The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches
Abstract
:1. Introduction
2. Myeloma-Promoting Immunological Changes of the BM Microenvironment Contribute to MGUS-to-MM Progression
3. Progressive Impairment of Effector Immune Functions in MGUS and MM Patients
4. Evidence of Myeloma-Specific T Cell Responses in MGUS and MM Patients
5. Therapeutic Strategies to Restore Specific T Cell Immunosurveillance against MM
6. Perspectives and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Van de Donk, N.W.C.J.; Pawlyn, C.; Yong, K.L. Multiple Myeloma. Lancet 2021, 397, 410–427. [Google Scholar] [CrossRef]
- Kazandjian, D.; Landgren, O. A Look Backward and Forward in the Regulatory and Treatment History of Multiple Myeloma: Approval of Novel-Novel Agents, New Drug Development, and Longer Patient Survival. Semin. Oncol. 2016, 43, 682–689. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Raju, G.K.; Gurumurthi, K.; Domike, R.; Kazandjian, D.; Landgren, O.; Blumenthal, G.M.; Farrell, A.; Pazdur, R.; Woodcock, J. A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma. Clin. Pharm. 2018, 103, 67–76. [Google Scholar] [CrossRef] [PubMed]
- Moreau, P.; Kumar, S.K.; San Miguel, J.; Davies, F.; Zamagni, E.; Bahlis, N.; Ludwig, H.; Mikhael, J.; Terpos, E.; Schjesvold, F.; et al. Treatment of Relapsed and Refractory Multiple Myeloma: Recommendations from the International Myeloma Working Group. Lancet Oncol. 2021, 22, e105–e118. [Google Scholar] [CrossRef]
- Dimopoulos, M.A.; Moreau, P.; Terpos, E.; Mateos, M.V.; Zweegman, S.; Cook, G.; Delforge, M.; Hájek, R.; Schjesvold, F.; Cavo, M.; et al. Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann. Oncol. 2021, 32, 309–322. [Google Scholar] [CrossRef]
- Cowan, A.J.; Green, D.J.; Kwok, M.; Lee, S.; Coffey, D.G.; Holmberg, L.A.; Tuazon, S.; Gopal, A.K.; Libby, E.N. Diagnosis and Management of Multiple Myeloma: A Review. JAMA 2022, 327, 464–477. [Google Scholar] [CrossRef]
- Perrot, A. How I Treat Frontline Transplant-Eligible Multiple Myeloma. Blood 2021. [Google Scholar] [CrossRef]
- Zamagni, E.; Barbato, S.; Cavo, M. How I Treat High-Risk Multiple Myeloma. Blood 2021. [Google Scholar] [CrossRef]
- Manier, S.; Ingegnere, T.; Escure, G.; Prodhomme, C.; Nudel, M.; Mitra, S.; Facon, T. Current State and Next-Generation CAR-T Cells in Multiple Myeloma. Blood Rev. 2022, 100929. [Google Scholar] [CrossRef]
- Terpos, E.; Zamagni, E.; Lentzsch, S.; Drake, M.T.; García-Sanz, R.; Abildgaard, N.; Ntanasis-Stathopoulos, I.; Schjesvold, F.; Rubia, J.; de la Kyriakou, C.; et al. Treatment of Multiple Myeloma-Related Bone Disease: Recommendations from the Bone Working Group of the International Myeloma Working Group. Lancet Oncol. 2021, 22, e119–e130. [Google Scholar] [CrossRef]
- Mouhieddine, T.H.; Weeks, L.D.; Ghobrial, I.M. Monoclonal Gammopathy of Undetermined Significance. Blood 2019, 133, 2484–2494. [Google Scholar] [CrossRef] [PubMed]
- Rajkumar, S.V.; Landgren, O.; Mateos, M.V. Smoldering Multiple Myeloma. Blood 2015, 125, 3069–3075. [Google Scholar] [CrossRef] [PubMed]
- Musto, P.; Engelhardt, M.; Caers, J.; Bolli, N.; Kaiser, M.; Donk, N.; van de Terpos, E.; Broijl, A.; de Larrea, C.F.; Gay, F.; et al. 2021 European Myeloma Network Review and Consensus Statement on Smoldering Multiple Myeloma: How to Distinguish (and Manage) Dr. Jekyll and Mr. Hyde. Haematologica 2021, 106, 2799–2812. [Google Scholar] [CrossRef] [PubMed]
- van Nieuwenhuijzen, N.; Spaan, I.; Raymakers, R.; Peperzak, V. From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells. Cancer Res. 2018, 78, 2449–2456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dutta, A.K.; Fink, J.L.; Grady, J.P.; Morgan, G.J.; Mullighan, C.G.; To, L.B.; Hewett, D.R.; Zannettino, A.C.W. Subclonal Evolution in Disease Progression from MGUS/SMM to Multiple Myeloma Is Characterised by Clonal Stability. Leukemia 2019, 33, 457–468. [Google Scholar] [CrossRef]
- Bolli, N.; Maura, F.; Minvielle, S.; Gloznik, D.; Szalat, R.; Fullam, A.; Martincorena, I.; Dawson, K.J.; Samur, M.K.; Zamora, J.; et al. Genomic Patterns of Progression in Smoldering Multiple Myeloma. Nat. Commun. 2018, 9, 3363. [Google Scholar] [CrossRef]
- Zhao, S.; Choi, M.; Heuck, C.; Mane, S.; Barlogie, B.; Lifton, R.P.; Dhodapkar, M.V. Serial Exome Analysis of Disease Progression in Premalignant Gammopathies. Leukemia 2014, 28, 1548–1552. [Google Scholar] [CrossRef]
- Ho, M.; Goh, C.Y.; Patel, A.; Staunton, S.; O’Connor, R.; Godeau, M.; Bianchi, G. Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance. Clin. Lymphoma Myeloma Leuk. 2020, 20, e752–e768. [Google Scholar] [CrossRef]
- Xu, S.; De Veirman, K.; De Becker, A.; Vanderkerken, K.; Van Riet, I. Mesenchymal Stem Cells in Multiple Myeloma: A Therapeutical Tool or Target? Leukemia 2018, 32, 1500–1514. [Google Scholar] [CrossRef]
- Terpos, E.; Ntanasis-Stathopoulos, I.; Gavriatopoulou, M.; Dimopoulos, M.A. Pathogenesis of Bone Disease in Multiple Myeloma: From Bench to Bedside. Blood Cancer J. 2018, 8, 7. [Google Scholar] [CrossRef] [Green Version]
- Favaloro, J.; Brown, R.; Aklilu, E.; Yang, S.; Suen, H.; Hart, D.; Fromm, P.; Gibson, J.; Khoo, L.; Ho, P.J.; et al. Myeloma Skews Regulatory T and Pro-Inflammatory T Helper 17 Cell Balance in Favor of a Suppressive State. Leuk. Lymphoma 2014, 55, 1090–1098. [Google Scholar] [CrossRef] [PubMed]
- Prabhala, R.H.; Pelluru, D.; Fulciniti, M.; Prabhala, H.K.; Nanjappa, P.; Song, W.; Pai, C.; Amin, S.; Tai, Y.T.; Richardson, P.G.; et al. Elevated IL-17 Produced by TH17 Cells Promotes Myeloma Cell Growth and Inhibits Immune Function in Multiple Myeloma. Blood 2010, 115, 5385–5392. [Google Scholar] [CrossRef] [PubMed]
- Noonan, K.; Marchionni, L.; Anderson, J.; Pardoll, D.; Roodman, G.D.; Borrello, I. A Novel Role of IL-17-Producing Lymphocytes in Mediating Lytic Bone Disease in Multiple Myeloma. Blood 2010, 116, 3554–3563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells. Nat. Immunol. 2003, 4, 330–336. [Google Scholar] [CrossRef] [PubMed]
- Lad, D.; Huang, Q.; Hoeppli, R.; Garcia, R.; Xu, L.; Levings, M.; Song, K.; Broady, R. Evaluating the Role of Tregs in the Progression of Multiple Myeloma. Leuk. Lymphoma 2019, 60, 2134–2142. [Google Scholar] [CrossRef] [PubMed]
- Muthu Raja, K.R.; Rihova, L.; Zahradova, L.; Klincova, M.; Penka, M.; Hajek, R. Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma. PLoS ONE 2012, 7, e47077. [Google Scholar] [CrossRef] [PubMed]
- Giannopoulos, K.; Kaminska, W.; Hus, I.; Dmoszynska, A. The Frequency of T Regulatory Cells Modulates the Survival of Multiple Myeloma Patients: Detailed Characterisation of Immune Status in Multiple Myeloma. Br. J. Cancer 2012, 106, 546–552. [Google Scholar] [CrossRef]
- Bryant, C.; Suen, H.; Brown, R.; Yang, S.; Favaloro, J.; Aklilu, E.; Gibson, J.; Ho, P.J.; Iland, H.; Fromm, P.; et al. Long-Term Survival in Multiple Myeloma Is Associated with a Distinct Immunological Profile, Which Includes Proliferative Cytotoxic T-Cell Clones and a Favourable Treg/Th17 Balance. Blood Cancer J. 2013, 3, e148. [Google Scholar] [CrossRef]
- Berardi, S.; Ria, R.; Reale, A.; De Luisi, A.; Catacchio, I.; Moschetta, M.; Vacca, A. Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment. J. Oncol. 2013, 2013, 183602. [Google Scholar] [CrossRef] [Green Version]
- Scavelli, C.; Nico, B.; Cirulli, T.; Ria, R.; Di Pietro, G.; Mangieri, D.; Bacigalupo, A.; Mangialardi, G.; Coluccia, A.M.L.; Caravita, T.; et al. Vasculogenic Mimicry by Bone Marrow Macrophages in Patients with Multiple Myeloma. Oncogene 2008, 27, 663–674. [Google Scholar] [CrossRef]
- 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] [PubMed]
- Nasillo, V.; Riva, G.; Paolini, A.; Forghieri, F.; Roncati, L.; Lusenti, B.; Maccaferri, M.; Messerotti, A.; Pioli, V.; Gilioli, A.; et al. Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies. Int. J. Mol. Sci. 2021, 22, 1906. [Google Scholar] [CrossRef] [PubMed]
- Görgün, G.T.; Whitehill, G.; Anderson, J.L.; Hideshima, T.; Maguire, C.; Laubach, J.; Raje, N.; Munshi, N.C.; Richardson, P.G.; Anderson, K.C. Tumor-Promoting Immune-Suppressive Myeloid-Derived Suppressor Cells in the Multiple Myeloma Microenvironment in Humans. Blood 2013, 121, 2975–2987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, B.; Pan, P.-Y.; Li, Q.; Sato, A.I.; Levy, D.E.; Bromberg, J.; Divino, C.M. Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host—PubMed. Cancer Res. 2006, 66, 1123–1131. [Google Scholar] [CrossRef] [Green Version]
- Brown, R.D.; Pope, B.; Murray, A.; Esdale, W.; Sze, D.M.; Gibson, J.; Ho, P.J.; Hart, D.; Joshua, D. Dendritic Cells from Patients with Myeloma Are Numerically Normal but Functionally Defective as They Fail to Up-Regulate CD80 (B7-1) Expression after HuCD40LT Stimulation Because of Inhibition by Transforming Growth Factor-Beta1 and Interleukin-10. Blood 2001, 98, 2992–2998. [Google Scholar] [CrossRef] [Green Version]
- Chauhan, D.; Singh, A.V.; Brahmandam, M.; Carrasco, R.; Bandi, M.; Hideshima, T.; Bianchi, G.; Podar, K.; Tai, Y.-T.; Mitsiades, C.; et al. Functional Interaction of Plasmacytoid Dendritic Cells with Multiple Myeloma Cells: A Novel Therapeutic Target. Cancer Cell 2009, 16, 309–323. [Google Scholar] [CrossRef] [Green Version]
- Leone, P.; Berardi, S.; Frassanito, M.A.; Ria, R.; De Re, V.; Cicco, S.; Battaglia, S.; Ditonno, P.; Dammacco, F.; Vacca, A.; et al. Dendritic Cells Accumulate in the Bone Marrow of Myeloma Patients Where They Protect Tumor Plasma Cells from CD8+ T-Cell Killing. Blood 2015, 126, 1443–1451. [Google Scholar] [CrossRef] [Green Version]
- Banerjee, D.K.; Dhodapkar, M.V.; Matayeva, E.; Steinman, R.M.; Dhodapkar, K.M. Expansion of FOXP3high Regulatory T Cells by Human Dendritic Cells (DCs) in Vitro and after Injection of Cytokine-Matured DCs in Myeloma Patients. Blood 2006, 108, 2655–2661. [Google Scholar] [CrossRef] [Green Version]
- Dhodapkar, K.M.; Barbuto, S.; Matthews, P.; Kukreja, A.; Mazumder, A.; Vesole, D.; Jagannath, S.; Dhodapkar, M.V. Dendritic Cells Mediate the Induction of Polyfunctional Human IL17-Producing Cells (Th17-1 Cells) Enriched in the Bone Marrow of Patients with Myeloma. Blood 2008, 112, 2878–2885. [Google Scholar] [CrossRef]
- Ray, A.; Das, D.S.; Song, Y.; Richardson, P.; Munshi, N.C.; Chauhan, D.; Anderson, K.C. Targeting PD1–PDL1 Immune Checkpoint in Plasmacytoid Dendritic Cell Interactions with T Cells, Natural Killer Cells and Multiple Myeloma Cells. Leukemia 2015, 29, 1441–1444. [Google Scholar] [CrossRef] [Green Version]
- Joshua, D.; Suen, H.; Brown, R.; Bryant, C.; Ho, P.J.; Hart, D.; Gibson, J. The T Cell in Myeloma. Clin. Lymphoma Myeloma Leuk. 2016, 16, 537–542. [Google Scholar] [CrossRef] [PubMed]
- Cook, G.; Campbell, J.D.; Carr, C.E.; Boyd, K.S.; Franklin, I.M. Transforming Growth Factor Beta from Multiple Myeloma Cells Inhibits Proliferation and IL-2 Responsiveness in T Lymphocytes. J. Leukoc Biol. 1999, 66, 981–988. [Google Scholar] [CrossRef] [PubMed]
- Mozaffari, F.; Hansson, L.; Kiaii, S.; Ju, X.; Rossmann, E.D.; Rabbani, H.; Mellstedt, H.; Osterborg, A. Signalling Molecules and Cytokine Production in T Cells of Multiple Myeloma-Increased Abnormalities with Advancing Stage. Br. J. Haematol. 2004, 124, 315–324. [Google Scholar] [CrossRef] [PubMed]
- Bailur, J.K.; McCachren, S.S.; Doxie, D.B.; Shrestha, M.; Pendleton, K.; Nooka, A.K.; Neparidze, N.; Parker, T.L.; Bar, N.; Kaufman, J.L.; et al. Early Alterations in Stem-like/Marrow-Resident T Cells and Innate and Myeloid Cells in Preneoplastic Gammopathy. JCI Insight 2019, 4, e127807. [Google Scholar] [CrossRef] [PubMed]
- Zelle-Rieser, C.; Thangavadivel, S.; Biedermann, R.; Brunner, A.; Stoitzner, P.; Willenbacher, E.; Greil, R.; Jöhrer, K. T Cells in Multiple Myeloma Display Features of Exhaustion and Senescence at the Tumor Site. J. Hematol. Oncol. 2016, 9, 116. [Google Scholar] [CrossRef] [Green Version]
