Advances in mRNA vaccines for pancreatic cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HUANG Hongcai ¹ ,  YU Hua ²

1. College of Medicine and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, P. R. China;
2. Department of General Surgery, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610040, P. R. China;

Corresponding author：

YU Hua, Email: yuhua1232021@163.com

Keywords：

pancreatic cancer; precise therapy; cancer vaccine; mRNA vaccine; tumor antigen; immune subtype

DOI：

10.7507/1007-9424.202407017

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To explore feasibility of mRNA vaccines as a novel strategy for individualized precision treatment of pancreatic cancer. Method The recent domestic and international literature on vaccine research in pancreatic cancer was reviewed. Results The heterogeneity between and within the pancreatic tumors had limited the efficacy of traditional vaccines based on cells, exosomes, proteins, peptides, or DNA for pancreatic cancer. The mRNA vaccine was considered as a promising alternative therapy due to their precise targeting, low toxicity, and ability to induce long-lasting immune memory. Breakthroughs in the tumor antigen recognition, immune subtype differentiation, and mRNA vaccine construction, the development strategy of pancreatic cancer mRNA vaccine would further facilitate the development of personalized precision medicine. The existing mRNA vaccines usually need to be combined with other immunotherapy methods to improve efficacy, while the development of preventive vaccines is still exploraing. Conclusions mRNA vaccines, as an innovative and promising platform, offer a new hope for the development of pancreatic cancer vaccines. However, the heterogeneity of pancreatic tumors has resulted in poor efficacy with traditional vaccines. Although the limitations of traditional vaccines and the heterogeneity of pancreatic cancer itself, the more challenges of vaccine research of pancreatic cancer is facing, the advantages of mRNA vaccine still make it possible to treat pancreatic cancer. In the face of the challenge of complex disease characteristics of pancreatic cancer, more research is needed to support the transformation and application of mRNA vaccine in clinical therapy.

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2. GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol, 2019, 4(12): 934-947.
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4. Park W, Chawla AO, Reilly EM. Pancreatic cancer: a review. JAMA, 2021, 326(9): 851-862.
5. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 2017, 377(25): 2500-2501.
6. Bear AS, Vonderheide RH, O'Hara MH. Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell, 2020, 38(6): 788-802.
7. Makohon-Moore AP, Zhang M, Reiter JG, et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet, 2017, 49(3): 358-366.
8. Huang X, Zhang G, Liang T. Subtyping for pancreatic cancer precision therapy. Trends Pharmacol Sci, 2022, 43(6): 482-494.
9. Peng J, Sun BF, Chen CY, et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res, 2019, 29(9): 725-738.
10. Chan-Seng-Yue M, Kim JC, Wilson GW, et al. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat Genet, 2020, 52(2): 231-240.
11. Łuksza M, Sethna ZM, Rojas LA, et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature, 2022, 606(7913): 389-395.
12. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature, 2023, 618(7963): 144-150.
13. Zhong H, Liu S, Cao F, et al. Dissecting tumor antigens and immune subtypes of glioma to develop mRNA vaccine. Front Immunol, 2021, 12: 709986. doi: 10.3389/fimmu.2021.709986.
14. Xie N, Shen G, Gao W, et al. Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther, 2023, 8(1): 9. doi: 10.1038/s41392-022-01270-x.
15. Sahin U, Derhovanessian E, Miller M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature, 2017, 547(7662): 222-226.
16. Amedei A, Niccolai E, Prisco D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum Vaccin Immunother, 2014, 10(11): 3354-3368.
17. Yanagisawa R, Koizumi T, Koya T, et al. WT1-pulsed dendritic cell vaccine combined with chemotherapy for resected pancreatic cancer in a phase Ⅰ study. Anticancer Res, 2018, 38(4): 2217-2225.
18. Shima H, Tsurita G, Wada S, et al. Randomized phase Ⅱ trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma. Cancer Sci, 2019, 110(8): 2378-2385.
19. van’t Land FR, Willemsen M, et al. Dendritic cell-based immunotherapy in patients with resected pancreatic cancer. J Clin Oncol, 2024, 42(26): 3083-3093.
20. Zheng L, Ding D, Edil BH, et al. Vaccine-induced intratumoral lymphoid aggregates correlate with survival following treatment with a neoadjuvant and adjuvant vaccine in patients with resectable pancreatic adenocarcinoma. Clin Cancer Res, 2021, 27(5): 1278-1286.
21. Hardacre JM, Mulcahy M, Small W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg, 2013, 17(1): 94-100.
22. Strobel O, Neoptolemos J, Jäger D, et al. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol, 2019, 16(1): 11-26.
23. Naseri M, Bozorgmehr M, Zöller M, et al. Tumor-derived exosomes: the next generation of promising cell-free vaccines in cancer immunotherapy. Oncoimmunology, 2020, 9(1): 1779991. doi: 10.1080/2162402X.2020.1779991.
24. Xiao L, Erb U, Zhao K, et al. Efficacy of vaccination with tumor-exosome loaded dendritic cells combined with cytotoxic drug treatment in pancreatic cancer. Oncoimmunology, 2017, 6(6): e1319044. doi: 10.1080/2162402X.2017.1319044.
25. Zhou W, Chen X, Zhou Y, et al. Exosomes derived from immunogenically dying tumor cells as a versatile tool for vaccination against pancreatic cancer. Biomaterials, 2022, 280: 121306. doi: 10.1016/j.biomaterials.2021.121306.
26. Fathollahi A, Hashemi SM, Haji Molla Hoseini M, et al. In vitro analysis of immunomodulatory effects of mesenchymal stem cell- and tumor cell -derived exosomes on recall antigen-specific responses. Int Immunopharmacol, 2019, 67: 302-310.
27. Liu W, Tang H, Li L, et al. Peptide-based therapeutic cancer vaccine: Current trends in clinical application. Cell Prolif, 2021, 54(5): e13025. doi: 10.1111/cpr.13025.
28. Palmer DH, Valle JW, Ma YT, et al. TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas (CT TG01-01): a single-arm, phase 1/2 trial. Br J Cancer, 2020, 122(7): 971-977.
29. Bernhardt SL, Gjertsen MK, Trachsel S, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase Ⅰ/Ⅱ study. Br J Cancer, 2006, 95(11): 1474-1482.
30. Middleton G, Silcocks P, Cox T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol, 2014, 15(8): 829-840.
31. Tiptiri-Kourpeti A, Spyridopoulou K, Pappa A, et al. DNA vaccines to attack cancer: Strategies for improving immunogenicity and efficacy. Pharmacol Ther, 2016, 165: 32-49.
32. Cappello P, Rolla S, Chiarle R, et al. Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer. Gastroenterology, 2013, 144(5): 1098-1106.
33. Yefei Rong, Jin Dayong, Wu Wenchuan, et al. Induction of protective and therapeutic anti-pancreatic cancer immunity using a reconstructed MUC1 DNA vaccine[J]. BMC cancer, 2009, 91-11.
34. Zhu K, Qin H, Cha SC, et al. Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models. Vaccine, 2007, 25(46): 7955-7961.
35. Schmitz-Winnenthal FH, Hohmann N, Schmidt T, et al. A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. Oncoimmunology, 2018, 7(4): e1303584. doi: 10.1080/2162402X.2017.1303584.
36. Heine A, Juranek S, Brossart P. Clinical and immunological effects of mRNA vaccines in malignant diseases. Mol Cancer, 2021, 20(1): 52. doi: 10.1186/s12943-021-01339-1.
37. Conry RM, LoBuglio AF, Loechel F, et al. A carcinoembryonic antigen polynucleotide vaccine for human clinical use. Cancer Gene Ther, 1995, 2(1): 33-38.
38. Hajj KA, Whitehead KA. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nature Reviews Materials, 2017, 2(10): natrevmats201756. doi:10.1038/natrevmats.2017.56.
39. Kim J, Eygeris Y, Gupta M, et al. Self-assembled mRNA vaccines. Adv Drug Deliv Rev, 2021, 170: 83-112.
40. Rzymski P, Szuster-Ciesielska A, Dzieciątkowski T, et al. mRNA vaccines: The future of prevention of viral infections?. J Med Virol, 2023, 95(2): e28572. doi: 10.1002/jmv.28572.
41. Liu Y, Yan Q, Zeng Z, et al. Advances and prospects of mRNA vaccines in cancer immunotherapy. Biochim Biophys Acta Rev Cancer, 2024, 1879(2): 189068. doi: 10.1016/j.bbcan.2023.189068.
42. Yao R, Xie C, Xia X. Recent progress in mRNA cancer vaccines. Hum Vaccin Immunother, 2024, 20(1): 2307187. doi: 10.1080/21645515.2024.2307187.
43. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med, 2020, 383(27): 2603-2615.
44. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med, 2021, 384(5): 403-416.
45. Fang E, Liu X, Li M, et al. Advances in COVID-19 mRNA vaccine development. Signal Transduct Target Ther, 2022, 7(1): 94. doi: 10.1038/s41392-022-00950-y.
46. Lin H, Wang K, Xiong Y, et al. Identification of tumor antigens and immune subtypes of glioblastoma for mRNA vaccine development. Front Immunol, 2022, 13: 773264. doi: 10.3389/fimmu.2022.773264.
47. Weide B, Pascolo S, Scheel B, et al. Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. J Immunother, 2009, 32(5): 498-507.
48. Lutz J, Meister M, Habbeddine M, et al. Local immunotherapy with the RNA-based immune stimulator CV8102 induces substantial anti-tumor responses and enhances checkpoint inhibitor activity. Cancer Immunol Immunother, 2023, 72(5): 1075-1087.
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