Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cancer mRNA vaccines: clinical advances and future opportunities

Abstract

mRNA vaccines have been revolutionary in terms of their rapid development and prevention of SARS-CoV-2 infections during the COVID-19 pandemic, and this technology has considerable potential for application to the treatment of cancer. Compared with traditional cancer vaccines based on proteins or peptides, mRNA vaccines reconcile the needs for both personalization and commercialization in a manner that is unique to each patient but not beholden to their HLA haplotype. A further advantage of mRNA vaccines is the availability of engineering strategies to improve their stability while retaining immunogenicity, enabling the induction of complementary innate and adaptive immune responses. Thus far, no mRNA-based cancer vaccines have received regulatory approval, although several phase I–II trials have yielded promising results, including in historically poorly immunogenic tumours. Furthermore, many early phase trials testing a wide range of vaccine designs are currently ongoing. In this Review, we describe the advantages of cancer mRNA vaccines and advances in clinical trials using both cell-based and nanoparticle-based delivery methods, with discussions of future combinations and iterations that might optimize the activity of these agents.

Key points

  • The advent of mRNA-based vaccines against SARS-CoV-2 has ushered in a new era of mRNA vaccines against other infectious diseases as well as cancer.

  • Advantages of directly injected mRNA vaccines include safety and flexibility in terms of the speed with which personalized epitopes or antigens can be produced in the form of mRNA.

  • mRNA is a labile molecule and is best delivered in nanoparticles, which are not currently developed to target specific cell types for the induction of immune responses. Alternatively, mRNA can be loaded into antigen-presenting cells that can then be administered as a vaccine.

  • SARS-CoV-2 vaccines use mRNA incorporating modified nucleotides to minimize the risk of a type I interferon response. However, this response might be beneficial in the setting of cancer vaccines, which must generate immune responses against antigens that are overexpressed self-antigens or those that result in only slightly altered proteins and are therefore likely to be less immunogenic.

  • The future of mRNA vaccines will include optimization of the nanoparticles used to deliver the vaccine as well as of the mRNA itself.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Challenges to the success of cancer vaccines.
Fig. 2: mRNA-loaded DC trafficking in the presence of a recall antigen.
Fig. 3: RNA-loaded DC manufacturing.
Fig. 4: Different types of RNA-loaded nanoparticles in clinical trials.
Fig. 5: mRNA backbone design.

Similar content being viewed by others

References

  1. McCarthy, E. F. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J. 26, 154–158 (2006).

    PubMed  PubMed Central  Google Scholar 

  2. van der Burg, S. H., Arens, R., Ossendorp, F., van Hall, T. & Melief, C. J. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat. Rev. Cancer 16, 219–233 (2016).

    Article  PubMed  Google Scholar 

  3. Pollack, I. F. et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J. Clin. Oncol. 32, 2050–2058 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sampson, J. H. et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Prins, R. M., Cloughesy, T. F. & Liau, L. M. Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N. Engl. J. Med. 359, 539–541 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shi, G. N. et al. Enhanced antitumor immunity by targeting dendritic cells with tumor cell lysate-loaded chitosan nanoparticles vaccine. Biomaterials 113, 191–202 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Coban, C. et al. Novel strategies to improve DNA vaccine immunogenicity. Curr. Gene Ther. 11, 479–484 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Lancet Commission on COVID-19 Vaccines and Therapeutics Task Force Members.Operation warp speed: implications for global vaccine security. Lancet Glob. Health 9, e1017–e1021 (2021).

    Article  Google Scholar 

  10. U.S. Department of Health and Human Services. Explaining Operation Warp Speed https://www.nihb.org/covid-19/wp-content/uploads/2020/08/Fact-sheet-operation-warp-speed.pdf (accessed May 2024).

  11. Mikulic, M. Number of COVID-19 vaccine doses administered in the United States as of April 26, 2023, by vaccine manufacturer. statista, https://www.statista.com/statistics/1198516/covid-19-vaccinations-administered-us-by-company/ (accessed May 2024).