- Suen, H.; Brown, R.; Yang, S.; Weatherburn, C.; Ho, P.J.; Woodland, N.; Nassif, N.; Barbaro, P.; Bryant, C.; Hart, D.; et al. Multiple Myeloma Causes Clonal T-Cell Immunosenescence: Identification of Potential Novel Targets for Promoting Tumour Immunity and Implications for Checkpoint Blockade. Leukemia 2016, 30, 1716–1724. [Google Scholar] [CrossRef]
- Tamura, H.; Ishibashi, M.; Sunakawa-Kii, M.; Inokuchi, K. PD-L1-PD-1 Pathway in the Pathophysiology of Multiple Myeloma. Cancers 2020, 12, 924. [Google Scholar] [CrossRef]
- Jelinek, T.; Paiva, B.; Hajek, R. Update on PD-1/PD-L1 Inhibitors in Multiple Myeloma. Front. Immunol. 2018, 9, 2431. [Google Scholar] [CrossRef] [Green Version]
- Usmani, S.Z.; Schjesvold, F.; Oriol, A.; Karlin, L.; Cavo, M.; Rifkin, R.M.; Yimer, H.A.; LeBlanc, R.; Takezako, N.; McCroskey, R.D.; et al. Pembrolizumab plus Lenalidomide and Dexamethasone for Patients with Treatment-Naive Multiple Myeloma (KEYNOTE-185): A Randomised, Open-Label, Phase 3 Trial. Lancet Haematol. 2019, 6, e448–e458. [Google Scholar] [CrossRef]
- Mateos, M.V.; Blacklock, H.; Schjesvold, F.; Oriol, A.; Simpson, D.; George, A.; Goldschmidt, H.; Larocca, A.; Chanan-Khan, A.; Sherbenou, D.; et al. Pembrolizumab plus Pomalidomide and Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma (KEYNOTE-183): A Randomised, Open-Label, Phase 3 Trial. Lancet Haematol. 2019, 6, e459–e469. [Google Scholar] [CrossRef]
- Guillerey, C.; Harjunpää, H.; Carrié, N.; Kassem, S.; Teo, T.; Miles, K.; Krumeich, S.; Weulersse, M.; Cuisinier, M.; Stannard, K.; et al. TIGIT Immune Checkpoint Blockade Restores CD8+ T-Cell Immunity against Multiple Myeloma. Blood 2018, 132, 1689–1694. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Minnie, S.A.; Kuns, R.D.; Gartlan, K.H.; Zhang, P.; Wilkinson, A.N.; Samson, L.; Guillerey, C.; Engwerda, C.; MacDonald, K.P.A.; Smyth, M.J.; et al. Myeloma Escape after Stem Cell Transplantation Is a Consequence of T-Cell Exhaustion and Is Prevented by TIGIT Blockade. Blood 2018, 132, 1675–1688. [Google Scholar] [CrossRef] [PubMed]
- Sze, D.M.; Giesajtis, G.; Brown, R.D.; Raitakari, M.; Gibson, J.; Ho, J.; Baxter, A.G.; de St Groth, B.F.; Basten, A.; Joshua, D.E. Clonal Cytotoxic T Cells Are Expanded in Myeloma and Reside in the CD8(+)CD57(+)CD28(−) Compartment. Blood 2011, 98, 2817–2827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vuckovic, S.; Bryant, C.E.; Lau, K.H.A.; Yang, S.; Favaloro, J.; McGuire, H.M.; Clark, G.; de St Groth, B.F.; Marsh-Wakefield, F.; Nassif, N.; et al. Inverse Relationship between Oligoclonal Expanded CD69− TTE and CD69+ TTE Cells in Bone Marrow of Multiple Myeloma Patients. Blood Adv. 2020, 4, 4593–4604. [Google Scholar] [CrossRef] [PubMed]
- Brown, R.D.; Spencer, A.; Ho, P.J.; Kennedy, N.; Kabani, K.; Yang, S.; Sze, D.M.; Aklilu, E.; Gibson, J.; Joshua, D.E. Prognostically Significant Cytotoxic T Cell Clones Are Stimulated after Thalidomide Therapy in Patients with Multiple Myeloma. Leuk. Lymphoma 2009, 50, 1860–1864. [Google Scholar] [CrossRef]
- Dhodapkar, M.V.; Dhodapkar, K.M. Tissue-Resident Memory-like T Cells in Tumor Immunity: Clinical Implications. Semin. Immunol. 2020, 49, 101415. [Google Scholar] [CrossRef]
- Kumar, B.V.; Ma, W.; Miron, M.; Granot, T.; Guyer, R.S.; Carpenter, D.J.; Senda, T.; Sun, X.; Ho, S.-H.; Lerner, H.; et al. Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites. Cell Rep. 2017, 20, 2921–2934. [Google Scholar] [CrossRef] [Green Version]
- Godfrey, J.; Benson, D.M. The Role of Natural Killer Cells in Immunity against Multiple Myeloma. Leuk. Lymphoma 2012, 53, 1666–1676. [Google Scholar] [CrossRef]
- Weng, J.; Neelapu, S.S.; Woo, A.F.; Kwak, L.W. Identification of Human Idiotype-Specific T Cells in Lymphoma and Myeloma. In Cancer Immunology and Immunotherapy; Dranoff, G., Ed.; Current Topics in Microbiology and Immunology; Springer: Berlin/Heidelberg, Germany, 2011; pp. 193–210. ISBN 978-3-642-14136-2. [Google Scholar]
- Bogen, B.; Ruffini, P.A.; Corthay, A.; Fredriksen, A.B.; Frøyland, M.; Lundin, K.; Røsjø, E.; Thompson, K.; Massaia, M. Idiotype-Specific Immunotherapy in Multiple Myeloma: Suggestions for Future Directions of Research. Haematologica 2006, 91, 941–948. [Google Scholar]
- Wen, Y.-J.; Barlogie, B.; Yi, Q. Idiotype-Specific Cytotoxic T Lymphocytes in Multiple Myeloma: Evidence for Their Capacity to Lyse Autologous Primary Tumor Cells. Blood 2001, 97, 1750–1755. [Google Scholar] [CrossRef] [Green Version]
- Zhang, L.; Götz, M.; Hofmann, S.; Greiner, J. Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma. Clin. Dev. Immunol. 2012, 2012, 820394. [Google Scholar] [CrossRef] [PubMed]
- Dhodapkar, M.V.; Krasovsky, J.; Olson, K. T Cells from the Tumor Microenvironment of Patients with Progressive Myeloma Can Generate Strong, Tumor-Specific Cytolytic Responses to Autologous, Tumor-Loaded Dendritic Cells. Proc. Natl. Acad. Sci. USA 2002, 99, 13009–13013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dhodapkar, M.V.; Krasovsky, J.; Osman, K.; Geller, M.D. Vigorous Premalignancy-Specific Effector T Cell Response in Bone Marrow of Patients with Monoclonal Gammopathy. J. Exp. Med. 2003, 198, 1753–1757. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spisek, R.; Kukreja, A.; Chen, L.-C.; Matthews, P.; Mazumder, A.; Vesole, D.; Jagannath, S.; Zebroski, H.A.; Simpson, A.J.G.; Ritter, G.; et al. Frequent and Specific Immunity to the Embryonal Stem Cell-Associated Antigen SOX2 in Patients with Monoclonal Gammopathy. J. Exp. Med. 2007, 204, 831–840. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Goodyear, O.C.; Pratt, G.; McLarnon, A.; Cook, M.; Piper, K.; Moss, P. Differential Pattern of CD4+ and CD8+ T-Cell Immunity to MAGE-A1/A2/A3 in Patients with MGUS and Multiple Myeloma. Blood 2008, 112, 3362–3372. [Google Scholar] [CrossRef]
- Racanelli, V.; Leone, P.; Frassanito, M.A.; Brunetti, C.; Perosa, F.; Ferrone, S.; Dammacco, F. Alterations in the Antigen Processing-Presenting Machinery of Transformed Plasma Cells Are Associated with Reduced Recognition by CD8+ T Cells and Characterize the Progression of MGUS to Multiple Myeloma. Blood 2010, 115, 1185–1193. [Google Scholar] [CrossRef] [Green Version]
