The Road Ahead in Pancreatic Cancer: Emerging Trends and Therapeutic Prospects
Abstract
:1. Introduction
2. Tumor Microenvironment of PDAC
3. Role of the Extracellular Matrix and Stiffness in Tumor Invasion
4. Targeting the Desmoplastic Barrier in PDAC
5. Neutralizing Immunosuppressive Cells
6. Overcoming Metabolic Barriers
7. Blocking Immune Checkpoints
8. Potential Novel Approaches to PDAC Immunotherapy
8.1. Enhancing Antigen Presentation
8.2. Cancer Vaccines
8.3. Neoantigen-Based mRNA Vaccines
8.4. Neoantigen-Based Peptide Vaccines
8.5. Neoantigen-Based DNA Vaccines
8.6. Re-Engineered Pancreatic Cancer Cells as a Vaccine Modality
8.7. Combination of Epigenetic Drugs with Immune Checkpoint Inhibitors
9. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Annual Cancer Facts & Figures|American Cancer Society. Available online: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures.html (accessed on 1 July 2024).
- Marstrand-Daucé, L.; Lorenzo, D.; Chassac, A.; Nicole, P.; Couvelard, A.; Haumaitre, C. Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer. Int. J. Mol. Sci. 2023, 24, 9946. [Google Scholar] [CrossRef]
- Saiki, Y.; Jiang, C.; Ohmuraya, M.; Furukawa, T. Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models. Cancers 2021, 14, 71. [Google Scholar] [CrossRef] [PubMed]
- Tonini, V.; Zanni, M. Pancreatic cancer in 2021: What you need to know to win. World J. Gastroenterol. 2021, 27, 5851–5889. [Google Scholar] [CrossRef]
- Principe, D.R.; Underwood, P.W.; Korc, M.; Trevino, J.G.; Munshi, H.G.; Rana, A. The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy. Front. Oncol. 2021, 11, 688377. [Google Scholar] [CrossRef] [PubMed]
- Freelove, R.; Walling, A.D. Pancreatic cancer: Diagnosis and management. Am. Fam. Physician 2006, 73, 485–492. [Google Scholar] [PubMed]
- Truong, L.-H.; Pauklin, S. Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches. Cancers 2021, 13, 5028. [Google Scholar] [CrossRef] [PubMed]
- Survival Rates for Pancreatic Cancer|American Cancer Society. Available online: https://www.cancer.org/cancer/types/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html (accessed on 15 August 2024).
- Nakaoka, K.; Ohno, E.; Kawabe, N.; Kuzuya, T.; Funasaka, K.; Nakagawa, Y.; Nagasaka, M.; Ishikawa, T.; Watanabe, A.; Tochio, T.; et al. Current Status of the Diagnosis of Early-Stage Pancreatic Ductal Adenocarcinoma. Diagnostics 2023, 13, 215. [Google Scholar] [CrossRef]
- Zhang, Y.; Yang, J.; Li, H.; Wu, Y.; Zhang, H.; Chen, W. Tumor markers CA19-9, CA242 and CEA in the diagnosis of pancreatic cancer: A meta-analysis. Int. J. Clin. Exp. Med. 2015, 8, 11683–11691. [Google Scholar] [PubMed]
- Hosein, A.N.; Brekken, R.A.; Maitra, A. Pancreatic cancer stroma: An update on therapeutic targeting strategies. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 487–505. [Google Scholar] [CrossRef]
- Bowers, J.S.; Bailey, S.R.; Rubinstein, M.P.; Paulos, C.M.; Camp, E.R. Genomics meets immunity in pancreatic cancer: Current research and future directions for pancreatic adenocarcinoma immunotherapy. Oncol. Rev. 2019, 13, 430. [Google Scholar] [CrossRef]
- Daniel, S.K.; Sullivan, K.M.; Labadie, K.P.; Pillarisetty, V.G. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin. Transl. Med. 2019, 8, e10. [Google Scholar] [CrossRef]
- Gautam, S.K.; Batra, S.K.; Jain, M. Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma. Mol. Cancer 2023, 22, 118. [Google Scholar] [CrossRef]
- Fan, J.; Wang, M.-F.; Chen, H.-L.; Shang, D.; Das, J.K.; Song, J. Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma. Mol. Cancer 2020, 19, 32. [Google Scholar] [CrossRef]
- Murakami, T.; Hiroshima, Y.; Matsuyama, R.; Homma, Y.; Hoffman, R.M.; Endo, I. Role of the tumor microenvironment in pancreatic cancer. Ann. Gastroent Surg. 2019, 3, 130–137. [Google Scholar] [CrossRef] [PubMed]
- Ren, B.; Cui, M.; Yang, G.; Wang, H.; Feng, M.; You, L.; Zhao, Y. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol. Cancer 2018, 17, 108. [Google Scholar] [CrossRef] [PubMed]
- Huber, M.; Brehm, C.U.; Gress, T.M.; Buchholz, M.; Alashkar Alhamwe, B.; Von Strandmann, E.; Slater, E.P.; Bartsch, J.W.; Bauer, C.; Lauth, M. The Immune Microenvironment in Pancreatic Cancer. Int. J. Mol. Sci. 2020, 21, 7307. [Google Scholar] [CrossRef] [PubMed]
- Pascual-García, M.; Bonfill-Teixidor, E.; Planas-Rigol, E.; Rubio-Perez, C.; Iurlaro, R.; Arias, A.; Cuartas, I.; Sala-Hojman, A.; Escudero, L.; Martínez-Ricarte, F.; et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nat. Commun. 2019, 10, 2416. [Google Scholar] [CrossRef] [PubMed]
- Akbani, R.; Akdemir, K.C.; Aksoy, B.A.; Albert, M.; Ally, A.; Amin, S.B.; Arachchi, H.; Arora, A.; Auman, J.T.; Ayala, B.; et al. Genomic Classification of Cutaneous Melanoma. Cell 2015, 161, 1681–1696. [Google Scholar] [CrossRef]
- Łuksza, M.; Sethna, Z.M.; Rojas, L.A.; Lihm, J.; Bravi, B.; Elhanati, Y.; Soares, K.; Amisaki, M.; Dobrin, A.; Hoyos, D.; et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature 2022, 606, 389–395. [Google Scholar] [CrossRef]
- Australian Pancreatic Cancer Genome Initiative; Balachandran, V.P.; Łuksza, M.; Zhao, J.N.; Makarov, V.; Moral, J.A.; Remark, R.; Herbst, B.; Askan, G.; Bhanot, U.; et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 2017, 551, 512–516. [Google Scholar] [CrossRef]
- Feng, M.; Xiong, G.; Cao, Z.; Yang, G.; Zheng, S.; Song, X.; You, L.; Zheng, L.; Zhang, T.; Zhao, Y. PD-1/PD-L1 and immunotherapy for pancreatic cancer. Cancer Lett. 2017, 407, 57–65. [Google Scholar] [CrossRef] [PubMed]
- Zou, W.; Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 2008, 8, 467–477. [Google Scholar] [CrossRef]
- Tao, J.; Yang, G.; Zhou, W.; Qiu, J.; Chen, G.; Luo, W.; Zhao, F.; You, L.; Zheng, L.; Zhang, T.; et al. Targeting hypoxic tumor microenvironment in pancreatic cancer. J. Hematol. Oncol. 2021, 14, 14. [Google Scholar] [CrossRef]