  12. Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, A., Farmer, E., Wu, T. C. & Hung, C. F. Perspectives for therapeutic HPV vaccine development. J. Biomed. Sci. 23, 75 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lei, J. et al. HPV vaccination and the risk of invasive cervical cancer. N. Engl. J. Med. 383, 1340–1348 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Navid, F. et al. Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J. Clin. Oncol. 32, 1445–1452 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu, A. L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Riedmann, E. M. World’s first cancer vaccine licensed: PROVENGE®. Hum. Vaccin. 6, 430–435 (2010).

    Google Scholar 

  21. Bot, A. The landmark approval of Provenge, what it means to immunology and “in this issue”: the complex relation between vaccines and autoimmunity. Int. Rev. Immunol. 29, 235–238 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Brower, V. Approval of provenge seen as first step for cancer treatment vaccines. J. Natl Cancer Inst. 102, 1108–1110 (2010).

    Article  PubMed  Google Scholar 

  23. Jahnisch, H. et al. Dendritic cell-based immunotherapy for prostate cancer. Clin. Dev. Immunol. 2010, 517493 (2010).

    PubMed  PubMed Central  Google Scholar 

  24. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Paller, C. J. & Antonarakis, E. S. Sipuleucel-T for the treatment of metastatic prostate cancer: promise and challenges. Hum. Vaccin. Immunother. 8, 509–519 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Sheikh, N. A. et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol. Immunother. 62, 137–147 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Sanchez-Perez, L. et al. Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. Cancer Res. 65, 2009–2017 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Bloch, O. et al. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin. Cancer Res. 19, 3165–3175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Morse, M. A. et al. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res. 59, 56–58 (1999).

    CAS  PubMed  Google Scholar 

  30. Quillien, V. et al. Biodistribution of radiolabelled human dendritic cells injected by various routes. Eur. J. Nucl. Med. Mol. Imaging 32, 731–741 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Bandola-Simon, J. & Roche, P. A. Dysfunction of antigen processing and presentation by dendritic cells in cancer. Mol. Immunol. 113, 31–37 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Demoulin, S., Herfs, M., Delvenne, P. & Hubert, P. Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms. J. Leukoc. Biol. 93, 343–352 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Oble, D. A., Loewe, R., Yu, P. & Mihm, M. C. Jr Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 9, 3 (2009).

    PubMed  PubMed Central  Google Scholar 

  34. Hutchison, S. et al. Characterization of myeloid-derived suppressor cells and cytokines GM-CSF, IL-10 and MCP-1 in dogs with malignant melanoma receiving a GD3-based immunotherapy. Vet. Immunol. Immunopathol. 216, 109912 (2019).

    Article  CAS  PubMed  Google Scholar 

  35. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lohr, J. et al. Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-β. Clin. Cancer Res. 17, 4296–4308 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Hwang, S. L., Chung, N. P., Chan, J. K. & Lin, C. L. Indoleamine 2, 3-dioxygenase (IDO) is essential for dendritic cell activation and chemotactic responsiveness to chemokines. Cell Res. 15, 167–175 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Toda, Y. et al. PD-L1 and IDO1 expression and tumor-infiltrating lymphocytes in osteosarcoma patients: comparative study of primary and metastatic lesions. J. Cancer Res. Clin. Oncol. 146, 2607–2620 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Wainwright, D. A. et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin. Cancer Res. 18, 6110–6121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tavernier, G. et al. mRNA as gene therapeutic: how to control protein expression. J. Control. Rel. 150, 238–247 (2011).

    Article  CAS  Google Scholar 

  41. Malone, R. W., Felgner, P. L. & Verma, I. M. Cationic liposome-mediated RNA transfection. Proc. Natl Acad. Sci. USA 86, 6077–6081 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wolff, J. A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).

    Article  CAS  PubMed  Google Scholar 

  43. Martinon, F. et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 23, 1719–1722 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Conry, R. M. et al. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res. 55, 1397–1400 (1995).

