curran, M.A.; Keler, T.; et al. PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8(+) T-Cell-Driven Antitumor Immunity. Clin. Cancer Res. 2018, 24, 2383–2394. [Google Scholar] [CrossRef] [Green Version]
- Advani, R.; Forero-Torres, A.; Furman, R.R.; Rosenblatt, J.D.; Younes, A.; Ren, H.; Harrop, K.; Whiting, N.; Drachman, J.G. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma. J. Clin. Oncol. 2009, 27, 4371–4377. [Google Scholar] [CrossRef]
- Furman, R.R.; Forero-Torres, A.; Shustov, A.; Drachman, J.G. A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leuk. Lymphoma 2010, 51, 228–235. [Google Scholar] [CrossRef] [PubMed]
- De Vos, S.; Forero-Torres, A.; Ansell, S.M.; Kahl, B.; Cheson, B.D.; Bartlett, N.L.; Furman, R.R.; Winter, J.N.; Kaplan, H.; Timmerman, J.; et al. A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors. J. Hematol. Oncol. 2014, 7, 44. [Google Scholar] [CrossRef] [Green Version]
- Forero-Torres, A.; Bartlett, N.; Beaven, A.; Myint, H.; Nasta, S.; Northfelt, D.W.; Whiting, N.C.; Drachman, J.G.; Lobuglio, A.F.; Moskowitz, C.H. Pilot study of dacetuzumab in combination with rituximab and gemcitabine for relapsed or refractory diffuse large B-cell lymphoma. Leuk. Lymphoma 2013, 54, 277–283. [Google Scholar] [CrossRef] [PubMed]
- Fayad, L.; Ansell, S.M.; Advani, R.; Coiffier, B.; Stuart, R.; Bartlett, N.L.; Forero-Torres, A.; Kuliczkowski, K.; Belada, D.; Ng, E.; et al. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: A randomized, double-blind, placebo-controlled phase 2b trial. Leuk. Lymphoma 2015, 56, 2569–2578. [Google Scholar] [CrossRef] [PubMed]
- Byrd, J.C.; Kipps, T.J.; Flinn, I.W.; Cooper, M.; Odenike, O.; Bendiske, J.; Rediske, J.; Bilic, S.; Dey, J.; Baeck, J.; et al. Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk. Lymphoma 2012, 53, 2136–2142. [Google Scholar] [CrossRef] [Green Version]
- Fanale, M.; Assouline, S.; Kuruvilla, J.; Solal-Céligny, P.; Heo, D.S.; Verhoef, G.; Corradini, P.; Abramson, J.S.; Offner, F.; Engert, A.; et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br. J. Haematol. 2014, 164, 258–265. [Google Scholar] [CrossRef]
- Segal, N.H.; Logan, T.F.; Hodi, F.S.; McDermott, D.; Melero, I.; Hamid, O.; Schmidt, H.; Robert, C.; Chiarion-Sileni, V.; Ascierto, P.A.; et al. Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. Clin. Cancer Res. 2017, 23, 1929–1936. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Segal, N.H.; He, A.R.; Doi, T.; Levy, R.; Bhatia, S.; Pishvaian, M.J.; Cesari, R.; Chen, Y.; Davis, C.B.; Huang, B.; et al. Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer. Clin. Cancer Res. 2018, 24, 1816–1823. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gopal, A.K.; Levy, R.; Houot, R.; Patel, S.P.; Popplewell, L.; Jacobson, C.; Mu, X.J.; Deng, S.; Ching, K.A.; Chen, Y.; et al. First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20(+) Non-Hodgkin Lymphomas. Clin. Cancer Res. 2020, 26, 2524–2534. [Google Scholar] [CrossRef] [Green Version]
- Timmerman, J.; Herbaux, C.; Ribrag, V.; Zelenetz, A.D.; Houot, R.; Neelapu, S.S.; Logan, T.; Lossos, I.S.; Urba, W.; Salles, G.; et al. Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma. Am. J. Hematol. 2020, 95, 510–520. [Google Scholar] [CrossRef]
- Ansell, S.M.; Flinn, I.; Taylor, M.H.; Sikic, B.I.; Brody, J.; Nemunaitis, J.; Feldman, A.; Hawthorne, T.R.; Rawls, T.; Keler, T.; et al. Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies. Blood Adv. 2020, 4, 1917–1926. [Google Scholar] [CrossRef]
- Van Oers, M.H.; Pals, S.T.; Evers, L.M.; van der Schoot, C.E.; Koopman, G.; Bonfrer, J.M.; Hintzen, R.Q.; von dem Borne, A.E.; van Lier, R.A. Expression and release of CD27 in human B-cell malignancies. Blood 1993, 82, 3430–3436. [Google Scholar] [CrossRef] [Green Version]
- Dong, H.Y.; Shahsafaei, A.; Dorfman, D.M. CD148 and CD27 are expressed in B cell lymphomas derived from both memory and naïve B cells. Leuk. Lymphoma 2002, 43, 1855–1858. [Google Scholar] [CrossRef]
- Vitale, L.A.; He, L.Z.; Thomas, L.J.; Widger, J.; Weidlick, J.; Crocker, A.; O’Neill, T.; Storey, J.; Glennie, M.J.; Grote, D.M.; et al. Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clin. Cancer Res. 2012, 18, 3812–3821. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ramakrishna, V.; Sundarapandiyan, K.; Zhao, B.; Bylesjo, M.; Marsh, H.C.; Keler, T. Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J. Immunother. Cancer 2015, 3, 37. [Google Scholar] [CrossRef] [Green Version]
- He, L.Z.; Prostak, N.; Thomas, L.J.; Vitale, L.; Weidlick, J.; Crocker, A.; Pilsmaker, C.D.; Round, S.M.; Tutt, A.; Glennie, M.J.; et al. Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice. J. Immunol. 2013, 191, 4174–4183. [Google Scholar] [CrossRef] [Green Version]
- Wasiuk, A.; Testa, J.; Weidlick, J.; Sisson, C.; Vitale, L.; Widger, J.; Crocker, A.; Thomas, L.J.; Goldstein, J.; Marsh, H.C.; et al. CD27-Mediated Regulatory T Cell Depletion and Effector T Cell Costimulation Both Contribute to Antitumor Efficacy. J. Immunol. 2017, 199, 4110–4123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Labrijn, A.F.; Janmaat, M.L.; Reichert, J.M.; Parren, P. Bispecific antibodies: A mechanistic review of the pipeline. Nat. Rev. Drug Discov. 2019, 18, 585–608. [Google Scholar] [CrossRef]
- Velasquez, M.P.; Bonifant, C.L.; Gottschalk, S. Redirecting T cells to hematological malignancies with bispecific antibodies. Blood 2018, 131, 30–38. [Google Scholar] [CrossRef]
- Bargou, R.; Leo, E.; Zugmaier, G.; Klinger, M.; Goebeler, M.; Knop, S.; Noppeney, R.; Viardot, A.; Hess, G.; Schuler, M.; et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008, 321, 974–977. [Google Scholar] [CrossRef] [PubMed]
- Przepiorka, D.; Ko, C.W.; Deisseroth, A.; Yancey, C.L.; Candau-Chacon, R.; Chiu, H.J.; Gehrke, B.J.; Gomez-Broughton, C.; Kane, R.C.; Kirshner, S.; et al. FDA Approval: Blinatumomab. Clin. Cancer Res. 2015, 21, 4035–4039. [Google Scholar] [CrossRef] [Green Version]
- Goebeler, M.E.; Knop, S.; Viardot, A.; Kufer, P.; Topp, M.S.; Einsele, H.; Noppeney, R.; Hess, G.; Kallert, S.; Mackensen, A.; et al. Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study. J. Clin. Oncol. 2016, 34, 1104–1111. [Google Scholar] [CrossRef] [PubMed]
- Viardot, A.; Goebeler, M.E.; Hess, G.; Neumann, S.; Pfreundschuh, M.; Adrian, N.; Zettl, F.; Libicher, M.; Sayehli, C.; Stieglmaier, J.; et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood 2016, 127, 1410–1416. [Google Scholar] [CrossRef]
- Coyle, L.; Morley, N.J.; Rambaldi, A.; Mason, K.D.; Verhoef, G.; Furness, C.; Desai, R.; Mergen, N. Updated Analysis of an Open-Label, Phase 2 Study of Blinatumomab As Second Salvage Therapy in Adults with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma. Blood 2020, 136, 14–15. [Google Scholar] [CrossRef]
- Poh, C.; Frankel, P.; Ruel, C.; Abedi, M.; Schwab, E.; Costello, C.L.; Zain, J.; Budde, L.E.; William, B.M.; Foss, F.M.; et al. Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin’s Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis. Blood 2019, 134, 760. [Google Scholar] [CrossRef]
- Katz, D.A.; Chu, M.P.; David, K.A.; Thieblemont, C.; Morley, N.J.; Khan, S.S.; Chen, Y.; Kalabus, J.; Morris, J.; Anderson, A.; et al. Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma. Blood 2019, 134, 4077. [Google Scholar] [CrossRef]
- Guieze, R.; Ysebaert, L.; Molina, L.; Roos-Weil, D.; Michallet, A.-S.; Hivert, B.; Gay, J.; Saad, A.; Fornecker, L.M.; Broséus, J.; et al. Blinatumomab after R-CHOP Debulking Therapy for Patients with Richter Transformation: Preliminary Results of the Multicenter Phase 2 Blinart Trial from the Filo Group. Blood 2020, 136, 4–5. [Google Scholar] [CrossRef]
- Bannerji, R.; Arnason, J.E.; Advani, R.; Brown, J.R.; Allan, J.N.; Ansell, S.M.; Barnes, J.; O’Brien, S.M.; Chavez, J.C.; Duell, J.; et al. Emerging Clinical Activity of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Follicular Lymphoma (FL), Diffuse Large B-Cell Lymphoma (DLBCL), and Other B-Cell Non-Hodgkin Lymphoma (B-NHL) Subtypes. Blood 2018, 132, 1690. [Google Scholar] [CrossRef]
- Bannerji, R.; Allan, J.N.; Arnason, J.E.; Brown, J.R.; Advani, R.H.; Barnes, J.A.; Ansell, S.M.; O’Brien, S.M.; Chavez, J.; Duell, J.; et al. Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL). Blood 2019, 134, 762. [Google Scholar] [CrossRef]
- Bannerji, R.; Allan, J.N.; Arnason, J.E.; Brown, J.R.; Advani, R.; Ansell, S.M.; O’Brien, S.M.; Duell, J.; Martin, P.; Joyce, R.M.; et al. Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy. Blood 2020, 136, 42–43. [Google Scholar] [CrossRef]
- Schuster, S.J.; Bartlett, N.L.; Assouline, S.; Yoon, S.-S.; Bosch, F.; Sehn, L.H.; Cheah, C.Y.; Shadman, M.; Gregory, G.P.; Ku, M.; et al. Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines. Blood 2019, 134, 6. [Google Scholar] [CrossRef]
- Assouline, S.E.; Kim, W.S.; Sehn, L.H.; Schuster, S.J.; Cheah, C.Y.; Nastoupil, L.J.; Shadman, M.; Yoon, S.-S.; Matasar, M.J.; Diefenbach, C.; et al. Mosunetuzumab Shows Promising Efficacy in Patients with Multiply Relapsed Follicular Lymphoma: Updated Clinical Experience from a Phase I Dose-Escalation Trial. Blood 2020, 136, 42–44. [Google Scholar] [CrossRef]
- Olszewski, A.J.; Avigdor, A.; Babu, S.; Levi, I.; Abadi, U.; Holmes, H.; McKinney, M.; McCord, R.; Xie, Y.; Chen, C.; et al. Single-Agent Mosunetuzumab Is a Promising Safe and Efficacious Chemotherapy-Free Regimen for Elderly/Unfit Patients with Previously Untreated Diffuse Large B-Cell Lymphoma. Blood 2020, 136, 43–45. [Google Scholar] [CrossRef]
- Bacac, M.; Colombetti, S.; Herter, S.; Sam, J.; Perro, M.; Chen, S.; Bianchi, R.; Richard, M.; Schoenle, A.; Nicolini, V.; et al. CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies. Clin. Cancer Res. 2018, 24, 4785–4797. [Google Scholar] [CrossRef] [Green Version]
- Morschhauser, F.; Carlo-Stella, C.; Offner, F.; Salles, G.A.; Hutchings, M.; Iacoboni, G.; Sureda, A.; Crump, M.; Martinez-Lopez, J.; Thomas, D.; et al. Dual CD20-Targeted Therapy with Concurrent CD20-TCB and Obinutuzumab Shows Highly Promising Clinical Activity and Manageable Safety in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: Preliminary Results from a Phase Ib Trial. Blood 2019, 134, 1584. [Google Scholar] [CrossRef]
- Engelberts, P.J.; Hiemstra, I.H.; de Jong, B.; Schuurhuis, D.H.; Meesters, J.; Beltran Hernandez, I.; Oostindie, S.C.; Neijssen, J.; van den Brink, E.N.; Horbach, G.J.; et al. DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine 2020, 52, 102625. [Google Scholar] [CrossRef]
- Hutchings, M.; Mous, R.; Clausen, M.R.; Johnson, P.; Linton, K.M.; Chamuleau, M.E.D.; Lewis, D.J.; Sureda Balari, A.; Cunningham, D.; Oliveri, R.S.; et al. Subcutaneous Epcoritamab Induces Complete Responses with an Encouraging Safety Profile across Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma Subtypes, Including Patients with Prior CAR-T Therapy: Updated Dose Escalation Data. Blood 2020, 136, 45–46. [Google Scholar] [CrossRef]
- Matasar, M.J.; Cheah, C.Y.; Yoon, D.H.; Assouline, S.E.; Bartlett, N.L.; Ku, M.; Giri, P.; Johnston, A.; Flinn, I.W.; Goy, A.H.; et al. Subcutaneous Mosunetuzumab in Relapsed or Refractory B-Cell Lymphoma: Promising Safety and Encouraging Efficacy in Dose Escalation Cohorts. Blood 2020, 136, 45–46. [Google Scholar] [CrossRef]
- Da Costa, L.; Renner, C.; Hartmann, F.; Pfreundschuh, M. Immune recruitment by bispecific antibodies for the treatment of Hodgkin disease. Cancer Chemother. Pharmacol. 2000, 46, S33–S36. [Google Scholar] [CrossRef]
- Hartmann, F.; Renner, C.; Jung, W.; da Costa, L.; Tembrink, S.; Held, G.; Sek, A.; König, J.; Bauer, S.; Kloft, M.; et al. Anti-CD16/CD30 bispecific antibody treatment for Hodgkin’s disease: Role of infusion schedule and costimulation with cytokines. Clin. Cancer Res. 2001, 7, 1873–1881. [Google Scholar]
- Borchmann, P.; Schnell, R.; Fuss, I.; Manzke, O.; Davis, T.; Lewis, L.D.; Behnke, D.; Wickenhauser, C.; Schiller, P.; Diehl, V.; et al. Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma. Blood 2002, 100, 3101–3107. [Google Scholar] [CrossRef]
- Reusch, U.; Burkhardt, C.; Fucek, I.; Le Gall, F.; Le Gall, M.; Hoffmann, K.; Knackmuss, S.H.; Kiprijanov, S.; Little, M.; Zhukovsky, E.A. A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells. MAbs 2014, 6, 728–739. [Google Scholar] [CrossRef] [Green Version]
- Bartlett, N.L.; Herrera, A.F.; Domingo-Domenech, E.; Mehta, A.; Forero-Torres, A.; Garcia-Sanz, R.; Armand, P.; Devata, S.; Izquierdo, A.R.; Lossos, I.S.; et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2020, 136, 2401–2409. [Google Scholar] [CrossRef]
- Ansell, S.M.; Bartlett, N.L.; Chen, R.W.; Herrera, A.; Domingo-Domenech, E.; Mehta, A.; Forero-Torres, A.; Garcia-Sanz, R.; Armand, P.; Devata, S.; et al. Investigating safety and preliminary efficacy of AFM13 plus pembrolizumab in patients with relapsed/refractory Hodgkin lymphoma after brentuximab vedotin failure. Hematol. Oncol. 2019, 37, 177–178. [Google Scholar] [CrossRef] [Green Version]
- Felices, M.; Kodal, B.; Hinderlie, P.; Kaminski, M.F.; Cooley, S.; Weisdorf, D.J.; Vallera, D.A.; Miller, J.S.; Bachanova, V. Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL. Blood Adv. 2019, 3, 897–907. [Google Scholar] [CrossRef]
- Schmohl, J.U.; Gleason, M.K.; Dougherty, P.R.; Miller, J.S.; Vallera, D.A. Heterodimeric Bispecific Single Chain Variable Fragments (scFv) Killer Engagers (BiKEs) Enhance NK-cell Activity Against CD133+ Colorectal Cancer Cells. Target. Oncol. 2016, 11, 353–361. [Google Scholar] [CrossRef] [Green Version]
- Warlick, E.D.; Weisdorf, D.J.; Vallera, D.A.; Wangen, R.; Lewis, D.; Knox, J.; Schroeder, M.; Felices, M.; Miller, J.S. GTB-3550 TriKE™ for the Treatment of High-Risk Myelodysplastic Syndromes (MDS) and Refractory/Relapsed Acute Myeloid Leukemia (AML) Safely Drives Natural Killer (NK) Cell Proliferation At Initial Dose Cohorts. Blood 2020, 136, 7–8. [Google Scholar] [CrossRef]
- Roemer, M.G.M.; Redd, R.A.; Cader, F.Z.; Pak, C.J.; Abdelrahman, S.; Ouyang, J.; Sasse, S.; Younes, A.; Fanale, M.; Santoro, A.; et al. Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. J. Clin. Oncol. 2018, 36, 942–950. [Google Scholar] [CrossRef]
- Hellmann, M.D.; Ciuleanu, T.-E.; Pluzanski, A.; Lee, J.S.; Otterson, G.A.; Audigier-Valette, C.; Minenza, E.; Linardou, H.; Burgers, S.; Salman, P.; et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N. Engl. J. Med. 2018, 378, 2093–2104. [Google Scholar] [CrossRef] [PubMed]
- Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015, 372, 2509–2520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mandal, R.; Samstein, R.M.; Lee, K.W.; Havel, J.J.; Wang, H.; Krishna, C.; Sabio, E.Y.; Makarov, V.; Kuo, F.; Blecua, P.; et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 2019, 364, 485–491. [Google Scholar] [CrossRef] [PubMed]
- Alexandrov, L.B.; Kim, J.; Haradhvala, N.J.; Huang, M.N.; Tian Ng, A.W.; Wu, Y.; Boot, A.; Covington, K.R.; Gordenin, D.A.; Bergstrom, E.N.; et al. The repertoire of mutational signatures in human cancer. Nature 2020, 578, 94–101. [Google Scholar] [CrossRef] [Green Version]
- Qi, X.; Li, F.; Wu, Y.; Cheng, C.; Han, P.; Wang, J.; Yang, X. Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Nat. Commun 2019, 10, 2141. [Google Scholar] [CrossRef] [PubMed]
- Ho, S.K.; Xu, Z.; Thakur, A.; Fox, M.; Tan, S.S.; DiGiammarino, E.; Zhou, L.; Sho, M.; Cairns, B.; Zhao, V.; et al. Epitope and Fc-Mediated Cross-linking, but Not High Affinity, Are Critical for Antitumor Activity of CD137 Agonist Antibody with Reduced Liver Toxicity. Mol. Cancer Ther. 2020, 19, 1040–1051. [Google Scholar] [CrossRef]
- Kontermann, R.E.; Brinkmann, U. Bispecific antibodies. Drug Discov Today 2015, 20, 838–847. [Google Scholar] [CrossRef] [Green Version]
- Mazor, Y.; Sachsenmeier, K.F.; Yang, C.; Hansen, A.; Filderman, J.; Mulgrew, K.; Wu, H.; Dall’Acqua, W.F. Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence. Sci. Rep. 2017, 7, 40098. [Google Scholar] [CrossRef]
- Csizmar, C.M.; Petersburg, J.R.; Perry, T.J.; Rozumalski, L.; Hackel, B.J.; Wagner, C.R. Multivalent Ligand Binding to Cell Membrane Antigens: Defining the Interplay of Affinity, Valency, and Expression Density. J. Am. Chem. Soc. 2019, 141, 251–261. [Google Scholar] [CrossRef]
- Petersburg, J.; Shen, J.; Csizmar, C.M.; Murphy, K.A.; Spanier, J.; Gabrielse, K.; Griffith, T.S.; Fife, B.; Wagner, C.R. Eradication of Established Tumors by Chemically Self-Assembled Nanoring (CSAN) Targeted T-cells. ACS Nano 2018. [Google Scholar] [CrossRef]
- Arcangeli, S.; Rotiroti, M.C.; Bardelli, M.; Simonelli, L.; Magnani, C.F.; Biondi, A.; Biagi, E.; Tettamanti, S.; Varani, L. Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia. Mol. Ther. 2017, 25, 1933–1945. [Google Scholar] [CrossRef]
- Liu, X.; Jiang, S.; Fang, C.; Yang, S.; Olalere, D.; Pequignot, E.C.; Cogdill, A.P.; Li, N.; Ramones, M.; Granda, B.; et al. Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice. Cancer Res. 2015, 75, 3596–3607. [Google Scholar] [CrossRef] [Green Version]
- Park, S.; Shevlin, E.; Vedvyas, Y.; Zaman, M.; Hsu, Y.S.; Min, I.M.; Jin, M.M. Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci. Rep. 2017, 7, 14366. [Google Scholar] [CrossRef] [Green Version]
- Drent, E.; Themeli, M.; Poels, R.; de Jong-Korlaar, R.; Yuan, H.; de Bruijn, J.; Martens, A.C.M.; Zweegman, S.; van de Donk, N.; Groen, R.W.J.; et al. A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization. Mol. Ther. 2017, 25, 1946–1958. [Google Scholar] [CrossRef]
- Caruso, H.G.; Hurton, L.V.; Najjar, A.; Rushworth, D.; Ang, S.; Olivares, S.; Mi, T.; Switzer, K.; Singh, H.; Huls, H.; et al. Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. Cancer Res. 2015, 75, 3505–3518. [Google Scholar] [CrossRef] [Green Version]
- Lu, G.; Middleton, R.E.; Sun, H.; Naniong, M.; Ott, C.J.; Mitsiades, C.S.; Wong, K.K.; Bradner, J.E.; Kaelin, W.G., Jr. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014, 343, 305–309. [Google Scholar] [CrossRef] [Green Version]
- Gandhi, A.K.; Kang, J.; Havens, C.G.; Conklin, T.; Ning, Y.; Wu, L.; Ito, T.; Ando, H.; Waldman, M.F.; Thakurta, A.; et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br. J. Haematol. 2014, 164, 811–821. [Google Scholar] [CrossRef] [Green Version]
- Dredge, K.; Marriott, J.B.; Todryk, S.M.; Muller, G.W.; Chen, R.; Stirling, D.I.; Dalgleish, A.G. Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity. J. Immunol. 2002, 168, 4914–4919. [Google Scholar] [CrossRef] [Green Version]
- Galustian, C.; Meyer, B.; Labarthe, M.C.; Dredge, K.; Klaschka, D.; Henry, J.; Todryk, S.; Chen, R.; Muller, G.; Stirling, D.; et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol. Immunother. 2009, 58, 1033–1045. [Google Scholar] [CrossRef] [PubMed]
- Mamontov, P.; Eberwine, R.A.; Perrigoue, J.; Das, A.; Friedman, J.R.; Mora, J.R. A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation. PLoS ONE 2019, 14, e0215963. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dubovsky, J.A.; Beckwith, K.A.; Natarajan, G.; Woyach, J.A.; Jaglowski, S.; Zhong, Y.; Hessler, J.D.; Liu, T.M.; Chang, B.Y.; Larkin, K.M.; et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013, 122, 2539–2549. [Google Scholar] [CrossRef] [Green Version]
- Younes, A.; Brody, J.; Carpio, C.; Lopez-Guillermo, A.; Ben-Yehuda, D.; Ferhanoglu, B.; Nagler, A.; Ozcan, M.; Avivi, I.; Bosch, F.; et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: A phase 1/2a study. Lancet Haematol. 2019, 6, e67–e78. [Google Scholar] [CrossRef]
Trial ID (Name) | Authors | Year | Intervention(s) | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|
NCT00089076 | Ansell et al. | 2009 | Ipilimumab | I | FL DLBCL MCL | 14 3 1 | 0% 33% 0% | 7% 33% 0% | N.A. |
NCT00904722 | Westin et al. | 2014 | Pidilizumab + Rituximab | II | FL | 29 | 52% | 66% | N.A. |
NCT01592370 (CHECKMATE-039) | Ansell et al. | 2016 | Nivolumab + Ipilimumab | Ib | B-NHL | 15 | 0% | 20% | median 1.5 months |
NCT01592370 (CHECKMATE-039) | Lesokhin et al. | 2016 | Nivolumab | Ib | FL DLBCL Other B-NHL | 10 11 10 | 10% 18% 0% | 40% 36% 0% | median 23 weeks |
- | Nayak et al. | 2017 | Nivolumab | I | PCNSL PTL | 4 1 | 75% 100% | 100% 100% | N.A |
NCT01953692 (KEYNOTE-013) | Zinzani et al. | 2017 | Pembrolizumab | Ib | PMBCL | 17 | 12% | 41% | N.A. |
NCT02220842 | Palomba et al. | 2017 | Atezolizumab + Obinutuzumab | Ib | FL DLBCL | 26 23 | N.A. N.A. | 57% 16% | N.A. |
NCT02332980 | Ding et al. | 2017 | Pembrolizumab | II | CLL CLL with RT | 16 9 | 0% 11% | 0% 44% | median 2.4 months median 5.4 months |
NCT02446457 | Nastoupil et al. | 2017 | Pembrolizumab + Rituximab | II | FL | 25 | 60% | 80% | N.A. |
NCT02596971 | Younes et al. | 2017 | Atezolizumab + Obinutuzumab + Bendamustine | Ib/II | untreated FL | 15 | 67% | 80% | N.A. |
NCT02596971 | Younes et al. | 2018 | Atezolizumab + R-CHOP | I/II | untreated DLBCL | 40 | 78% | 88% | N.A. |
NCT01729806 | Tuscano et al. | 2019 | Ipilimumab + Rituximab | I | FL Other B-NHL | 13 20 | 15% 0% | 38% 3% | median 2.6 months |
NCT01953692 (KEYNOTE-013) | Armand et al. | 2019 | Pembrolizumab | Ib | PMBCL | 21 | 33% | 48% | median 10.4 months |
NCT02038933 (CHECKMATE-139) | Ansell et al. | 2019 | Nivolumab | II | DLBCL s/p failed auto-HSCT DLBCL ineligible for auto-HSCT | 87 34 | 3% 0% | 10% 3% | median 1.9 months median 1.4 months |
NCT02329847 | Younes et al. | 2019 | Nivolumab + Ibrutinib | I/II | CLL/SLL FL DLBCL CLL with RT | 36 40 45 20 | 0% 10% 16% 10% | 61% 33% 36% 65% | N.A. median 9.1 months median 2.6 months median 5.0 months |
NCT02576990 (KEYNOTE-170) | Armand et al. | 2019 | Pembrolizumab | II | PMBCL | 53 | 13% | 45% | median 5.5 months |
NCT02581631 (CHECKMATE-436) | Zinzani et al. | 2019 | Nivolumab + BV | I/II | PMBCL | 30 | 37% | 73% | 63.5% at 6 months |
NCT02733042 (FUSION NHL-001) | Casulo et al. | 2019 | DurvalumabDurvalumab + Lenalidomide ± RituximabDurvalumab + Rituximab ± Bendamustine | I/II | DLBCL FL | 38 22 | 8% 27% | 18% 59% | median 2.5 months median 10.6 months |
- | Smith et al. | 2020 | Pembrolizumab + R-CHOP | II | untreated DLBCL untreated FL | 27 3 | 77% | 90% | 83% at 24 months |
NCT02401048 | Herrera et al. | 2020 | Durvalumab + Ibrutinib | Ib/II | FL DLBCL (GC) DLBCL (non-GC) | 27 16 16 | 4% 6% 31% | 26% 13% 38% | median 10.2 months median 2.9 months median 4.1 months |
NCT02038946 (CHECKMATE-140) | Armand et al. | 2021 | Nivolumab | II | FL | 92 | 1% | 4% | median 2.2 months |
Trial ID (Name) | Authors | Year | Intervention(s) | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|
NCT01592370 | Ansell et al. | 2015 | Nivolumab | I | cHL | 23 | 17% | 87% | 86% at 24 weeks |
NCT01592370 (CHECKMATE-039) | Ansell et al. | 2016 | Nivolumab + Ipilimumab | Ib | cHL | 31 | 19% | 74% | N.A. |
NCT01953692 (KEYNOTE-013) | Armand et al. | 2016 | Pembrolizumab | Ib | cHL | 31 | 16% | 65% | 46% at 52 weeks |
NCT02181738 (CHECKMATE-205) | Younes et al. | 2016 | Nivolumab | II | cHL | 80 | 9% | 66% | 77% at 6 months |
JapicCPI-142755 | Maruyama et al. | 2017 | Nivolumab | II | cHL | 16 | 25% | 81% | 60% at 6 months |
NCT02453594 (KEYNOTE-087) | Chen et al. | 2017 | Pembrolizumab | II | cHL | 210 | 22% | 69% | 72% at 6 months |
NCT02181738 (CHECKMATE-205) | Armand et al. | 2018 | Nivolumab | II | cHL | 243 | 16% | 69% | median 14.7 months |
NCT02572167 | Herrera et al. | 2018 | Nivolumab + BV | I/II | cHL | 61 | 61% | 82% | 89% at 6 months |
NCT03114683 (ORIENT-1) | Shi et al. | 2019 | Sintilimab | II | cHL | 92 | N.A. | 80% | N.A. |
NCT02181738 (CHECKMATE-205) | Ramchandren et al. | 2019 | Nivolumab + AVD | II | untreated cHL | 51 | 80% | 84% | 92% at 9 months |
NCT02453594 (KEYNOTE-087) | Chen et al. | 2019 | Pembrolizumab | II | cHL | 210 | 28% | 72% | median 13.7 months |
NCT03155425 | Song et al. | 2019 | Camrelizumab | II | cHL | 75 | 28% | 76% | median 11.3 months |
JapicCPI-142755 | Maruyama et al. | 2020 | Nivolumab | II | cHL | 16 | 31% | 88% | median 11.7 months |
NCT01896999 | Diefenbach et al. | 2020 | Ipilimumab + BV Nivolumab + BV Ipilimumab + Nivolumab + BV | I/II | cHL | 23 19 22 | 57% 61% 73% | 76% 89% 82% | 61% at 12 months 70% at 12 months 80% at 12 months |
NCT02304458 (ADVL1412) | Davis et al. | 2020 | Nivolumab | I/II | cHL | 12 | 10% | 30% | N.A. |
NCT02332668 (KEYNOTE-051) | Geoerger et al. | 2020 | Pembrolizumab | I/II | cHL | 18 | 13% | 60% | median 12.2 months |
NCT02541604 (iMATRIX) | Geoerger et al. | 2020 | Atezolizumab | I/II | cHL | 9 | 0% | 22% | median 1.3 months a |
NCT02758717 (ACCRU) | Cheson et al. | 2020 | Nivolumab + BV | II | untreated cHL | 46 | 48% | 61% | median 18.3 months |
NCT03004833 (NIVAHL) | Brockelmann et al. | 2020 | Nivolumab then AVD Nivolumab with AVD | II | untreated cHL | 50 51 | 84% 83% | 98% 100% | 98% at 12 months 100% at 12 months |
NCT03209973 | Song et al. | 2020 | Tislelizumab | II | cHL | 70 | 63% | 87% | 75% at 9 months |
Trial ID (Name) | Authors | Year | Intervention(s) | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|
NCT01592370 (CHECKMATE-039) | Lesokhin et al. | 2016 | Nivolumab | Ib | MF PTCL Other CTCL Other non-CTCL | 13 5 3 2 | 0% 0% 0% 0% | 15% 40% 0% 0% | median 10 weeks |
NCT01592370 (CHECKMATE-039) | Ansell et al. | 2016 | Nivolumab + Ipilimumab | Ib | T-NHL | 11 | 0% | 9% | median 2.0 months |
- | Kwong et al. | 2017 | Pembrolizumab | R a | NKTCL | 7 | 71% | 100% | N.A. |
- | Li et al. | 2018 | Pembrolizumab | R a | NKTCL | 7 | 29% | 57% | median 4.8 months |
NCT03075553 | Bennani et al. | 2019 | Nivolumab | II | ALK-neg ALCL AITL PTCL Other Non-CTCL | 1 6 3 2 | 100% 17% 0% 0% | 100% 17% 33% 50% | median 1.9 months |
NCT02535247 | Barta et al. | 2019 | Pembrolizumab | II | PTCL FTL MF Other non-CTCL | 7 4 3 3 | 0% 50% 33% 33% | 14% 50% 33% 33% | median 3.2 months |
NCT02243579 (CITN-10) | Khodadoust et al. | 2020 | Pembrolizumab | II | MF SS | 9 15 | 0% 13% | 56% 27% | 65% at 1 year |
Trial ID (Name) | Authors | Year | Intervention(s) | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|
NCT00060372 (CTEP 6082) | Bashey et al. | 2009 | Ipilimumab after allo-HSCT | I | cHL B-NHL | 14 3 | 14% 0% | 14% 33% | N.A. |
NCT00532259 | Armand et al. | 2013 | Pidilizumab after auto-HSCT | II | DLBCL | 35 | 34% | 51% | 72% at 16 months |
NCT01822509 | Davids et al. | 2016 | Ipilimumab after allo-HSCT | I/Ib | cHL B-NHL | 7 4 | 0% 0% | 14% 0% | N.A. |
NCT01919619 | Khouri et al. | 2018 | Ipilimumab + Lenalidomide after HSCT | II | B-NHL (allo-HSCT) B-NHL (auto-HSCT) | 8 6 | 38% 83% | 75% 83% | 56% at 12 months 86% at 12 months |
NCT02362997 | Frigault et al. | 2020 | Pembrolizumab after auto-HSCT | II | DLBCL | 29 | 59% | 59% | 58% at 18.5 months |
Trial ID | Phase | Target(s) | Intervention(s) | Population(s) | Status |
---|---|---|---|---|---|
NCT03489343 | I | TIM-3 | Sym023 | Advanced malignancies, including lymphomas | Completed |
NCT03311412 | I | TIM-3 LAG-3 | Sym021 + Sym022 (LAG-3) Sym021 + Sym023 (TIM-3) Sym021 + Sym022 + Sym023 | Advanced malignancies, including lymphomas | Recruiting |
NCT02061761 | I | LAG-3 | BMS-986016 ± Nivolumab (PD-1) | Hematologic malignancies, including cHL, NHL, CLL, and MM | Active |
NCT03538028 | I | LAG-3 | INCAGN02385 | Advanced malignancies, including DLBCL | Completed |
NCT03365791 | II | LAG-3 | LAG525 + PDR001 (PD-1) | Advanced malignancies, including DLBCL | Completed |
NCT03005782 | I | LAG-3 | REGN3767 ± Cemiplimab (PD-1) | Advanced solid malignancies or lymphomas | Recruiting |
NCT03489369 | I | LAG-3 | Sym022 | Advanced malignancies, including lymphomas | Completed |
NCT04254107 | I | TIGIT | SGN-TGT ± Pembrolizumab | Advanced malignancies, including cHL, DLBCL, and PTCL | Recruiting |
NCT04353830 | I | TIGIT | IBI939 ± Sintilimab (PD-1) | Advanced malignancies (no further specification) | Recruiting |
Trial ID | Authors | Year | Intervention(s) | Target(s) | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|---|
NCT02953509 | Advani et al. | 2018 | Hu5F9-G4 | CD47 | Ib | DLBCL FL | 15 7 | 33% 43% | 40% 71% | 91% at 6.2 months 91% at 8.1 months |
NCT02216409 | Sikic et al. | 2019 | Hu5F9-G4 | CD47 | I | DLBCL | 2 | 0% | 50% | N.A. |
NCT02367196 | Abrisqueta et al. | 2019 | CC-90002 | CD47 | I | B-NHL | 24 | 4% | 13% | N.A. |
NCT02663518 | Johnson et al. | 2019 | TTI-621 | CD47 | Ia | CTCL with SS | 5 | 0% | 80% | N.A. |
NCT03530683 | Patel et al. | 2020 | TTI-622 | CD47 | I | cHL B-NHL T-NHL | 5 16 4 | 0% 6% 0% | 0% 19% 50% | N.A. |
NCT02663518 | Ansell et al. | 2021 | TTI-621 TTI-621 + Rituximab TTI-621 + Nivolumab | CD47 | I | B-NHL (monotherapy) B-NHL (w/Rituximab) cHL (monotherapy) cHL (w/Nivolumab) T-NHL CLL | 21 35 20 4 40 3 | 5% 9% 0% 25% 3% 0% | 10% 23% 5% 50% 20% 0% | N.A |
EUDRACT 2009-011526-33 | Vey et al. | 2018 | Lirilumab | KIR | I | CLL other B-NHL | 6 11 | 0% | 0% | median 19.6 months median not reached |
NCT01592370 | Armand et al. | 2020 | Lirilumab + Nivolumab | KIR | Ib | cHL B-NHL T-NHL | 21 32 9 | 24% 3% 0% | 76% 13% 22% | 62% at 12 months median 1 months median 6 months |
Trial ID (Name) | Authors | Year | Intervention(s) | Target(s) | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|---|
NCT01471210 (CA186-011) | Segal et al. | 2017 | Urelumab | CD137 (4-1BB) | I | B-NHL | 11 | N.A. | N.A. | N.A. |
NCT01307267 | Segal et al. | 2018 | Utomilumab | CD137 (4-1BB) | I | Lymphoma a | 2 | N.A. | N.A. | N.A. |
NCT01307267 | Gopal et al. | 2020 | Utomilumab + Rituximab | CD137 (4-1BB) | I | FL DLBCL MCL CLL/SLL MZL NLPHL | 47 7 6 3 2 1 | 9% 0% 0% 0% 0% 0% | 23% 14% 17% 0% 0% 100% | median 4.6 months b |
NCT01471210 (CA186-011) | Timmerman et al. | 2020 | Urelumab | CD137 (4-1BB) | I | DLBCL FL other B-NHL | 31 29 12 | 0% 6% 17% | 6% 12% 17% | median 8.1 weeks median 8.9 weeks median 13.4 weeks |
NCT01775631 (CA186-017) | Timmerman et al. | 2020 | Urelumab + Rituximab | CD137 (4-1BB) | Ib | DLBCL FL | 29 17 | 7% 12% | 10% 35% | median 9.0 weeks median 40.4 weeks |
NCT01470134 | Ansell et al. | 2020 | Varlilumab | CD27 | I | DLBCL FL other B-NHL cHL PTCL CTCL MF | 10 6 2 11 2 1 2 | 0% 0% 0% 9% 0% 0% 0% | 0% 0% 0% 9% 0% 0% 0% | N.A. |
NCT00103779 | Advani et al. | 2009 | Dacetuzumab | CD40 | I | DLBCL FL MCL MZL CLL/SLL other NHL | 21 12 10 3 1 3 | 5% 0% 0% 0% 0% 0% | 10% 0% 10% 33% 0% 0% | N.A. |
NCT00283101 | Furman et al. | 2010 | Dacetuzumab | CD40 | I | CLL | 12 | 0% | 0% | N.A. |
NCT00108108 | Byrd et al. | 2012 | Lucatumumab | CD40 | I | CLL | 24 | 0% | 4% | N.A. |
NCT00655837 | Forero-Torres et al. | 2013 | Dacetuzumab + Rituximab + Gemcitabine | CD40 | Ib | DLBCL | 30 | 20% | 47% | median 25 weeks |
NCT00435916 | de Vos et al. | 2014 | Dacetuzumab | CD40 | II | DLBCL FL MZL | 40 3 2 | 5% 0% 0% | 8% 33% 0% | median 36 days |
NCT00670592 | Fanale et al. | 2014 | Lucatumumab | CD40 | Ia/II | FL DLBCL MALT MCL cHL | 21 34 7 12 37 | 5% 6% 14% 0% 0% | 33% 12% 43% 0% 14% | N.A. |
NCT00529503 | Fayad et al. | 2015 | Dacetuzumab + R-ICE Placebo + R-ICE | CD40 | IIb | DLBCL | 75 76 | 33% 36% | 67% 64% | median 12.1 months median 6.5 months |
Trial ID (Name) | Authors | Year | Intervention(s) | Target(s) | Format | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|---|---|
NCT00274742 | Goebeler et al. | 2016 | Blinatumomab | CD3 × CD19 | BiTE | I | FL MCL DLBCL | 15 7 11 | 40% 43% 36% | 80% 71% 55% | N.A. |
NCT01741792 | Viardot et al. | 2016 | Blinatumomab | CD3 × CD19 | BiTE | II | DLBCL | 21 | 19% | 43% | median 3.7 months |
NCT02910063 | Coyle et al. | 2020 | Blinatumomab | CD3 × CD19 | BiTE | II | B-NHL | 41 | 22% | 37% | median 8.4 months a |
NCT02568553 | Poh et al. | 2019 | Blinatumomab + Lenalidomide | CD3 × CD19 | BiTE | I | B-NHL | 18 | 50% | 83% | median 8.3 months |
NCT03023878 | Katz et al. | 2019 | Blinatumomab after R-chemotherapy | CD3 × CD19 | BiTE | II | DLBCL | 28 | N.A. | 89% | N.A. |
NCT03931642 (BLINART) | Guieze et al. | 2020 | Blinatumomab after R-CHOP | CD3 × CD19 | BiTE | II | CLL with RT | 5 | 40% | 60% | N.A. |
NCT03075696 (NP30179) | Morschhauser et al. | 2019 | Glofitamab and Obinutuzumab | CD3 × CD20 | BsAb | I/Ib | B-NHL (all patients) B-NHL (highest dose) | 21 10 | 43% 80% | 48% 90% | N.A. |
NCT03075696 (NP30179) | Hutchings et al. | 2020 | Glofitamab and Obinutuzumab | CD3 × CD20 | BsAb | I/Ib | aggressive B-NHL indolent B-NHL | 24 8 | 29% 75% | 50% 100% | N.A. |
NCT02290951 | Bannerji et al. | 2018 | Odronextamab (REGN1979) | CD3 × CD20 | BsAb | I | DLBCL FL MCL | 15 7 2 | 0% 71% 0% | 40% 100% 100% | N.A. |
NCT02290951 | Bannerji et al. | 2020 | Odronextamab (REGN1979) | CD3 × CD20 | BsAb | I | FL (≥5 mg) FL (≥80 mg) DLBCL (no prior CAR, ≥5 mg) DLBCL (no prior CAR, ≥80 mg) DLBCL (relapse after CAR, ≥5 mg) DLBCL (relapse after CAR, ≥80 mg) | 28 16 30 10 23 21 | 75% 69% 30% 60% 22% 24% | 93% 94% 47% 60% 30% 33% | median 12.8 months median 12.8 months median 5.1 months median 11.1 months median 2.5 months median 2.5 months |
NCT03625037 | Hutchings et al. | 2020 | Epcoritamab (GEN3013, SQ) | CD3 × CD20 | BsAb | I/II | DLBCL FL | 18 8 | 33% 25% | 67% 100% | N.A. |
NCT02500407 (GO29781) | Schuster et al. | 2019 | Mosunetuzumab (RG7828) | CD3 × CD20 | BsAb | I/Ib | aggressive B-NHL indolent B-NHL | 119 64 | 19% 42% | 35% 64% | N.A. |
NCT02500407 (GO29781) | Assouline et al. | 2020 | Mosunetuzumab (RG7828) | CD3 × CD20 | BsAb | I/Ib | FL | 62 | 50% | 68% | median 11.8 months |
NCT02500407 (GO29781) | Matasar et al. | 2020 | Mosunetuzumab (RG7828, SQ) | CD3 × CD20 | BsAb | I/Ib | aggressive B-NHL indolent B-NHL | 15 7 | 20% 29% | 60% 86% | N.A. |
NCT03677154 (GO40554) | Olszewski et al. | 2020 | Mosunetuzumab (RG7828) | CD3 × CD20 | BsAb | I/II | untreated DLBCL | 19 | 42% | 58% | N.A. |
NCT03677141 (GO40515) | Phillips et al. | 2020 | Mosunetuzumab (RG7828) + CHOP | CD3 × CD20 | BsAb | I/II | B-NHL untreated DLBCL | 7 36 | 71% 85% | 86% 96% | N.A. |
Trial ID | Authors | Year | Intervention(s) | Target(s) | Format | Phase | Disease(s) | N | CR | OR | PFS |
---|---|---|---|---|---|---|---|---|---|---|---|
NCT01221571 | Rothe et al. | 2015 | AFM13 | CD16 × CD30 | TandAb | I | cHL | 26 | 0% | 12% | N.A. |
NCT02321592 | Sasse et al. | 2020 | AFM13 | CD16 × CD30 | TandAb | II | cHL | 24 | 4% | 17% | 12.6% at 12 months a |
NCT02665650 | Bartlett et al. | 2020 | AFM13 + Pembrolizumab | CD16 × CD30 | TandAb | Ib | cHL | 30 | 37% | 83% | 77% at 6 months b |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Csizmar, C.M.; Ansell, S.M. Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma. Int. J. Mol. Sci. 2021, 22, 3302. https://doi.org/10.3390/ijms22073302
Csizmar CM, Ansell SM. Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma. International Journal of Molecular Sciences. 2021; 22(7):3302. https://doi.org/10.3390/ijms22073302
Chicago/Turabian StyleCsizmar, Clifford M., and Stephen M. Ansell. 2021. "Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma" International Journal of Molecular Sciences 22, no. 7: 3302. https://doi.org/10.3390/ijms22073302