- Hu, Q.; Qin, Y.; Ji, S.; Xu, W.; Liu, W.; Sun, Q.; Zhang, Z.; Liu, M.; Ni, Q.; Yu, X.; et al. UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer. Cancer Lett. 2019, 452, 226–236. [Google Scholar] [CrossRef]
- Erkan, M.; Hausmann, S.; Michalski, C.W.; Fingerle, A.A.; Dobritz, M.; Kleeff, J.; Friess, H. The role of stroma in pancreatic cancer: Diagnostic and therapeutic implications. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 454–467. [Google Scholar] [CrossRef]
- Yamamoto, K.; Venida, A.; Yano, J.; Biancur, D.E.; Kakiuchi, M.; Gupta, S.; Sohn, A.S.W.; Mukhopadhyay, S.; Lin, E.Y.; Parker, S.J.; et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 2020, 581, 100–105. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, K.; Venida, A.; Perera, R.M.; Kimmelman, A.C. Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer. Autophagy 2020, 16, 1524–1525. [Google Scholar] [CrossRef]
- York, I.A.; Rock, K.L. Antigen processing and presentation by the class I major histocompatibility complex. Annu. Rev. Immunol. 1996, 14, 369–396. [Google Scholar] [CrossRef] [PubMed]
- Pu, N.; Gao, S.; Yin, H.; Li, J.; Wu, W.; Fang, Y.; Zhang, L.; Rong, Y.; Xu, X.; Wang, D.; et al. Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway. Cancer Lett. 2019, 460, 42–53. [Google Scholar] [CrossRef]
- Hessmann, E.; Buchholz, S.M.; Demir, I.E.; Singh, S.K.; Gress, T.M.; Ellenrieder, V.; Neesse, A. Microenvironmental Determinants of Pancreatic Cancer. Physiol. Rev. 2020, 100, 1707–1751. [Google Scholar] [CrossRef]
- Wang, D.; Li, Y.; Ge, H.; Ghadban, T.; Reeh, M.; Güngör, C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers 2022, 14, 3998. [Google Scholar] [CrossRef] [PubMed]
- Kai, F.; Drain, A.P.; Weaver, V.M. The Extracellular Matrix Modulates the Metastatic Journey. Dev. Cell 2019, 49, 332–346. [Google Scholar] [CrossRef]
- Zanconato, F.; Forcato, M.; Battilana, G.; Azzolin, L.; Quaranta, E.; Bodega, B.; Rosato, A.; Bicciato, S.; Cordenonsi, M.; Piccolo, S. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 2015, 17, 1218–1227. [Google Scholar] [CrossRef]
- Di Agostino, S.; Sorrentino, G.; Ingallina, E.; Valenti, F.; Ferraiuolo, M.; Bicciato, S.; Piazza, S.; Strano, S.; Del Sal, G.; Blandino, G. YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins. EMBO Rep. 2016, 17, 188–201. [Google Scholar] [CrossRef] [PubMed]
- Tsukita, S.; Furuse, M. The Structure and Function of Claudins, Cell Adhesion Molecules at Tight Junctions. Ann. N. Y. Acad. Sci. 2000, 915, 129–135. [Google Scholar] [CrossRef]
- Tsukita, S.; Tanaka, H.; Tamura, A. The Claudins: From Tight Junctions to Biological Systems. Trends Biochem. Sci. 2019, 44, 141–152. [Google Scholar] [CrossRef] [PubMed]
- Otani, T.; Furuse, M. Tight Junction Structure and Function Revisited. Trends Cell Biol. 2020, 30, 805–817. [Google Scholar] [CrossRef]
- Hewitt, K.J.; Agarwal, R.; Morin, P.J. The claudin gene family: Expression in normal and neoplastic tissues. BMC Cancer 2006, 6, 186. [Google Scholar] [CrossRef]
- Sahin, U.; Koslowski, M.; Dhaene, K.; Usener, D.; Brandenburg, G.; Seitz, G.; Huber, C.; Türeci, Ö. Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development. Clin. Cancer Res. 2008, 14, 7624–7634. [Google Scholar] [CrossRef]
- Cao, W.; Xing, H.; Li, Y.; Tian, W.; Song, Y.; Jiang, Z.; Yu, J. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark. Res. 2022, 10, 38. [Google Scholar] [CrossRef]
- Bähr-Mahmud, H.; Ellinghaus, U.; Stadler, C.R.; Fischer, L.; Lindemann, C.; Chaturvedi, A.; Diekmann, J.; Wöll, S.; Biermann, I.; Hebich, B.; et al. Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody. OncoImmunology 2023, 12, 2255041. [Google Scholar] [CrossRef] [PubMed]
- Papadopoulos, K.P.; Tehfe, M.; Abdul Razak, A.R.; Pant, S.; Chung, V.; Rasco, D.W.; Jamal, R.; Willis, J.; Fuentes Antrás, J.; Brettschneider, K.; et al. A phase I/II dose escalation and expansion trial to evaluate safety and preliminary efficacy of BNT141 in patients with claudin-18.2-positive solid tumors. J. Clin. Oncol. 2023, 41, TPS2670. [Google Scholar] [CrossRef]
- Shitara, K.; Lordick, F.; Bang, Y.-J.; Enzinger, P.; Ilson, D.; Shah, M.A.; Van Cutsem, E.; Xu, R.-H.; Aprile, G.; Xu, J.; et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): A multicentre, randomised, double-blind, phase 3 trial. Lancet 2023, 401, 1655–1668. [Google Scholar] [CrossRef] [PubMed]
- Diebold, S.S.; Kaisho, T.; Hemmi, H.; Akira, S.; Reis E Sousa, C. Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA. Science 2004, 303, 1529–1531. [Google Scholar] [CrossRef]
- Zhang, Z.; Ohto, U.; Shibata, T.; Krayukhina, E.; Taoka, M.; Yamauchi, Y.; Tanji, H.; Isobe, T.; Uchiyama, S.; Miyake, K.; et al. Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA. Immunity 2016, 45, 737–748. [Google Scholar] [CrossRef]
- Landskron, G.; De La Fuente, M.; Thuwajit, P.; Thuwajit, C.; Hermoso, M.A. Chronic Inflammation and Cytokines in the Tumor Microenvironment. J. Immunol. Res. 2014, 2014, 149185. [Google Scholar] [CrossRef]
- Gastl, G.A.; Abrams, J.S.; Nanus, D.M.; Oosterkamp, R.; Silver, J.; Liu, F.; Chen, M.; Albino, A.P.; Bander, N.H. Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression. Int. J. Cancer 1993, 55, 96–101. [Google Scholar] [CrossRef]
- Inamoto, R.; Takahashi, N.; Yamada, Y. Claudin18.2 in Advanced Gastric Cancer. Cancers 2023, 15, 5742. [Google Scholar] [CrossRef]
- Byrne, W.L.; Mills, K.H.G.; Lederer, J.A.; O’Sullivan, G.C. Targeting Regulatory T Cells in Cancer. Cancer Res. 2011, 71, 6915–6920. [Google Scholar] [CrossRef]
- Fleming, V.; Hu, X.; Weber, R.; Nagibin, V.; Groth, C.; Altevogt, P.; Utikal, J.; Umansky, V. Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression. Front. Immunol. 2018, 9, 398. [Google Scholar] [CrossRef]