    CAS  PubMed  Google Scholar 

  45. Johanning, F. W. et al. A Sindbis virus mRNA polynucleotide vector achieves prolonged and high level heterologous gene expression in vivo. Nucleic Acids Res. 23, 1495–1501 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Aliahmad, P., Miyake-Stoner, S. J., Geall, A. J. & Wang, N. S. Next generation self-replicating RNA vectors for vaccines and immunotherapies. Cancer Gene Ther. 30, 785–793 (2023).

    Article  CAS  PubMed  Google Scholar 

  47. Morse, M. A. et al. Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Ther. 30, 803–811 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ulmer, J. B., Mason, P. W., Geall, A. & Mandl, C. W. RNA-based vaccines. Vaccine 30, 4414–4418 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Schlake, T., Thess, A., Fotin-Mleczek, M. & Kallen, K. J. Developing mRNA-vaccine technologies. RNA Biol. 9, 1319–1330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Boczkowski, D., Nair, S. K., Nam, J. H., Lyerly, H. K. & Gilboa, E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res. 60, 1028–1034 (2000).

    CAS  PubMed  Google Scholar 

  51. Boczkowski, D., Nair, S. K., Snyder, D. & Gilboa, E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J. Exp. Med. 184, 465–472 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Nair, S. K. et al. Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nat. Biotechnol. 16, 364–369 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Heiser, A. et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J. Clin. Invest. 109, 409–417 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Van Tendeloo, V. F. et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 98, 49–56 (2001).

    Article  PubMed  Google Scholar 

  55. Zhang, S. N. et al. Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF. Mol. Ther. 19, 1558–1568 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Khoury, H. J. et al. Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia. Cancer 123, 3061–3072 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Anguille, S. et al. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood 130, 1713–1721 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Boudewijns, S. et al. Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial. Cancer Immunol. Immun. 69, 477–488 (2020).

    Article  CAS  Google Scholar 

  59. Kongsted, P. et al. Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer: a randomized phase II study. Cytotherapy 19, 500–513 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Batich, K. A., Mitchell, D. A., Healy, P., Herndon, J. E. & Sampson, J. H. Once, twice, three times a finding: reproducibility of dendritic cell vaccine trials targeting cytomegalovirus in glioblastoma. Clin. Cancer Res. 26, 5297–5303 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mitchell, D. A. et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Batich, K. A. et al. Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. Clin. Cancer Res. 23, 1898–1909 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Batich, K. A., Swartz, A. M. & Sampson, J. H. Preconditioning vaccine sites for mRNA-transfected dendritic cell therapy and antitumor efficacy. Methods Mol. Biol. 1403, 819–838 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wilgenhof, S. et al. Phase II study of autologous monocyte-derived mRNA electroporated dendritic cells (TriMixDC-MEL) plus ipilimumab in patients with pretreated advanced melanoma. J. Clin. Oncol. 34, 1330 (2016).

    Article  PubMed  Google Scholar 

  65. Dannull, J. et al. Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. J. Clin. Invest. 123, 3135–3145 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dannull, J. et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J. Clin. Invest. 115, 3623–3633 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Su, Z. et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. 63, 2127–2133 (2003).

    CAS  PubMed  Google Scholar 

  68. Heiser, A. et al. Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors. Cancer Res. 61, 3388–3393 (2001).

    CAS  PubMed  Google Scholar 

  69. Caruso, D. A. et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro Oncol. 6, 236–246 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sayour, E. J. et al. Personalized tumor RNA loaded lipid-nanoparticles prime the systemic and intratumoral milieu for response to cancer immunotherapy. Nano Lett. 18, 6195–6206 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nair, S. K. et al. Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma. J. Neurooncol. 125, 65–74 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Figlin, R. A. et al. Results of the ADAPT phase 3 study of rocapuldencel-T in combination with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 26, 2327–2336 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. DeBenedette, M., Gamble, A., Norris, M., Horvatinovich, J. & Nicolette, C. A. A review of the clinical experience with CMN-001, a tumor RNA loaded dendritic cell immunotherapy for the treatment of metastatic renal cell carcinoma. Hum. Vaccin. Immunother. 19, 2220629 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Lorentzen, C. L., Haanen, J. B., Met, O. & Svane, I. M. Clinical advances and ongoing trials on mRNA vaccines for cancer treatment. Lancet Oncol. 23, e450–e458 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Benteyn, D., Heirman, C., Bonehill, A., Thielemans, K. & Breckpot, K. mRNA-based dendritic cell vaccines. Expert Rev. Vaccin. 14, 161–176 (2015).

