A therapeutic cancer vaccine delivers antigens and adjuvants to lymphoid tissues using genetically modified T cells

• Published in: The Journal of clinical investigation Vol. 131; no. 16; pp. 1 - 16
• Main Authors: Veatch, Joshua R, Singhi, Naina, Srivastava, Shivani, Szeto, Julia L, Jesernig, Brenda, Stull, Sylvia M, Fitzgibbon, Matthew, Sarvothama, Megha, Yechan-Gunja, Sushma, James, Scott E, Riddell, Stanley R
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 16.08.2021
• Subjects: Adjuvants; Adjuvants, Immunologic - administration & dosage; Allografts; Animal models; Animals; Antigen (tumor-associated); Antigen Presentation; Antigens; Antigens, Neoplasm - administration & dosage; Antitumor activity; Autocrine signalling; Autografts; Biomedical research; Cancer; Cancer vaccines; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; CD80 antigen; Cell culture; Clinical trials; Cross Reactions - immunology; Dendritic Cells - immunology; Epitopes; Female; FLT3L protein; Genetic aspects; Genetic engineering; Granulocyte-macrophage colony-stimulating factor; Health aspects; Humans; Immunologic Memory; Immunological adjuvants; Immunological research; Immunotherapy; Immunotherapy, Adoptive; Interleukin 12; Interleukin-12 - immunology; Lymphocytes; Lymphocytes T; Lymphoid tissue; Lymphoid Tissue - immunology; Male; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastases; Methods; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoantigens; Proteins; T cells; Transgenes; Translational Research, Biomedical; Tumor antigens; Vaccines; β-Interferon; United States; Cancer immunotherapy; Immunology; Vaccines
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI144195

Therapeutic vaccines that augment T cell responses to tumor antigens have been limited by poor potency in clinical trials. In contrast, the transfer of T cells modified with foreign transgenes frequently induces potent endogenous T cell responses to epitopes in the transgene product, and these responses are undesirable, because they lead to rejection of the transferred T cells. We sought to harness gene-modified T cells as a vaccine platform and developed cancer vaccines composed of autologous T cells modified with tumor antigens and additional adjuvant signals (Tvax). T cells expressing model antigens and a broad range of tumor neoantigens induced robust and durable T cell responses through cross-presentation of antigens by host DCs. Providing Tvax with signals such as CD80, CD137L, IFN-β, IL-12, GM-CSF, and FLT3L enhanced T cell priming. Coexpression of IL-12 and GM-CSF induced the strongest CD4+ and CD8+ T cell responses through complimentary effects on the recruitment and activation of DCs, mediated by autocrine IL-12 receptor signaling in the Tvax. Therapeutic vaccination with Tvax and adjuvants showed antitumor activity in subcutaneous and metastatic preclinical mouse models. Human T cells modified with neoantigens readily activated specific T cells derived from patients, providing a path for clinical translation of this therapeutic platform in cancer.