- Ohue, Y.; Nishikawa, H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019, 110, 2080–2089. [Google Scholar] [CrossRef]
- Jang, J.-E.; Hajdu, C.H.; Liot, C.; Miller, G.; Dustin, M.L.; Bar-Sagi, D. Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer. Cell Rep. 2017, 20, 558–571. [Google Scholar] [CrossRef]
- Stromnes, I.M.; Brockenbrough, J.S.; Izeradjene, K.; Carlson, M.A.; Cuevas, C.; Simmons, R.M.; Greenberg, P.D.; Hingorani, S.R. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 2014, 63, 1769–1781. [Google Scholar] [CrossRef] [PubMed]
- Trovato, R.; Fiore, A.; Sartori, S.; Canè, S.; Giugno, R.; Cascione, L.; Paiella, S.; Salvia, R.; De Sanctis, F.; Poffe, O.; et al. Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3. J. Immunother. Cancer 2019, 7, 255. [Google Scholar] [CrossRef] [PubMed]
- Eriksson, E.; Wenthe, J.; Irenaeus, S.; Loskog, A.; Ullenhag, G. Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J. Transl. Med. 2016, 14, 282. [Google Scholar] [CrossRef] [PubMed]
- Shi, Y.; Gao, W.; Lytle, N.K.; Huang, P.; Yuan, X.; Dann, A.M.; Ridinger-Saison, M.; DelGiorno, K.E.; Antal, C.E.; Liang, G.; et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 2019, 569, 131–135. [Google Scholar] [CrossRef]
- Peng, F.; Zhou, J.; Sheng, W.; Zhang, D.; Dong, M. Expression and significance of leukemia inhibitory factor in human pancreatic cancer. Zhonghua Yi Xue Za Zhi 2014, 94, 90–95. [Google Scholar]
- Wang, D.; Liu, K.; Yang, Y.; Wang, T.; Rao, Q.; Guo, W.; Zhang, Z. Prognostic value of leukemia inhibitory factor and its receptor in pancreatic adenocarcinoma. Future Oncol. 2020, 16, 4461–4473. [Google Scholar] [CrossRef]
- Borazanci, E.; Schram, A.M.; Garralda, E.; Brana, I.; Vieito Villar, M.; Spreafico, A.; Oliva, M.; Lakhani, N.J.; Hoffman, K.; Hallett, R.M.; et al. Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors. ESMO Open 2022, 7, 100530. [Google Scholar] [CrossRef]
- Williams, R.L.; Hilton, D.J.; Pease, S.; Willson, T.A.; Stewart, C.L.; Gearing, D.P.; Wagner, E.F.; Metcalf, D.; Nicola, N.A.; Gough, N.M. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 1988, 336, 684–687. [Google Scholar] [CrossRef]
- Halbrook, C.J.; Pasca Di Magliano, M.; Lyssiotis, C.A. Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 2018, 315, G27–G35. [Google Scholar] [CrossRef]
- Saka, D.; Gökalp, M.; Piyade, B.; Cevik, N.C.; Arik Sever, E.; Unutmaz, D.; Ceyhan, G.O.; Demir, I.E.; Asimgil, H. Mechanisms of T-Cell Exhaustion in Pancreatic Cancer. Cancers 2020, 12, 2274. [Google Scholar] [CrossRef] [PubMed]
- Marcon, F.; Zuo, J.; Pearce, H.; Nicol, S.; Margielewska-Davies, S.; Farhat, M.; Mahon, B.; Middleton, G.; Brown, R.; Roberts, K.J.; et al. NK cells in pancreatic cancer demonstrate impaired cytotoxicity and a regulatory IL-10 phenotype. OncoImmunology 2020, 9, 1845424. [Google Scholar] [CrossRef] [PubMed]
- Yang, R.; Elsaadi, S.; Misund, K.; Abdollahi, P.; Vandsemb, E.N.; Moen, S.H.; Kusnierczyk, A.; Slupphaug, G.; Standal, T.; Waage, A.; et al. Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade. J. Immunother. Cancer 2020, 8, e000610. [Google Scholar] [CrossRef]
- Zahavi, D.; Hodge, J. Targeting Immunosuppressive Adenosine Signaling: A Review of Potential Immunotherapy Combination Strategies. Int. J. Mol. Sci. 2023, 24, 8871. [Google Scholar] [CrossRef]
- Kang, C. Retifanlimab: First Approval. Drugs 2023, 83, 731–737. [Google Scholar] [CrossRef]
- Wang, H.; Alexandra, A.; Hansbury, M.; Mason, J.; Harris, J.; Stevens, C.; Maddage, C.; Ren, X.; Gao, M.; Kurzeja-Lipinski, K.; et al. Abstract LB157: Discovery and characterization of INCB106385: A novel A2A/A2B adenosine receptor antagonist, as a cancer immunotherapy. Cancer Res. 2021, 81, LB157. [Google Scholar] [CrossRef]
- Bach, N.; Winzer, R.; Tolosa, E.; Fiedler, W.; Brauneck, F. The Clinical Significance of CD73 in Cancer. Int. J. Mol. Sci. 2023, 24, 11759. [Google Scholar] [CrossRef]
- Stewart, S.; Buonpane, R.; Zhou, J.; Hansbury, M.; Smith, M.; Wang, H.; Lu; Su, B.; Awdew, R.; Huang, C.-Y.; et al. Abstract LB174: Discovery and preclinical characterization of INCA00186, a humanized monoclonal antibody antagonist of CD73, as a cancer immunotherapy. Cancer Res. 2021, 81, LB174. [Google Scholar] [CrossRef]
- Hori, M.; Kitakaze, M. Adenosine, the heart, and coronary circulation. Hypertension 1991, 18, 565–574. [Google Scholar] [CrossRef]
- Belardinelli, L.; Shryock, J.C.; Snowdy, S.; Zhang, Y.; Monopoli, A.; Lozza, G.; Ongini, E.; Olsson, R.A.; Dennis, D.M. The A2A adenosine receptor mediates coronary vasodilation. J. Pharmacol. Exp. Ther. 1998, 284, 1066–1073. [Google Scholar] [PubMed]
- Allard, B.; Pommey, S.; Smyth, M.J.; Stagg, J. Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs. Clin. Cancer Res. 2013, 19, 5626–5635. [Google Scholar] [CrossRef]
- Regateiro, F.S.; Howie, D.; Nolan, K.F.; Agorogiannis, E.I.; Greaves, D.R.; Cobbold, S.P.; Waldmann, H. Generation of anti-inflammatory adenosine byleukocytes is regulated by TGF-β. Eur. J. Immunol. 2011, 41, 2955–2965. [Google Scholar] [CrossRef]
- Tolcher, A.W.; Gordon, M.; Mahoney, K.M.; Seto, A.; Zavodovskaya, M.; Hsueh, C.-H.; Zhai, S.; Tarnowski, T.; Jürgensmeier, J.M.; Stinson, S.; et al. Phase 1 first-in-human study of dalutrafusp alfa, an anti–CD73-TGF-β-trap bifunctional antibody, in patients with advanced solid tumors. J. Immunother. Cancer 2023, 11, e005267. [Google Scholar] [CrossRef]
- He, X.; Xu, C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020, 30, 660–669. [Google Scholar] [CrossRef]
- Lim, S.; Phillips, J.B.; Madeira Da Silva, L.; Zhou, M.; Fodstad, O.; Owen, L.B.; Tan, M. Interplay between Immune Checkpoint Proteins and Cellular Metabolism. Cancer Res. 2017, 77, 1245–1249. [Google Scholar] [CrossRef]
- Keir, M.E.; Butte, M.J.; Freeman, G.J.; Sharpe, A.H. PD-1 and Its Ligands in Tolerance and Immunity. Annu. Rev. Immunol. 2008, 26, 677–704. [Google Scholar] [CrossRef]
- Haanen, J.B.A.G.; Robert, C. Immune Checkpoint Inhibitors. In Progress in Tumor Research; Michielin, O., Coukos, G., Eds.; S. Karger AG: Basel, Switzerland, 2015; Volume 42, pp. 55–66. ISBN 978-3-318-05589-4. [Google Scholar]
- Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.M.; Hwu, W.-J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef]
- McCoy, K.D.; Le Gros, G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol. Cell Biol. 1999, 77, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Schildberg, F.A.; Klein, S.R.; Freeman, G.J.; Sharpe, A.H. Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 2016, 44, 955–972. [Google Scholar] [CrossRef] [PubMed]
- Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J. Exp. Clin. Cancer Res. 2019, 38, 255. [Google Scholar] [CrossRef]
- Nishio, M.; Ohe, Y.; Ikeda, S.; Yokoyama, T.; Hayashi, H.; Fukuhara, T.; Sato, Y.; Tanaka, H.; Hotta, K.; Sugawara, S.; et al. First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1. Int. J. Clin. Oncol. 2023, 28, 1354–1368. [Google Scholar] [CrossRef] [PubMed]
- Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010, 363, 711–723. [Google Scholar] [CrossRef]
- Gao, M.; Lin, M.; Moffitt, R.A.; Salazar, M.A.; Park, J.; Vacirca, J.; Huang, C.; Shroyer, K.R.; Choi, M.; Georgakis, G.V.; et al. Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer. Br. J. Cancer 2019, 120, 88–96. [Google Scholar] [CrossRef]
- Pu, N.; Lou, W.; Yu, J. PD-1 immunotherapy in pancreatic cancer: Current status. J. Pancreatol. 2019, 2, 6–10. [Google Scholar] [CrossRef]
- Zhang, L.; Mai, W.; Jiang, W.; Geng, Q. Sintilimab: A Promising Anti-Tumor PD-1 Antibody. Front. Oncol. 2020, 10, 594558. [Google Scholar] [CrossRef]
- Brown, J.S.; Sundar, R.; Lopez, J. Combining DNA damaging therapeutics with immunotherapy: More haste, less speed. Br. J. Cancer 2018, 118, 312–324. [Google Scholar] [CrossRef] [PubMed]
- Langer, C.J.; Gadgeel, S.M.; Borghaei, H.; Papadimitrakopoulou, V.A.; Patnaik, A.; Powell, S.F.; Gentzler, R.D.; Martins, R.G.; Stevenson, J.P.; Jalal, S.I.; et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016, 17, 1497–1508. [Google Scholar] [CrossRef] [PubMed]
- Poole, R.M. Pembrolizumab: First Global Approval. Drugs 2014, 74, 1973–1981. [Google Scholar] [CrossRef]
- Deeks, E.D. Olaparib: First Global Approval. Drugs 2015, 75, 231–240. [Google Scholar] [CrossRef]
- Hao, Z.; Wang, P. Lenvatinib in Management of Solid Tumors. Oncologist 2020, 25, e302–e310. [Google Scholar] [CrossRef]
- Kudo, M.; Finn, R.S.; Qin, S.; Han, K.-H.; Ikeda, K.; Piscaglia, F.; Baron, A.; Park, J.-W.; Han, G.; Jassem, J.; et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 2018, 391, 1163–1173. [Google Scholar] [CrossRef]
- Schlumberger, M.; Tahara, M.; Wirth, L.J.; Robinson, B.; Brose, M.S.; Elisei, R.; Habra, M.A.; Newbold, K.; Shah, M.H.; Hoff, A.O.; et al. Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer. N. Engl. J. Med. 2015, 372, 621–630. [Google Scholar] [CrossRef]
- Waterhouse, P.; Penninger, J.M.; Timms, E.; Wakeham, A.; Shahinian, A.; Lee, K.P.; Thompson, C.B.; Griesser, H.; Mak, T.W. Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4. Science 1995, 270, 985–988. [Google Scholar] [CrossRef]
- Tivol, E.A.; Borriello, F.; Schweitzer, A.N.; Lynch, W.P.; Bluestone, J.A.; Sharpe, A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995, 3, 541–547. [Google Scholar] [CrossRef]
- Bullock, A.; Grossman, J.; Fakih, M.; Lenz, H.; Gordon, M.; Margolin, K.; Wilky, B.; Mahadevan, D.; Trent, J.; Bockorny, B.; et al. LBA O-9 Botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer. Ann. Oncol. 2022, 33, S376. [Google Scholar] [CrossRef]
- Balsano, R.; Zanuso, V.; Pirozzi, A.; Rimassa, L.; Bozzarelli, S. Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights. Curr. Oncol. 2023, 30, 3871–3885. [Google Scholar] [CrossRef]
- Germano, G.; Lamba, S.; Rospo, G.; Barault, L.; Magrì, A.; Maione, F.; Russo, M.; Crisafulli, G.; Bartolini, A.; Lerda, G.; et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017, 552, 116–120. [Google Scholar] [CrossRef] [PubMed]
- Macarulla Mercade, T.; McAndrews, K.; Pazo Cid, R.A.; Medina Rodríguez, L.; Gil-Negrete, A.; Rivera Herrero, F.; Varela Pose, V.; Martín-Muñoz, A.; Ruiz-Heredia, Y.; Kalluri, R.; et al. 331P Phase Ib/IIa study to evaluate safety and efficacy of priming treatment with the hedgehog inhibitor NLM-001 prior to gemcitabine and nab-paclitaxel plus zalifrelimab as first-line treatment in patients with advanced pancreatic cancer: NUMANTIA study. Ann. Oncol. 2024, 35, S139–S140. [Google Scholar] [CrossRef]
- Karhadkar, S.S.; Steven Bova, G.; Abdallah, N.; Dhara, S.; Gardner, D.; Maitra, A.; Isaacs, J.T.; Berman, D.M.; Beachy, P.A. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004, 431, 707–712. [Google Scholar] [CrossRef]
- Feldmann, G.; Dhara, S.; Fendrich, V.; Bedja, D.; Beaty, R.; Mullendore, M.; Karikari, C.; Alvarez, H.; Iacobuzio-Donahue, C.; Jimeno, A.; et al. Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers. Cancer Res. 2007, 67, 2187–2196. [Google Scholar] [CrossRef]
- Berman, D.M.; Karhadkar, S.S.; Maitra, A.; Montes De Oca, R.; Gerstenblith, M.R.; Briggs, K.; Parker, A.R.; Shimada, Y.; Eshleman, J.R.; Watkins, D.N.; et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003, 425, 846–851. [Google Scholar] [CrossRef] [PubMed]
- Outram, S.V.; Varas, A.; Pepicelli, C.V.; Crompton, T. Hedgehog Signaling Regulates Differentiation from Double-Negative to Double-Positive Thymocyte. Immunity 2000, 13, 187–197. [Google Scholar] [CrossRef]
- Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. N. Engl. J. Med. 2012, 366, 2443–2454. [Google Scholar] [CrossRef] [PubMed]