- Dhodapkar, M.V.; Sexton, R.; Das, R. Prospective Analysis of Antigen-Specific Immunity, Stem-Cell Antigens, and Immune Checkpoints in Monoclonal Gammopathy. Blood 2015, 126, 2475–2478. [Google Scholar] [CrossRef] [Green Version]
- van Rhee, F.; Szmania, S.M.; Zhan, F.; Gupta, S.K.; Pomtree, M.; Lin, P.; Batchu, R.B.; Moreno, A.; Spagnoli, G.; Shaughnessy, J.; et al. NY-ESO-1 Is Highly Expressed in Poor-Prognosis Multiple Myeloma and Induces Spontaneous Humoral and Cellular Immune Responses. Blood 2005, 105, 3939–3944. [Google Scholar] [CrossRef]
- Tyler, E.M.; Jungbluth, A.A.; O’Reilly, R.J.; Koehne, G. WT1-Specific T-Cell Responses in High-Risk Multiple Myeloma Patients Undergoing Allogeneic T Cell-Depleted Hematopoietic Stem Cell Transplantation and Donor Lymphocyte Infusions. Blood 2013, 121, 308–317. [Google Scholar] [CrossRef] [Green Version]
- Cohen, A.D.; Lendvai, N.; Nataraj, S.; Imai, N.; Jungbluth, A.A.; Tsakos, I.; Rahman, A.; Mei, A.H.-C.; Singh, H.; Zarychta, K.; et al. Autologous Lymphocyte Infusion Supports Tumor Antigen Vaccine-Induced Immunity in Autologous Stem Cell Transplant for Multiple Myeloma. Cancer Immunol. Res. 2019, 7, 658–669. [Google Scholar] [CrossRef]
- Christensen, O.; Lupu, A.; Schmidt, S.; Condomines, M.; Belle, S.; Maier, A.; Hose, D.; Neuber, B.; Moos, M.; Kleist, C.; et al. Melan-A/MART1 Analog Peptide Triggers Anti-Myeloma T-Cells through Crossreactivity with HM1.24. J. Immunother. 2009, 32, 613–621. [Google Scholar] [CrossRef] [PubMed]
- Greiner, J.; Schmitt, A.; Giannopoulos, K.; Rojewski, M.T.; Götz, M.; Funk, I.; Ringhoffer, M.; Bunjes, D.; Hofmann, S.; Ritter, G.; et al. High-Dose RHAMM-R3 Peptide Vaccination for Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome and Multiple Myeloma. Haematologica 2010, 95, 1191–1197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schmitt, M.; Schmitt, A.; Rojewski, M.T.; Chen, J.; Giannopoulos, K.; Fei, F.; Yu, Y.; Götz, M.; Heyduk, M.; Ritter, G.; et al. RHAMM-R3 Peptide Vaccination in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Multiple Myeloma Elicits Immunologic and Clinical Responses. Blood 2008, 111, 1357–1365. [Google Scholar] [CrossRef] [PubMed]
- Ocadlikova, D.; Kryukov, F.; Mollova, K.; Kovarova, L.; Buresdova, I.; Matejkova, E.; Penka, M.; Buchler, T.; Hajek, R.; Michalek, J. Generation of Myeloma-Specific T Cells Using Dendritic Cells Loaded with MUC1- and HTERT- Drived Nonapeptides or Myeloma Cell Apoptotic Bodies. Neoplasma 2010, 57, 455–464. [Google Scholar] [CrossRef] [PubMed]
- Qian, J.; Xie, J.; Hong, S.; Yang, J.; Zhang, L.; Han, X.; Wang, M.; Zhan, F.; Shaughnessy, J.D.; Epstein, J.; et al. Dickkopf-1 (DKK1) Is a Widely Expressed and Potent Tumor-Associated Antigen in Multiple Myeloma. Blood 2007, 110, 1587–1594. [Google Scholar] [CrossRef]
- Bae, J.; Smith, R.; Daley, J.; Mimura, N.; Tai, Y.T.; Anderson, K.C.; Munshi, N.C. Myeloma-Specific Multiple Peptides Able to Generate Cytotoxic T Lymphocytes: A Potential Therapeutic Application in Multiple Myeloma and Other Plasma Cell Disorders. Clin. Cancer Res. 2012, 18, 4850–4860. [Google Scholar] [CrossRef] [Green Version]
- Bae, J.; Hideshima, T.; Zhang, G.L.; Zhou, J.; Keskin, D.B.; Munshi, N.C.; Anderson, K.C. Identification and Characterization of HLA-A24 Specific XBP1, CD138 (Syndecan-1), and CS1 (SLAMF7) Peptides Inducing Antigens-Specific Memory Cytotoxic T Lymphocytes Targeting Multiple Myeloma. Leukemia 2018, 32, 752–764. [Google Scholar] [CrossRef] [Green Version]
- Bae, J.; Prabhala, R.; Voskertchian, A.; Brown, A.; Maguire, C.; Richardson, P.; Dranoff, G.; Anderson, K.C.; Munshi, N.C. A Multiepitope of XBP1, CD138 and CS1 Peptides Induces Myeloma-Specific Cytotoxic T Lymphocytes in T Cells of Smoldering Myeloma Patients. Leukemia 2015, 29, 218–229. [Google Scholar] [CrossRef] [Green Version]
- Perumal, D.; Imai, N.; Laganà, A.; Finnigan, J.; Melnekoff, D.; Leshchenko, V.V.; Solovyov, A.; Madduri, D.; Chari, A.; Cho, H.J.; et al. Mutation-Derived Neoantigen-Specific T-Cell Responses in Multiple Myeloma. Clin. Cancer Res. 2020, 26, 450–464. [Google Scholar] [CrossRef] [Green Version]
- Tura, S.; Cavo, M. Allogeneic Bone Marrow Transplantation in Multiple Myeloma. Hematol. Oncol. Clin. N. Am. 1992, 6, 425–435. [Google Scholar] [CrossRef] [Green Version]
- Gahrton, G.; Iacobelli, S.; Björkstrand, B.; Hegenbart, U.; Gruber, A.; Greinix, H.; Volin, L.; Narni, F.; Carella, A.M.; Beksac, M.; et al. Autologous/Reduced-Intensity Allogeneic Stem Cell Transplantation vs Autologous Transplantation in Multiple Myeloma: Long-Term Results of the EBMT-NMAM2000 Study. Blood 2013, 121, 5055–5063. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sahebi, F.; Iacobelli, S.; Biezen, A.V.; Volin, L.; Dreger, P.; Michallet, M.; Ljungman, P.T.; de Witte, T.; Henseler, A.; Schaap, N.P.M.; et al. Comparison of Upfront Tandem Autologous-Allogeneic Transplantation versus Reduced Intensity Allogeneic Transplantation for Multiple Myeloma. Bone Marrow Transpl. 2015, 50, 802–807. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Auner, H.W.; Szydlo, R.; van Biezen, A.; Iacobelli, S.; Gahrton, G.; Milpied, N.; Volin, L.; Janssen, J.; Nguyen Quoc, S.; Michallet, M.; et al. Reduced Intensity-Conditioned Allogeneic Stem Cell Transplantation for Multiple Myeloma Relapsing or Progressing after Autologous Transplantation: A Study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transpl. 2013, 48, 1395–1400. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Porrata, L.F. Autologous Graft-versus-Tumor Effect: Reality or Fiction? Adv. Hematol. 2016, 2016, 5385972. [Google Scholar] [CrossRef] [Green Version]
- Schmidmaier, R.; Oversohl, N.; Schnabel, B.; Straka, C.; Emmerich, B. Helper T Cells (CD3+/CD4+) within the Autologous Peripheral Blood Stem Cell Graft Positively Correlate with Event Free Survival of Multiple Myeloma Patients. Exp. Oncol. 2008, 30, 240–243. [Google Scholar]
- Vuckovic, S.; Minnie, S.A.; Smith, D.; Gartlan, K.H.; Watkins, T.S.; Markey, K.A.; Mukhopadhyay, P.; Guillerey, C.; Kuns, R.D.; Locke, K.R.; et al. Bone Marrow Transplantation Generates T Cell-Dependent Control of Myeloma in Mice. J. Clin. Investig. 2019, 129, 106–121. [Google Scholar] [CrossRef] [Green Version]
- Bae, J.; Samur, M.; Richardson, P.; Munshi, N.C.; Anderson, K.C. Selective Targeting of Multiple Myeloma by B Cell Maturation Antigen (BCMA)-Specific Central Memory CD8+ Cytotoxic T Lymphocytes: Immunotherapeutic Application in Vaccination and Adoptive Immunotherapy. Leukemia 2019, 33, 2208–2226. [Google Scholar] [CrossRef]
- Quach, H.; Stewart, A.K.; Neeson, P.; Harrison, S.; Smyth, M.J.; Prince, H.M. Mechanism of Action of Immunomodulatory Drugs (IMiDS) in Multiple Myeloma. Leukemia 2010, 24, 22–32. [Google Scholar] [CrossRef] [Green Version]
- Krönke, J.; Udeshi, N.D.; Narla, A.; Grauman, P.; Hurst, S.N.; McConkey, M.; Svinkina, T.; Heckl, D.; Comer, E.; Li, X.; et al. Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells. Science 2014, 343, 301–305. [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. The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science 2014, 343, 305–309. [Google Scholar] [CrossRef] [Green Version]
- Luptakova, K.; Rosenblatt, J.; Glotzbecker, B.; Mills, H.; Stroopinsky, D.; Kufe, T.; Vasir, B.; Arnason, J.; Tzachanis, D.; Zwicker, J.I.; et al. Lenalidomide Enhances Anti-Myeloma Cellular Immunity. Cancer Immunol. Immunother. 2013, 62, 39–49. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Henry, J.Y.; Labarthe, M.-C.; Meyer, B.; Dasgupta, P.; Dalgleish, A.G.; Galustian, C. Enhanced Cross-Priming of Naive CD8+ T Cells by Dendritic Cells Treated by the IMiDs® Immunomodulatory Compounds Lenalidomide and Pomalidomide. Immunology 2013, 139, 377–385. [Google Scholar] [CrossRef]
- Dimopoulos, M.A.; Oriol, A.; Nahi, H.; San-Miguel, J.; Bahlis, N.J.; Usmani, S.Z.; Rabin, N.; Orlowski, R.Z.; Komarnicki, M.; Suzuki, K.; et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 1319–1331. [Google Scholar] [CrossRef] [Green Version]
- Dimopoulos, M.A.; San-Miguel, J.; Belch, A.; White, D.; Benboubker, L.; Cook, G.; Leiba, M.; Morton, J.; Ho, P.J.; Kim, K.; et al. Daratumumab plus Lenalidomide and Dexamethasone versus Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Updated Analysis of POLLUX. Haematologica 2018, 103, 2088–2096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Attal, M.; Richardson, P.G.; Rajkumar, S.V.; San-Miguel, J.; Beksac, M.; Spicka, I.; Leleu, X.; Schjesvold, F.; Moreau, P.; Dimopoulos, M.A.; et al. Isatuximab plus Pomalidomide and Low-Dose Dexamethasone versus Pomalidomide and Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma (ICARIA-MM): A Randomised, Multicentre, Open-Label, Phase 3 Study. Lancet 2019, 394, 2096–2107. [Google Scholar] [CrossRef]
- Paiva, B.; Mateos, M.V.; Sanchez-Abarca, L.I.; Puig, N.; Vidriales, M.B.; López Corral, L.; Corchete, R.A.; Hernandez, M.T.; Bargay, J.; de Arriba, F.; et al. Immune Status of High-Risk Smoldering Multiple Myeloma Patients and Its Therapeutic Modulation under LenDex: A Longitudinal Analysis. Blood 2016, 127, 1151–1162. [Google Scholar] [CrossRef] [Green Version]
- Mateos, M.V.; Hernandez, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; López Corral, L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma. N. Engl. J. Med. 2013, 369, 438–447. [Google Scholar] [CrossRef] [Green Version]
- Mateos, M.V.; Hernandez, M.T.; Giraldo, P.; de la Rubia, J.; de Arriba, F.; Corral, L.L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Lenalidomide plus Dexamethasone versus Observation in Patients with High-Risk Smouldering Multiple Myeloma (QuiRedex): Long-Term Follow-up of a Randomised, Controlled, Phase 3 Trial. Lancet Oncol. 2016, 17, 1127–1136. [Google Scholar] [CrossRef]
- Mateos, M.V.; Hernandez, M.T.; Salvador, C.; de la Rubia, J.; de Arriba, F.; López Corral, L.; Rosiñol, L.; Paiva, B.; Palomera, L.; Bargay, J.; et al. Over Ten Years Of F/U For Phase 3 Trial In Smoldering Myeloma At High Risk Of Progression To Myeloma: Sustained Ttp And Os Benefit With Rd Versus No Treatment. In Proceedings of the 25th EHA Congress, European Hematology Association, Virtual, The Hague, The Netherlands, 11–21 June 2020. e-Poster. [Google Scholar]
- 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]
- Badros, A.; Hyjek, E.; Ma, N.; Lesokhin, A.M.; Dogan, A.; Rapoport, A.P.; Kocoglu, M.; Lederer, E.; Philip, S.; Milliron, T.; et al. Pembrolizumab, Pomalidomide, and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma. Blood 2017, 130, 1189–1197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guillerey, C.; de Andrade, L.F.; Vuckovic, S.; Miles, K.; Ngiow, S.F.; Yong, M.C.R.; Teng, M.W.L.; Colonna, M.; Ritchie, D.S.; Chesi, M.; et al. Immunosurveillance and Therapy of Multiple Myeloma Are CD226 Dependent. J. Clin. Investig. 2015, 125, 2077–2089. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- D’Souza, A.; Hari, P.; Pasquini, M.; Braun, T.; Johnson, B.; Lundy, S.; Couriel, D.; Hamadani, M.; Magenau, J.; Dhakal, B.; et al. A Phase 2 Study of Pembrolizumab during Lymphodepletion after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma. Biol. Blood Marrow Transpl. 2019, 25, 1492–1497. [Google Scholar] [CrossRef] [PubMed]
- Harjunpää, H.; Guillerey, C. TIGIT as an Emerging Immune Checkpoint. Clin. Exp. Immunol. 2020, 200, 108–119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cencini, E.; Fabbri, A.; Sicuranza, A.; Gozzetti, A.; Bocchia, M. The Role of Tumor-Associated Macrophages in Hematologic Malignancies. Cancers 2021, 13, 3597. [Google Scholar] [CrossRef] [PubMed]
- Sun, J.; Park, C.; Guenthner, N.; Gurley, S.; Zhang, L.; Lubben, B.; Adebayo, O.; Bash, H.; Chen, Y.; Maksimos, M.; et al. Tumor-Associated Macrophages in Multiple Myeloma: Advances in Biology and Therapy. J. Immunother. Cancer 2022, 10, e003975. [Google Scholar] [CrossRef]
- Gutiérrez-González, A.; Martínez-Moreno, M.; Samaniego, R.; Arellano-Sánchez, N.; Salinas-Muñoz, L.; Relloso, M.; Valeri, A.; Martínez-López, J.; Corbí, Á.L.; Hidalgo, A.; et al. Evaluation of the Potential Therapeutic Benefits of Macrophage Reprogramming in Multiple Myeloma. Blood 2016, 128, 2241–2252. [Google Scholar] [CrossRef] [Green Version]
- Khalife, J.; Ghose, J.; Martella, M.; Viola, D.; Rocci, A.; Troadec, E.; Terrazas, C.; Satoskar, A.R.; Gunes, E.G.; Dona, A.; et al. MiR-16 Regulates Crosstalk in NF-ΚB Tolerogenic Inflammatory Signaling between Myeloma Cells and Bone Marrow Macrophages. JCI Insight 2019, 4, 129348. [Google Scholar] [CrossRef]
- Andersen, M.N.; Andersen, N.F.; Lauridsen, K.L.; Etzerodt, A.; Sorensen, B.S.; Abildgaard, N.; Plesner, T.; Hokland, M.; Møller, H.J. STAT3 Is Over-Activated within CD163pos Bone Marrow Macrophages in Both Multiple Myeloma and the Benign Pre-Condition MGUS. Cancer Immunol. Immunother. 2022, 71, 177–187. [Google Scholar] [CrossRef]
- Wudhikarn, K.; Wills, B.; Lesokhin, A.M. Monoclonal Antibodies in Multiple Myeloma: Current and Emerging Targets and Mechanisms of Action. Best Pr. Res. Clin. Haematol. 2020, 33, 101143. [Google Scholar] [CrossRef]
- Laubach, J.P.; Paba Prada, C.E.; Richardson, P.G.; Longo, D.I. Daratumumab, Elotuzumab, and the Development of Therapeutic Monoclonal Antibodies in Multiple Myeloma. Clin. Pharmacol. Ther. 2017, 101, 81–88. [Google Scholar] [CrossRef] [PubMed]
- Krejcik, J.; Casneuf, T.; Nijhof, I.S.; Verbist, B.; Bald, J.; Plesner, T.; Syed, K.; Liu, K.; van de Donk, N.W.C.J.; Weiss, B.M.; et al. Daratumumab Depletes CD38+ Immune Regulatory Cells, Promotes T-Cell Expansion, and Skews T-Cell Repertoire in Multiple Myeloma. Blood 2016, 128, 384–394. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lokhorst, H.M.; Plesner, T.; Laubach, J.P.; Nahi, H.; Gimsing, P.; Hansson, M.; Minnema, M.C.; Lassen, U.; Krejcik, J.; Palumbo, A.; et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N. Engl. J. Med. 2015, 373, 1207–1219. [Google Scholar] [CrossRef] [PubMed]
- Lonial, S.; Weiss, B.M.; Usmani, S.Z.; Singhal, S.; Chari, A.; Bahlis, N.J.; Belch, A.; Krishnan, A.; Vescio, R.A.; Mateos, M.V.; et al. Daratumumab Monotherapy in Patients with Treatment-Refractory Multiple Myeloma (SIRIUS): An Open-Label, Randomised, Phase 2 Trial. Lancet 2016, 387, 1551–1560. [Google Scholar] [CrossRef]
- Usmani, S.Z.; Weiss, B.M.; Plesner, T.; Bahlis, N.J.; Belch, A.; Lonial, S.; Lokhorst, H.M.; Voorhees, P.M.; Richardson, P.G.; Chari, A.; et al. Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. Blood 2016, 128, 37–44. [Google Scholar] [CrossRef]
- Palumbo, A.; Chanan-Khan, A.; Weisel, K.; AK, N.; Masszi, T.; Beksac, M.; Spicka, I.; Hungria, V.; Munder, M.; Mateos, M.V.; et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 754–766. [Google Scholar] [CrossRef]
- Facon, T.; Kumar, S.; Plesner, T.; Orlowski, R.Z.; Moreau, P.; Bahlis, N.; Basu, S.; Nahi, H.; Hulin, C.; Quach, H.; et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N. Engl. J. Med. 2019, 380, 2104–2115. [Google Scholar] [CrossRef]
- Moreau, P.; Attal, M.; Hulin, C.; Arnulf, B.; Belhadj, K.; Benboubker, L.; Béné, M.C.; Broijl, A.; Caillon, H.; Caillot, D.; et al. Bortezomib, Thalidomide, and Dexamethasone with or without Daratumumab before and after Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma (CASSIOPEIA): A Randomised, Open-Label, Phase 3 Study. Lancet 2019, 394, 29–38. [Google Scholar] [CrossRef]
- Malaer, J.D.; Mathew, P.A. CS1 (SLAMF7, CD319) Is an Effective Immunotherapeutic Target for Multiple Myeloma. Am. J. Cancer Res. 2017, 7, 1637–1641. [Google Scholar]
- Lonial, S.; Dimopoulos, M.; Palumbo, A.; White, D.; Grosicki, S.; Spicka, I.; Walter-Croneck, A.; Moreau, P.; Mateos, M.-V.; Magen, H.; et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2015, 373, 621–631. [Google Scholar] [CrossRef] [Green Version]
- Dimopoulos, M.A.; Lonial, S.; Betts, K.A.; Chen, C.; Zichlin, M.L.; Brun, A.; Signorovitch, J.E.; Makenbaeva, D.; Mekan, S.; Sy, O.; et al. Elotuzumab plus Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Extended 4-Year Follow-up and Analysis of Relative Progression-Free Survival from the Randomized ELOQUENT-2 Trial. Cancer 2018, 124, 4032–4043. [Google Scholar] [CrossRef] [PubMed]
- Dimopoulos, M.A.; Lonial, S.; White, D.; Moreau, P.; Weisel, K.; San-Miguel, J.; Shpilberg, O.; Grosicki, S.; Špička, I.; Walter-Croneck, A.; et al. Elotuzumab, Lenalidomide, and Dexamethasone in RRMM: Final Overall Survival Results from the Phase 3 Randomized ELOQUENT-2 Study. Blood Cancer J. 2020, 10, 91. [Google Scholar] [CrossRef] [PubMed]
- Yu, B.; Liu, D. Antibody-Drug Conjugates in Clinical Trials for Lymphoid Malignancies and Multiple Myeloma. J. Hematol. Oncol. 2019, 12, 94. [Google Scholar] [CrossRef] [PubMed]
- Richardson, P.G.; Lee, H.C.; Abdallah, O.-A.; Cohen, A.D.; Kapoor, P.; Voorhees, P.M.; Hoos, A.; Wang, K.; Baron, J.; Piontek, T.; et al. Single-Agent Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma: Analysis of the Lyophilised Presentation Cohort from the Pivotal DREAMM-2 Study. Blood Cancer J. 2020, 10, 106. [Google Scholar] [CrossRef]
- Tzogani, K.; Penttilä, K.; Lähteenvuo, J.; Lapveteläinen, T.; Lopez Anglada, L.; Prieto, C.; Garcia-Ochoa, B.; Enzmann, H.; Gisselbrecht, C.; Delgado, J.; et al. EMA Review of Belantamab Mafodotin (Blenrep) for the Treatment of Adult Patients with Relapsed/Refractory Multiple Myeloma. Oncologist 2021, 26, 70–76. [Google Scholar] [CrossRef]
- Shah, Z.; Malik, M.N.; Batool, S.S.; Kotapati, S.; Akhtar, A.; Rehman, O.; ur Ghani, M.O.; Sadiq, M.; Akbar, A.; Ashraf, A.; et al. Bispecific T-Cell Engager (BiTE) Antibody Based Immunotherapy for Treatment of Relapsed Refractory Multiple Myeloma (RRMM): A Systematic Review of Preclinical and Clinical Trials. Blood 2019, 134, 5567. [Google Scholar] [CrossRef]
- Baeuerle, P.A.; Reinhardt, C. Bispecific T-Cell Engaging Antibodies for Cancer Therapy. Cancer Res. 2009, 69, 4941–4944. [Google Scholar] [CrossRef] [Green Version]
- Frankel, S.R.; Baeuerle, P.A. Targeting T Cells to Tumor Cells Using Bispecific Antibodies. Curr. Opin. Chem. Biol. 2013, 17, 385–392. [Google Scholar] [CrossRef]
- Caraccio, C.; Krishna, S.; Phillips, D.J.; Schürch, C.M. Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions. Front. Immunol. 2020, 11, 501. [Google Scholar] [CrossRef]
- Topp, M.S.; Duell, J.; Zugmaier, G.; Attal, M.; Moreau, P.; Langer, C.; Krönke, J.; Facon, T.; Salnikov, A.V.; Lesley, R.; et al. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J. Clin. Oncol. 2020, 38, 775–783. [Google Scholar] [CrossRef]
- Raje, N.S.; Jakubowiak, A.; Gasparetto, C.; Cornell, R.F.; HI, K.; Navarro, D.; Forgie, A.J.; Udata, C.; Basu, C.; Chou, J.; et al. Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2019, 134, 1869. [Google Scholar] [CrossRef]
- Zhang, X.; Yang, Y.; Fan, D.; Xiong, D. The Development of Bispecific Antibodies and Their Applications in Tumor Immune Escape. Exp. Hematol. Oncol. 2017, 6, 12. [Google Scholar] [CrossRef] [PubMed]
- Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef] [PubMed]
- Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef] [PubMed]
- Dotti, G.; Gottschalk, S.; Savoldo, B.; Brenner, M.K. Design and Development of Therapies Using Chimeric Antigen Receptor-Expressing T Cells. Immunol. Rev. 2014, 257, 107–126. [Google Scholar] [CrossRef]
- Sidana, S.; Shah, N. CAR T-Cell Therapy: Is It Prime Time in Myeloma? Blood Adv. 2019, 3, 3473–3480. [Google Scholar] [CrossRef] [PubMed]
- Brudno, J.N.; Maric, I.; Hartman, S.D.; Rose, J.J.; Wang, M.; Lam, N.; Stetler-Stevenson, M.; Salem, D.; Yuan, C.; Pavletic, S.; et al. T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J. Clin. Oncol. 2018, 36, 2267–2280. [Google Scholar] [CrossRef]
- Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A.; et al. Anti-BCMA CAR T-Cell Therapy Bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef]
- Cohen, A.D.; Garfall, A.L.; Stadtmauer, E.A.; Melenhorst, J.J.; Lacey, S.F.; Lancaster, E.; Vogl, D.T.; Weiss, B.M.; Dengel, K.; Nelson, A.; et al. B Cell Maturation Antigen-Specific CAR T Cells Are Clinically Active in Multiple Myeloma. J. Clin. Investig. 2019, 129, 2210–2221. [Google Scholar] [CrossRef] [Green Version]
- Sun, C.; Mahendravada, A.; Ballard, B.; Kale, B.; Ramos, C.; West, J.; Maguire, T.; McKay, K.; Lichtman, E.; Tuchman, S.; et al. Safety and Efficacy of Targeting CD138 with a Chimeric Antigen Receptor for the Treatment of Multiple Myeloma. Oncotarget 2019, 10, 2369–2383. [Google Scholar] [CrossRef] [Green Version]
- Gogishvili, T.; Danhof, S.; Prommersberger, S.; Rydzek, J.; Schreder, M.; Brede, C.; Einsele, H.; Hudecek, M. SLAMF7-CAR T Cells Eliminate Myeloma and Confer Selective Fratricide of SLAMF7+ Normal Lymphocytes. Blood 2017, 130, 2838–2847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Smith, E.L.; Harrington, K.; Staehr, M.; Masakayan, R.; Jones, J.; Long, T.J.; Ng, K.Y.; Ghoddusi, M.; Purdon, T.J.; Wang, X.; et al. GPRC5D Is a Target for the Immunotherapy of Multiple Myeloma with Rationally Designed CAR T Cells. Sci. Transl. Med. 2019, 11, eaau7746. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.W.; Santomasso, B.D.; Locke, F.L.; Ghobadi, A.; Turtle, C.J.; Brudno, J.N.; Maus, M.V.; Park, J.H.; Mead, E.; Pavletic, S.; et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. 2019, 25, 625–638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shah, N.; Alsina, M.; Siegel, D.S.; Jagannath, S.; Madduri, D.; Kaufman, J.L.; Turka, A.; Lam, L.P.; Massaro, M.; Hege, K.; et al. Initial Results from a Phase 1 Clinical Study of Bb21217, a Next-Generation Anti Bcma CAR T Therapy. Blood 2018, 132, 488. [Google Scholar] [CrossRef]
- Mailankody, S.; Htut, M.; Lee, K.P.; Bensinger, W.; Devries, T.; Piasecki, J.; Ziyad, S.; Blake, M.; Byon, J.; Jakubowiak, A. JCARH125, Anti-BCMA CAR T-Cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE). Blood 2018, 132, 957. [Google Scholar] [CrossRef]
- Green, D.J.; Pont, M.; Sather, B.D.; Cowan, A.J.; Turtle, C.J.; Till, B.G.; Nagengast, A.M.; Libby, E.N.; Becker, P.S.; Coffey, D.G.; et al. Fully Human Bcma Targeted Chimeric Antigen Receptor T Cells Administered in a Defined Composition Demonstrate Potency at Low Doses in Advanced Stage High Risk Multiple Myeloma. Blood 2018, 132, 1011. [Google Scholar] [CrossRef]
- Sommer, C.; Boldajipour, B.; Kuo, T.C.; Bentley, T.; Sutton, J.; Chen, A.; Geng, T.; Dong, H.; Galetto, R.; Valton, J.; et al. Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma. Mol. Ther. 2019, 27, 1126–1138. [Google Scholar] [CrossRef]
- Mathur, R.; Zhang, Z.; He, J.; Galetto, R.; Gouble, A.; Chion-Sotinel, I.; Filipe, S.; Gariboldi, A.; Veeramachaneni, T.; Manasanch, E.E.; et al. Universal SLAMF7-Specific CAR T-Cells As Treatment for Multiple Myeloma. Blood 2017, 130, 502. [Google Scholar] [CrossRef]
- Dhakal, B.; Chhabra, S.; Savani, B.N.; Hamadani, M. Promise and Pitfalls of Allogeneic Chimeric Antigen Receptor Therapy in Plasma Cell and Lymphoid Malignancies. Br. J. Haematol. 2022, 197, 28–40. [Google Scholar] [CrossRef]
- Gagelmann, N.; Riecken, K.; Wolschke, C.; Berger, C.; Ayuk, F.A.; Fehse, B.; Kröger, N. Development of CAR-T Cell Therapies for Multiple Myeloma. Leukemia 2020, 34, 2317–2332. [Google Scholar] [CrossRef]
- Teoh, P.J.; Chng, W.J. CAR T-Cell Therapy in Multiple Myeloma: More Room for Improvement. Blood Cancer J. 2021, 11, 84. [Google Scholar] [CrossRef] [PubMed]
- Ebrahimiyan, H.; Tamimi, A.; Shokoohian, B.; Minaei, N.; Memarnejadian, A.; Hossein-Khannazer, N.; Hassan, M.; Vosough, M. Novel Insights in CAR-NK Cells beyond CAR-T Cell Technology; Promising Advantages. Int. Immunopharmacol. 2022, 106, 108587. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Wang, G.; Chai, D.; Dang, Y.; Zheng, J.; Li, H. INKT: A New Avenue for CAR-Based Cancer Immunotherapy. Transl. Oncol. 2022, 17, 101342. [Google Scholar] [CrossRef] [PubMed]
- Poels, R.; Drent, E.; Lameris, R.; Katsarou, A.; Themeli, M.; van der Vliet, H.J.; de Gruijl, T.D.; van de Donk, N.W.C.J.; Mutis, T. Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma. Int. J. Mol. Sci. 2021, 22, 1096. [Google Scholar] [CrossRef]
- Bae, J.; Parayath, N.; Ma, W.; Amiji, M.; Munshi, N.; Anderson, K.C. BCMA Peptide-Engineered Nanoparticles Enhance Induction and Function of Antigen-Specific CD8+ Cytotoxic T Lymphocytes against Multiple Myeloma: Clinical Applications. Leukemia 2020, 34, 210–223. [Google Scholar] [CrossRef]
- Noonan, K.A.; Huff, C.; Davis, J.; Lemas, M.V.; Fiorino, S.; Bitzan, J.; Ferguson, A.; Emerling, A.; Luznik, L.; Matsui, W.; et al. Adoptive Transfer of Activated Marrow-Infiltrating Lymphocytes Induces Measurable Antitumor Immunity in the Bone Marrow in Multiple Myeloma. Sci. Transl. Med. 2015, 7, 288ra78. [Google Scholar] [CrossRef] [Green Version]
- Riva, G.; Nasillo, V.; Ottomano, A.M.; Bergonzini, G.; Paolini, A.; Forghieri, F.; Lusenti, B.; Barozzi, P.; Lagreca, I.; Fiorcari, S.; et al. Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges. Cancers 2021, 13, 4582. [Google Scholar] [CrossRef]
References | Target Antigens | Disease Setting (Total Patients) | Sample Source | Immunoassays | Main Results |
---|---|---|---|---|---|
Spontaneous T Cell Responses | |||||
Dhodapkar et al., 2003 [64] | Whole tumor/preneoplastic cells | MM (12) MGUS (6) | PB, BM | ELISPOT, ICS | T cell responses to autologous premalignant plasma cells were detected in the BM of patients with MGUS, while tumor-specific T cell effector functions were absent in the BM of MM patients. |
Van Rhee et al., 2005 [69] | NY-ESO-1 | MM (3) | PB | ICS, Tetramer analysis, 51Cr-release-assay | Spontaneous NY-ESO-1-specific T cells were found in PB of MM patients, and were able to kill primary MM cells. |
Spisek et al., 2007 [65] | SOX-2 | MM (14) SMM (21) MGUS (16) | PB | Luminex, ICS | Spontaneous T cell responses against SOX2 were detected in MGUS patients, but not in MM patients. |
Goodyear et al., 2008 [66] | MAGE-A1/A2/A3 | MM (53 + 32) MGUS (25 + 30) | PB | IFN-γ CSA, 51Cr release assay | CD4+ T cell immunity to MAGE proteins was stronger and more frequent in MGUS, compared with MM. |
Tyler et al., 2013 [70] | WT-1 | MM (24) | PB, BM | ICS, Tetramer analyses | WT1-specific CTLs incremented after allogeneic T cell-depleted SCT + DLI and elicited a graft-versus-myeloma effect. |
Dhodapkar et al., 2015 [68] | SOX-2 | SMM (155) MGUS (132) | PB | Luminex | Anti-SOX2 T cells were detected in PB from MGUS and SMM patients, and correlated with reduced risk of progression to symptomatic MM. |
Cohen et al., 2019 [71] | MAGE-A3 | MM (13) | PB | ELISPOT, ICS | Autologous lymphocyte infusion associated with MAGE-A3 vaccination elicited antigen-specific T cell immunity in autologous SCT patients. |
Perumal et al., 2020 [80] | Mutation-derived neoantigens | MM (184) | PB | ICS, CFSE-based cytotoxicity assay | Shared neoantigens were detected across MM patients and were able to induce specific T cell activation associated with in vitro antitumor activity and clinical responses. |
Ex vivo Generated T-Cell Responses | |||||
Dhodapkar et al., 2002 [63] | Whole tumor cells | MM (7) | PB, BM | ELISPOT, 51Cr release assay | In vitro stimulation with DCs loaded with autologous tumor cells generated tumor-specific cytolytic T cell responses. |
Qian et al., 2007 [76] | DKK1 | MM (n.a.) | PB | Proliferation assay, 51Cr-release-assay, ELISPOT | DKK1-specific CTLs were generated from PB of MM patients and efficiently lysed DKK1-expressing cells, including primary myeloma cells. |
Christensen et al. 2009 [72] | Melan-A/MART-1 | MM (n.a.) | PB | ELISPOT, 51Cr-release-assay | Ex vivo expanded Melan-A-specific T cells were able to lyse autologous MM cells. |
Greiner et al., 2010 [73]; Schmitt et al., 2008 [74] | RHAMM | MM (7) | PB | ELISA, ELISPOT, Tetramer analysis, 51Cr-release-assay | Peptide vaccination with RHAMM-derived peptide R3 induced specific CD8+ effector T cells and positive clinical effects. |
Racanelli et al., 2010 [67] | Plasma cell lysates, NY-ESO-1 | MM (20) MGUS (20) | BM | 51Cr-release-assay | In vitro expanded antitumor CD8+ T cells in the BM of MM patients showed a reduced cytotoxic potential, compared with MGUS patients. |
Ocadlikova et al., 2010 [75] | hTERT, MUC-1 | Healthy subjects (n.a.) | PB | CSA; flowcytometric cytotoxicity test | DCs loaded with hTERT- and MUC1-derived peptides were able to generate specific CTLs with anti-myeloma cytotoxic activity. |
Bae et al., 2015 [79] | XBP-1, CD138, CS1 (SLAMF7) | SMM (8) | PB | Proliferation assay, ICS, CD107a degranulation | Multipeptide-specific CTLs were generated from SMM patients’ T cells and showed effective anti-MM responses. |
Bae et al., 2019 [88] | BCMA | Healthy subjects (n.a.) | PB | Proliferation assay, ICS, CD107a degranulation | BCMA-derived peptides were able to induce specific CTLs, showing polifunctional Th1-specific immune activities against MM. |
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Lagreca, I.; Riva, G.; Nasillo, V.; Barozzi, P.; Castelli, I.; Basso, S.; Bettelli, F.; Giusti, D.; Cuoghi, A.; Bresciani, P.; et al. The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches. Int. J. Mol. Sci. 2022, 23, 5242. https://doi.org/10.3390/ijms23095242
Lagreca I, Riva G, Nasillo V, Barozzi P, Castelli I, Basso S, Bettelli F, Giusti D, Cuoghi A, Bresciani P, et al. The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches. International Journal of Molecular Sciences. 2022; 23(9):5242. https://doi.org/10.3390/ijms23095242
Chicago/Turabian StyleLagreca, Ivana, Giovanni Riva, Vincenzo Nasillo, Patrizia Barozzi, Ilaria Castelli, Sabrina Basso, Francesca Bettelli, Davide Giusti, Angela Cuoghi, Paola Bresciani, and et al. 2022. "The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches" International Journal of Molecular Sciences 23, no. 9: 5242. https://doi.org/10.3390/ijms23095242