    Article  CAS  Google Scholar 

  76. Nair, S., Boczkowski, D., Pruitt, S. & Urban, J. in Cancer Vaccines: From Research to Clinical Practice 1st ed (Eds Bot, A., Obrocea, M. & Marincola, F. M.) 217–231 (2011).

  77. Dorrie, J., Schaft, N., Schuler, G. & Schuler-Thurner, B. Therapeutic cancer vaccination with ex vivo RNA-transfected dendritic cells-an update. Pharmaceutics 12, 92 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Van Driessche, A. et al. Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial. Cytotherapy 11, 653–668 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Grabbe, S. et al. Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma. Nanomedicine 11, 2723–2734 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Oberli, M. A. et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 17, 1326–1335 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Sayour, E. J. et al. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. OncoImmunology 6, e1256527 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).

    Article  PubMed  Google Scholar 

  84. Mendez-Gomez, H. R. et al. RNA aggregates harness the danger response for potent cancer immunotherapy. Cell 187, 2521–2535.e21 (2024).

    Article  CAS  PubMed  Google Scholar 

  85. Weide, B. et al. Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. J. Immunother. 32, 498–507 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Papachristofilou, A. et al. Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer. J. Immunother. Cancer 7, 38 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kubler, H. et al. Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study. J. Immunother. Cancer 3, 26 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Cafri, G. et al. mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J. Clin. Invest. 130, 5976–5988 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).

    Article  CAS  PubMed  Google Scholar 

  90. Raimondo, T. M., Reed, K., Shi, D. N., Langer, R. & Anderson, D. G. Delivering the next generation of cancer immunotherapies with RNA. Cell 186, 1535–1540 (2023).

    Article  CAS  PubMed  Google Scholar 

  91. Palmer, C. D. et al. Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results. Nat. Med. 28, 1619–1629 (2022).

    Article  CAS  PubMed  Google Scholar 

  92. Rappaport, A. R. et al. A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results. Nat. Med. 30, 1013–1022 (2024).

    Article  CAS  PubMed  Google Scholar 

  93. Cruz, L. J. et al. Targeting nanoparticles to dendritic cells for immunotherapy. Methods Enzymol. 509, 143–163 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Briquez, P. S. et al. Engineering targeting materials for therapeutic cancer vaccines. Front. Bioeng. Biotechnol. 8, 19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Eigentler, T. et al. A phase I dose-escalation and expansion study of intratumoral CV8102 as single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors. J. Clin. Oncol. 38, https://doi.org/10.1200/JCO.2020.38.15_suppl.3096 (2020).

  96. Eigentler, T. et al. Intratumorally administered CV8102 in patients with advanced solid tumors: preliminary results from ongoing expansion part in study 008. J. Immunother. Cancer 10, A818 (2022).

    Google Scholar 

  97. Patel, M. R. et al. A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. J. Clin. Oncol. 38, 3092 (2020).

    Article  Google Scholar 

  98. Jimeno, A. et al. A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies. Cancer Res. 80, CT032 (2020).

    Article  Google Scholar 

  99. Bechter, O. et al. Abstract LB198: a first-in-human, open-label, multicenter study of intratumoral SAR441000 (mixture of cytokine encoding mRNAs), as monotherapy and in combination with cemiplimab in patients with advanced solid tumors. Phase 1/2 study of mRNA-4359 administered alone and in combination with immune checkpoint blockade in adult participants with advanced solid tumors. Cancer Res. https://doi.org/10.1158/1538-7445.AM2023-LB198 (2023).