- Hoos, A.; Ibrahim, R.; Korman, A.; Abdallah, K.; Berman, D.; Shahabi, V.; Chin, K.; Canetta, R.; Humphrey, R. Development of Ipilimumab: Contribution to a New Paradigm for Cancer Immunotherapy. Semin. Oncol. 2010, 37, 533–546. [Google Scholar] [CrossRef]
- Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.-J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018, 19, 1480–1492. [Google Scholar] [CrossRef]
- Tawbi, H.A.; Forsyth, P.A.; Algazi, A.; Hamid, O.; Hodi, F.S.; Moschos, S.J.; Khushalani, N.I.; Lewis, K.; Lao, C.D.; Postow, M.A.; et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N. Engl. J. Med. 2018, 379, 722–730. [Google Scholar] [CrossRef]
- Postow, M.A.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.; McDermott, D.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N. Engl. J. Med. 2015, 372, 2006–2017. [Google Scholar] [CrossRef] [PubMed]
- Chen, I.M.; Johansen, J.S.; Theile, S.; Hjaltelin, J.X.; Novitski, S.I.; Brunak, S.; Hasselby, J.P.; Willemoe, G.L.; Lorentzen, T.; Madsen, K.; et al. Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). J. Clin. Oncol. 2022, 40, 3180–3189. [Google Scholar] [CrossRef]
- Valachis, A.; Rosén, C.; Koliadi, A.; Digkas, E.; Gustavsson, A.; Nearchou, A.; Ullenhag, G.J. Improved survival without increased toxicity with influenza vaccination in cancer patients treated with checkpoint inhibitors. OncoImmunology 2021, 10, 1886725. [Google Scholar] [CrossRef]
- Wu, X.; Li, T.; Jiang, R.; Yang, X.; Guo, H.; Yang, R. Targeting MHC-I molecules for cancer: Function, mechanism, and therapeutic prospects. Mol. Cancer 2023, 22, 194. [Google Scholar] [CrossRef]
- Salmon, H.; Idoyaga, J.; Rahman, A.; Leboeuf, M.; Remark, R.; Jordan, S.; Casanova-Acebes, M.; Khudoynazarova, M.; Agudo, J.; Tung, N.; et al. Expansion and Activation of CD103+ Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity 2016, 44, 924–938. [Google Scholar] [CrossRef]
- Sánchez-Paulete, A.R.; Cueto, F.J.; Martínez-López, M.; Labiano, S.; Morales-Kastresana, A.; Rodríguez-Ruiz, M.E.; Jure-Kunkel, M.; Azpilikueta, A.; Aznar, M.A.; Quetglas, J.I.; et al. Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti–PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells. Cancer Discov. 2016, 6, 71–79. [Google Scholar] [CrossRef]
- Khubchandani, S.; Czuczman, M.S.; Hernandez-Ilizaliturri, F.J. Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies. Curr. Opin. Investig. Drugs 2009, 10, 579–587. [Google Scholar]
- Johnson, P.W.; Steven, N.M.; Chowdhury, F.; Dobbyn, J.; Hall, E.; Ashton-Key, M.; Hodges, E.; Ottensmeier, C.H.; Williams, A.; Glennie, M. A Cancer Research UK phase I study evaluating safety, tolerability, and biological effects of chimeric anti-CD40 monoclonal antibody (MAb), Chi Lob 7/4. J. Clin. Oncol. 2010, 28, 2507. [Google Scholar] [CrossRef]
- McKenna, H.J. Role of hematopoietic growth factors/flt3 ligand in expansion and regulation of dendritic cells. Curr. Opin. Hematol. 2001, 8, 149–154. [Google Scholar] [CrossRef]
- Byrne, K.T.; Vonderheide, R.H. CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer. Cell Rep. 2016, 15, 2719–2732. [Google Scholar] [CrossRef]
- Miao, L.; Zhang, Y.; Huang, L. mRNA vaccine for cancer immunotherapy. Mol. Cancer 2021, 20, 41. [Google Scholar] [CrossRef]
- Saxena, M.; Van Der Burg, S.H.; Melief, C.J.M.; Bhardwaj, N. Therapeutic cancer vaccines. Nat. Rev. Cancer 2021, 21, 360–378. [Google Scholar] [CrossRef]
- Fioretti, D.; Iurescia, S.; Fazio, V.M.; Rinaldi, M. DNA Vaccines: Developing New Strategies against Cancer. J. Biomed. Biotechnol. 2010, 2010, 174378. [Google Scholar] [CrossRef]
- Liu, W.; Tang, H.; Li, L.; Wang, X.; Yu, Z.; Li, J. Peptide-based therapeutic cancer vaccine: Current trends in clinical application. Cell Prolif. 2021, 54, e13025. [Google Scholar] [CrossRef]
- Yuan, Y.; Gao, F.; Chang, Y.; Zhao, Q.; He, X. Advances of mRNA vaccine in tumor: A maze of opportunities and challenges. Biomark. Res. 2023, 11, 6. [Google Scholar] [CrossRef]
- Wijfjes, Z.; Van Dalen, F.J.; Le Gall, C.M.; Verdoes, M. Controlling Antigen Fate in Therapeutic Cancer Vaccines by Targeting Dendritic Cell Receptors. Mol. Pharm. 2023, 20, 4826–4847. [Google Scholar] [CrossRef] [PubMed]
- Sahin, U.; Oehm, P.; Derhovanessian, E.; Jabulowsky, R.A.; Vormehr, M.; Gold, M.; Maurus, D.; Schwarck-Kokarakis, D.; Kuhn, A.N.; Omokoko, T.; et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 2020, 585, 107–112. [Google Scholar] [CrossRef] [PubMed]
- Rosa, S.S.; Prazeres, D.M.F.; Azevedo, A.M.; Marques, M.P.C. mRNA vaccines manufacturing: Challenges and bottlenecks. Vaccine 2021, 39, 2190–2200. [Google Scholar] [CrossRef]
- Huang, X.; Zhang, G.; Tang, T.-Y.; Gao, X.; Liang, T.-B. Personalized pancreatic cancer therapy: From the perspective of mRNA vaccine. Mil. Med. Res. 2022, 9, 53. [Google Scholar] [CrossRef] [PubMed]
- Vishweshwaraiah, Y.L.; Dokholyan, N.V. mRNA vaccines for cancer immunotherapy. Front. Immunol. 2022, 13, 1029069. [Google Scholar] [CrossRef]
- Uehata, T.; Takeuchi, O. RNA Recognition and Immunity—Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms. Cells 2020, 9, 1701. [Google Scholar] [CrossRef]
- Rojas, L.A.; Sethna, Z.; Soares, K.C.; Olcese, C.; Pang, N.; Patterson, E.; Lihm, J.; Ceglia, N.; Guasp, P.; Chu, A.; et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 2023, 618, 144–150. [Google Scholar] [CrossRef]
- Wadhwa, A.; Aljabbari, A.; Lokras, A.; Foged, C.; Thakur, A. Opportunities and Challenges in the Delivery of mRNA-Based Vaccines. Pharmaceutics 2020, 12, 102. [Google Scholar] [CrossRef]
- Sahin, U.; Karikó, K.; Türeci, Ö. mRNA-based therapeutics—Developing a new class of drugs. Nat. Rev. Drug Discov. 2014, 13, 759–780. [Google Scholar] [CrossRef]
- Diken, M.; Kreiter, S.; Selmi, A.; Britten, C.M.; Huber, C.; Türeci, Ö.; Sahin, U. Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation. Gene Ther. 2011, 18, 702–708. [Google Scholar] [CrossRef] [PubMed]
- Kato, H.; Fujita, T. RIG-I-like receptors and autoimmune diseases. Curr. Opin. Immunol. 2015, 37, 40–45. [Google Scholar] [CrossRef] [PubMed]
- Minnaert, A.-K.; Vanluchene, H.; Verbeke, R.; Lentacker, I.; De Smedt, S.C.; Raemdonck, K.; Sanders, N.N.; Remaut, K. Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across. Adv. Drug Deliv. Rev. 2021, 176, 113900. [Google Scholar] [CrossRef] [PubMed]
- Hu, H.-G.; Li, Y.-M. Emerging Adjuvants for Cancer Immunotherapy. Front. Chem. 2020, 8, 601. [Google Scholar] [CrossRef] [PubMed]
- Van Lint, S.; Goyvaerts, C.; Maenhout, S.; Goethals, L.; Disy, A.; Benteyn, D.; Pen, J.; Bonehill, A.; Heirman, C.; Breckpot, K.; et al. Preclinical Evaluation of TriMix and Antigen mRNA-Based Antitumor Therapy. Cancer Res. 2012, 72, 1661–1671. [Google Scholar] [CrossRef]
- Andersen, M.H. Novel immune modulatory vaccines targeting TGFβ. Cell. Mol. Immunol. 2023, 20, 551–553. [Google Scholar] [CrossRef]
- Sugiyama, H. Wilms’ Tumor GeneWT1: Its Oncogenic Function and Clinical Application. Int. J. Hematol. 2001, 73, 177–187. [Google Scholar] [CrossRef]
- Oji, Y.; Nakamori, S.; Fujikawa, M.; Nakatsuka, S.; Yokota, A.; Tatsumi, N.; Abeno, S.; Ikeba, A.; Takashima, S.; Tsujie, M.; et al. Overexpression of the Wilms’ tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci. 2004, 95, 583–587. [Google Scholar] [CrossRef]
- Shourian, M.; Beltra, J.-C.; Bourdin, B.; Decaluwe, H. Common gamma chain cytokines and CD8 T cells in cancer. Semin. Immunol. 2019, 42, 101307. [Google Scholar] [CrossRef]
- Leonard, W.J.; Lin, J.-X.; O’Shea, J.J. The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications. Immunity 2019, 50, 832–850. [Google Scholar] [CrossRef]
- Chen, Z.; Zhang, S.; Han, N.; Jiang, J.; Xu, Y.; Ma, D.; Lu, L.; Guo, X.; Qiu, M.; Huang, Q.; et al. A Neoantigen-Based Peptide Vaccine for Patients With Advanced Pancreatic Cancer Refractory to Standard Treatment. Front. Immunol. 2021, 12, 691605. [Google Scholar] [CrossRef] [PubMed]
- Melief, C.J.M.; Van Der Burg, S.H. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat. Rev. Cancer 2008, 8, 351–360. [Google Scholar] [CrossRef]
- Pant, S.; Furqan, M.; Abdul-Karim, R.M.; Chung, V.; Devoe, C.E.; Johnson, M.L.; Leal, A.D.; Park, H.; Wainberg, Z.A.; Welkowsky, E.; et al. First-in-human phase 1 trial of ELI-002 immunotherapy as treatment for subjects with Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma and other solid tumors. J. Clin. Oncol. 2022, 40, TPS2701. [Google Scholar] [CrossRef]
- Belnoue, E.; Mayol, J.-F.; Carboni, S.; Di Berardino Besson, W.; Dupuychaffray, E.; Nelde, A.; Stevanovic, S.; Santiago-Raber, M.-L.; Walker, P.R.; Derouazi, M. Targeting self- and neoepitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019, 4, e127305. [Google Scholar] [CrossRef]
- Cullinan, D.; McLellan, M.; Zhang, X.; Vickery, T.; Myers, N.; Sturmoski, M.; Ruzinova, M.; Hundal, J.; Miller, C.; Griffith, M.; et al. Preliminary Results Of A Phase Ib Clinical Trial Of A Neoantigen Dna Vaccine For Pancreatic Cancer. HPB 2020, 22, S12–S13. [Google Scholar] [CrossRef]
- Le, D.T.; Lutz, E.; Uram, J.N.; Sugar, E.A.; Onners, B.; Solt, S.; Zheng, L.; Diaz, L.A.; Donehower, R.C.; Jaffee, E.M.; et al. Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer. J. Immunother. 2013, 36, 382–389. [Google Scholar] [CrossRef]
- Lipson, E.J.; Sharfman, W.H.; Chen, S.; McMiller, T.L.; Pritchard, T.S.; Salas, J.T.; Sartorius-Mergenthaler, S.; Freed, I.; Ravi, S.; Wang, H.; et al. Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. J. Transl. Med. 2015, 13, 214. [Google Scholar] [CrossRef]
- Laheru, D.; Lutz, E.; Burke, J.; Biedrzycki, B.; Solt, S.; Onners, B.; Tartakovsky, I.; Nemunaitis, J.; Le, D.; Sugar, E.; et al. Allogeneic Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation. Clin. Cancer Res. 2008, 14, 1455–1463. [Google Scholar] [CrossRef] [PubMed]
- Le, D.T.; Wang-Gillam, A.; Picozzi, V.; Greten, T.F.; Crocenzi, T.; Springett, G.; Morse, M.; Zeh, H.; Cohen, D.; Fine, R.L.; et al. Safety and Survival With GVAX Pancreas Prime and Listeria monocytogenes—Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. J. Clin. Oncol. 2015, 33, 1325–1333. [Google Scholar] [CrossRef]
- Le, D.T.; Brockstedt, D.G.; Nir-Paz, R.; Hampl, J.; Mathur, S.; Nemunaitis, J.; Sterman, D.H.; Hassan, R.; Lutz, E.; Moyer, B.; et al. A Live-Attenuated Listeria Vaccine (ANZ-100) and a Live-Attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase I Studies of Safety and Immune Induction. Clin. Cancer Res. 2012, 18, 858–868. [Google Scholar] [CrossRef]
- Pandey, S.; Gupta, V.K.; Lavania, S.P. Role of Epigenetics in Pancreatic Ductal Adenocarcinoma. Epigenomics 2023, 15, 89–110. [Google Scholar] [CrossRef]
- Gailhouste, L.; Liew, L.C.; Hatada, I.; Nakagama, H.; Ochiya, T. Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. Cell Death Dis. 2018, 9, 468. [Google Scholar] [CrossRef]
- Aumer, T.; Gremmelmaier, C.B.; Runtsch, L.S.; Pforr, J.C.; Yeşiltaç, G.N.; Kaiser, S.; Traube, F.R. Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line. Clin. Epigenet. 2022, 14, 113. [Google Scholar] [CrossRef]
- Gonda, T.A.; Fang, J.; Salas, M.; Do, C.; Hsu, E.; Zhukovskaya, A.; Siegel, A.; Takahashi, R.; Lopez-Bujanda, Z.A.; Drake, C.G.; et al. A DNA Hypomethylating Drug Alters the Tumor Microenvironment and Improves the Effectiveness of Immune Checkpoint Inhibitors in a Mouse Model of Pancreatic Cancer. Cancer Res. 2020, 80, 4754–4767. [Google Scholar] [CrossRef]
- Algaze, S.; Hanna, D.L.; Azad, N.S.; Thomas, J.S.; Iqbal, S.; Habib, D.; Ning, Y.; Barzi, A.; Patel, R.; Lenz, H.-J.; et al. A phase Ib study of guadecitabine and durvalumab in patients with advanced hepatocellular carcinoma, pancreatic adenocarcinoma, and biliary cancers. J. Clin. Oncol. 2022, 40, 574. [Google Scholar] [CrossRef]
- Abaza, Y.; Zeidan, A.M. Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Cells 2022, 11, 2249. [Google Scholar] [CrossRef]
- Tremblay-LeMay, R.; Rastgoo, N.; Pourabdollah, M.; Chang, H. EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies. Biomark. Res. 2018, 6, 34. [Google Scholar] [CrossRef]
- Duan, R.; Du, W.; Guo, W. EZH2: A novel target for cancer treatment. J. Hematol. Oncol. 2020, 13, 104. [Google Scholar] [CrossRef]
- Kang, N.; Eccleston, M.; Clermont, P.-L.; Latarani, M.; Male, D.K.; Wang, Y.; Crea, F. EZH2 Inhibition: A Promising Strategy to Prevent Cancer Immune Editing. Epigenomics 2020, 12, 1457–1476. [Google Scholar] [CrossRef]
Trial Identifier | Phase | Agent(s) | Molecular Targets | Mechanism | Population |
---|---|---|---|---|---|
NCT03948763 | I | mRNA-5671/V941 | KRASG12D KRASG12V KRASG13D KRASG12C | mRNA against KRAS elicits a T cell response | KRAS-mutated Non-small cell lung cancer, colorectal cancer or PDAC |
NCT05726864 | II | ELI-002 | KRASG12D KRASG12R | Lipid-conjugated immune-stimulatory oligonucleotide and a mixture of lipid-conjugated peptide-based antigens | KRAS-mutated PDAC, colorectal cancer, NSCLC, ovarian cancer, cholangiocarcinoma bile duct cancer or gallbladder carcinoma |
NCT05013216 | I | KRAS peptide vaccine + poly-ICLC | KRASG12D KRASG12R KRASG12V KRASG12 KRASG12C KRASG13D | Targeted long peptide vaccine against mutant KRAS | High risk of PDAC by family history or germline mutation status |
NCT04117087 | I | KRAS peptide vaccine plus poly-ICLC | KRASG12C KRASG12V KRASG12D KRASG12A KRASG13D KRASG12R | Targeted long peptide vaccine against mutant KRAS with the addition of enhanced cell-mediated immune response | Resected PDAC after neoadjuvant and/or adjuvant chemotherapy and/or radiation |
NCT03122106 | I | Neoantigen peptide vaccine plus poly-ICLC | Prioritized neoantigens and personalized mesothelin epitopes | Neoantigen peptide vaccine will be capable of generating neoantigen-specific CD4+ and CD8+ T cell responses | PDAC following surgical resection and adjuvant chemotherapy |
NCT04161755 | I | RO7198457 (mRNA-based personalized tumor vaccine) | Tumor-associated antigens | APCs take up the mRNA-based vaccine and express tumor-associated antigens, leading to cytotoxic and memory T cell immune responses against the tumor-associated antigens | PDAC, undergoing curative intent resection |
NCT02600949 | I | Synthetic personalized tumor-associated peptide vaccine therapy | Tumor-associated antigens | APC take up mRNA-based vaccine and express tumor-associated antigens, leading to cytotoxic and memory T cell immune responses against the tumor-associated antigens | Advanced PDAC and colorectal cancer |
NCT04683939 | I/IIA | BNT141 | Claudin 18.2 | APC take up the mRNA-based vaccine and express tumor-associated antigens, resulting in cytotoxic and memory T cell immune responses against the tumor-associated antigens. | Patients With CLDN18.2-positive Solid Tumors including pancreatic cancers. |
NCT04999969 | II | AZD0171 | LIF | AZD0171 is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation by modulating TAMs and inhibiting cancer stem cells, thereby slowing tumor growth. | First line (1L) metastatic PDAC |
NCT04580485 | I | INCB106385 | A2A and A2B receptors | Direct A2A/A2B antagonist. ATP released by dying cells is converted into adenosine, a potent suppressor of immune cell activity. Blocking both adenosine receptors on immune cells can be used as an immunotherapy to enhance anti-tumor immune responses. | CD8 T-cell-positive advanced solid tumors including PDAC |
NCT04989387 | I | INCA00186 | CD73 | Humanized monoclonal antibody antagonist of CD73, blocking the production of adenosine, thereby restoring immune function by reducing adenosine levels. | Advanced solid tumors; squamous cell carcinoma of the head and neck (SCCHN) and specified gastrointestinal (GI) malignancies. |
NCT05688215 | I/II | Zimberelimab and quemliclustat | Zimberelimab: PD-1 quemliclustat: CD73 | Selective small molecule inhibitor of CD73, blocking the production of adenosine, thereby restoring immune function by reducing adenosine levels. | Borderline resectable PDAC or locally advanced. |
NCT05632328 | II | AGEN1423 and Balstilimab | AGEN1423: CD73 and TGFβ, Balstilimab: PD-1 | 1) Preferential localization within the tumor microenvironment (TME) due to its CD73 targeting moiety; 2) Ability to reduce adenosine concentration in the TME by inhibiting CD73 enzymatic activity; and 3) Inhibition of the immunosuppressive effect of TGFβ. | Advanced PDAC |
NCT05562297 | II | Neoadjuvant/Adjuvant Sintilimab, Nab-paclitaxel, and Gemcitabine | Sintilimab: investigational PD-1 inhibitor | Binds to PD-1 molecules on the surface of T-cells, blocks the PD-1/PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells | Resectable/Borderline Resectable PDAC |
NCT04753879 | II | GAX-CI (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and irinotecan) | Gemcitabine: nucleoside analog; Nab-paclitaxel: microtubule inhibitor; Capecitabine: thymidylate synthase inhibitor; Cisplatin: DNA crosslinks; Irinotecan: topoisomerase I inhibitor. | Gemcitabine incorporates into DNA and inhibits ribonucleotide reductase. Nab-paclitaxel stabilizes microtubules, inducing apoptosis. Capecitabine, metabolized into 5-fluorouracil, inhibits thymidylate synthase, impairing DNA synthesis. Cisplatin forms DNA cross-links, preventing replication and transcription, leading to cell death. Irinotecan inhibits topoisomerase I, causing DNA damage during replication. | Metastatic PDAC |
NCT04887805 | II | Lenvatinib and Pembrolizumab | Lenvatinib: VEGFR FGFR, RET, PDGFRα, and KIT Pembrolizumab: PD-1 | Inhibition of VEGF receptors prevent tumor angiogenesis, while inhibiting FGFR, RET, PDGFRα, and KIT halts the further proliferation of malignant cells. | Advanced Unresectable PDAC |
NCT05630183 | II | Botensilimab | Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) | Expand therapy to cold or poorly immunogenic solid tumors. | Metastatic PDAC |
NCT04827953 | IB/IIA | NLM-001 | Hedgehog Inhibitor | NLM-001 targets the Hh pathway and disrupts the tumor microenvironment (TME) by decreasing cancer-associated fibroblasts and promoting immune cell infiltration into the TME. | Advanced PDAC |
NCT02866383 | II | Nivolumab & Ipilimumab & Radiotherapy | Nivolumab: PD-1, Ipilimumab: CTLA-4 | Nivolumab blocks PD-1, preventing T cell inhibition and enhancing the immune response against tumor cells. Ipilimumab blocks CTLA-4, further promoting T cell activation and proliferation. Radiotherapy can cause immunogenic cell death, leading to the release of tumor antigens. | metastatic PC or BTC refractory or intolerant to at least one line of prior systemic chemotherapy with gemcitabine or platinum-containing regimens. |
NCT05721846 | I | TGFβ-15 Peptide Vaccine | TGFβ1-derived peptides (MHC-I and MHC-II-restricted) | Immunosuppression and fibrosis are driven by TGFβ. Targeting the immunosuppressive and fibrotic TME in PDAC leads to increased infiltration of CD8+ T cells and a higher intratumoral M1/M2 macrophage ratio. | Refractory PDAC |
NCT05116917 | II | Influenza Vaccine | N/A | The influenza vaccine promotes the activation of T cells and B cells, triggering an interferon-gamma response. | Pancreatic Cancer |
NCT05638698 | II | Tg01 Vaccine/Qs-21 Stimulon™ (PD-1) | RAS-neoantigen peptide vaccine targeting the seven most frequent codon 12-13 RAS mutations | Activates mutant RAS-specific CD4+ and CD8+ T-cell responses. | Surgically resected Stage 1-3 RAS mutant PDAC who have ctDNA in the blood despite prior therapy. |
NCT05964361 | I/II | Interleukin-15-transpresenting Wilms’ Tumor Protein 1 Autologous Dendritic Cell Vaccination | WT1 | By targeting the tumor-associated antigen Wilms’ tumor-1 (WT1), the tumor-antigen specificity stimulates antigen-specific T cells using PD-L-silenced IL-15 dendritic cells (DCs). | Esophageal Cancer Pancreas Cancer Ovarian Cancer Liver Cancer. |
NCT05846516 | I | VSV-GP154, ATP150, ATP152, Ezabenlimab | KRAS G12D, KRAS G12V | Upon administration of ATP150 and ATP152, the Z12 moiety targets, binds to, and penetrates antigen-presenting cells (APCs), specifically dendritic cells (DCs). This promotes the loading of epitopes into the DCs and transports antigenic cargo into both endosomal and cytosolic compartments. | KRAS G12D/G12V Mutated PDAC |
NCT02451982 | II | GVAX + PD-1 inhibitors | Antigen-presenting tumor cells | GVAX vaccination stimulates local production of granulocyte-macrophage colony-stimulating factor (GM-CSF) at the vaccine site, leading to a systemic tumor-specific immune response. | Resectable PDAC |
NCT03190265 | II | GVAX Pancreas Vaccine (With Cyclophosphamide) + nivolumab and ipilimumab | Antigen-presenting tumor cells | GVAX enhances the presentation of tumor antigens to the immune system. Cyclophosphamide further amplifies this effect by reducing regulatory T cells. Nivolumab and ipilimumab inhibit the PD-1 and CTLA-4 pathways, which would normally suppress the immune response. | Metastatic PDAC |
NCT04853017 | I | ELI-002 | Lymph-node targeted amphiphile (AMP)-modified G12D and G12R mutant KRAS peptides together with an AMP-modified CpG oligonucleotide adjuvant. | Increased cytotoxic KRAS-specific T cells | KRAS Mutated PDAC |
NCT04257448 | I/II | Romidepsin Azacitidine + nab-Paclitaxel/Gemcitabine ± Lenalidomide + Durvalumab | Romidepsin: Histone Deacetylase (HDAC) Inhibitor, Azacitidine: DNA Methyltransferase (DNMT) Inhibitor, Nab-Paclitaxel: microtubules, Durvalumab: PD-L1 inhibitor | Romidepsin targets HDACs to induce apoptosis. Azacitidine inhibits DNMTs to reactivate tumor suppressor genes and induce differentiation. Nab-Paclitaxel stabilizes microtubules. Gemcitabine is incorporated into DNA to prevent synthesis. In the consolidation phase, Durvalumab enhances immune response by preventing T-cell inhibition, and Lenalidomide boosts immune activity and modulates the TME. | Advanced PDAC |
NCT04705818 | II | Tazemetostat + Durvalumab | Tazemetostat: EZH2 inhibitor, Durvalumab: PD-L1 inhibitor | Durvalumab blocks PD-L1 to enhance the immune response by preventing T-cell inhibition, while Tazemetostat inhibits EZH2, a histone methyltransferase that represses gene expression. | Advanced PDAC |
NCT06454448 | Ib/II | Adebrelimab, Decitabine, paclitaxel, gemcitabine | Adebrelimab: Anti-PD-L1, Decitabine: DNA Methyltransferase Inhibitor, Paclitaxel: microtubules, Gemcitabine: nucleoside analog | Adebrelimab blocks the PD-1 checkpoint receptor on T-cells, enhancing the immune response against PDAC. Decitabine induces hypomethylation of DNA, which can reactivate tumor suppressor genes, promoting apoptosis. Paclitaxel stabilizes microtubules, disrupting the mitotic spindle, leading to cell death. Gemcitabine incorporates into DNA, inhibiting DNA synthesis and causing DNA damage. | Metastatic PDAC |
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Do, C.T.P.; Prochnau, J.Y.; Dominguez, A.; Wang, P.; Rao, M.K. The Road Ahead in Pancreatic Cancer: Emerging Trends and Therapeutic Prospects. Biomedicines 2024, 12, 1979. https://doi.org/10.3390/biomedicines12091979
Do CTP, Prochnau JY, Dominguez A, Wang P, Rao MK. The Road Ahead in Pancreatic Cancer: Emerging Trends and Therapeutic Prospects. Biomedicines. 2024; 12(9):1979. https://doi.org/10.3390/biomedicines12091979
Chicago/Turabian StyleDo, Chris T. P., Jack Y. Prochnau, Angel Dominguez, Pei Wang, and Manjeet K. Rao. 2024. "The Road Ahead in Pancreatic Cancer: Emerging Trends and Therapeutic Prospects" Biomedicines 12, no. 9: 1979. https://doi.org/10.3390/biomedicines12091979