    Article  Google Scholar 

  100. Barral, P. M. et al. Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharmacol. Ther. 124, 219–234 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kang, D. C. et al. Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene. Oncogene 23, 1789–1800 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851–2858 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Takeuchi, O. & Akira, S. MDA5/RIG-I and virus recognition. Curr. Opin. Immunol. 20, 17–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Zhang, Y. L., Guo, Y. J., Bin, L. & Sun, S. H. Hepatitis C virus single-stranded RNA induces innate immunity via Toll-like receptor 7. J. Hepatol. 51, 29–38 (2009).

    Article  PubMed  Google Scholar 

  105. Saito, T., Owen, D. M., Jiang, F., Marcotrigiano, J. & Gale, M.Jr. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523–527 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Chattopadhyay, S. & Sen, G. C. dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J. Interferon Cytokine Res. 34, 427–436 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Broos, K. et al. Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon. Mol. Ther. Nucleic Acids 5, e326 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. & Lanzavecchia, A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat. Immunol. 6, 769–776 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sahin, U. et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature 586, 594–599 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427–2438 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Sittplangkoon, C. et al. mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model. Front. Immunol. 13, 983000 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ramos da Silva, J. et al. Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice. Sci. Transl. Med. 15, eabn3464 (2023).

    Article  CAS  PubMed  Google Scholar 

  113. Holtkamp, S. et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood 108, 4009–4017 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Bonehill, A. et al. Messenger RNA-electroporated dendritic cells presenting MAGE-A3 simultaneously in HLA class I and class II molecules. J. Immunol. 172, 6649–6657 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Su, Y., Connolly, M., Marketon, A. & Heiland, T. CryJ-LAMP DNA vaccines for Japanese red edar allergy induce robust Th1-type immune responses in murine model. J. Immunol. Res. 2016, 4857869 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Beck, J. D. et al. mRNA therapeutics in cancer immunotherapy. Mol. Cancer 20, 69 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Orlandini von Niessen, A. G. et al. Improving mRNA-Based therapeutic gene delivery by expression-augmenting 3’ UTRs identified by cellular library screening. Mol. Ther. 27, 824–836 (2019).

    Article  CAS  PubMed  Google Scholar 

  118. Niu, D., Wu, Y. & Lian, J. Circular RNA vaccine in disease prevention and treatment. Signal. Transduct. Target. Ther. 8, 341 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mackensen, A. et al. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial. Nat. Med. 29, 2844–2853 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Yap, T. A. et al. A phase I/II dose escalation trial with expansion cohorts to evaluate safety and preliminary efficacy of BNT142 in patients with prospectively confirmed claudin 6-positive solid tumors J. Clin. Oncol. 41, https://doi.org/10.1200/JCO.2023.41.16_suppl.TPS2669 (2023).

  123. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    Article  CAS  PubMed  Google Scholar 

  124. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).

    Article  CAS  PubMed  Google Scholar 

  125. Lopez, J. S. et al. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. Cancer Res. 80, CT301 (2020).

    Article  Google Scholar 

  126. Castañón, E. et al. Intratumoral (IT) MEDI1191 + durvalumab (D): update on the first-in-human study in advanced solid tumors. Cancer Res. 83, CT004 (2023).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

E.J.S., D.B. and S.K.N. researched data for the manuscript. E.J.S. and D.B. wrote the manuscript. All authors made a substantial contribution to discussions of content and reviewed and/or edited the manuscript prior to submission.

Corresponding author

Correspondence to Smita K. Nair.

Ethics declarations

Competing interests

E.J.S. has acted as a consultant of Siren Biotechnology and is listed on pending patent applications relating to technologies discussed in this manuscript that are optioned to license to iOncologi, Inc. D.A.M. is listed on pending patent applications on technologies discussed in this manuscript that are optioned to license to iOncologi, Inc. and holds ownership interests in iOncologi, Inc. S.K.N. and D.B. declare no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks Z. Berneman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sayour, E.J., Boczkowski, D., Mitchell, D.A. et al. Cancer mRNA vaccines: clinical advances and future opportunities. Nat Rev Clin Oncol 21, 489–500 (2024). https://doi.org/10.1038/s41571-024-00902-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-024-00902-1

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing