A therapeutic cancer vaccine delivers antigens and adjuvants to lymphoid tissues using genetically modified T cells
Joshua R. Veatch, … , Scott E. James, Stanley R. Riddell
Joshua R. Veatch, … , Scott E. James, Stanley R. Riddell
Published August 16, 2021
Citation Information: J Clin Invest. 2021;131(16):e144195. https://doi.org/10.1172/JCI144195.
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Research Article Immunology

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

Abstract

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.

Authors

Joshua R. Veatch, Naina Singhi, Shivani Srivastava, Julia L. Szeto, Brenda Jesernig, Sylvia M. Stull, Matthew Fitzgibbon, Megha Sarvothama, Sushma Yechan-Gunja, Scott E. James, Stanley R. Riddell

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Figure 4

Tvax induces T cell responses to naturally occurring neoantigens.

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Tvax induces T cell responses to naturally occurring neoantigens. (A) Mi...
(A) Mice were injected with Tvax expressing sequences spanning the Alg8 and Lama4 point mutations previously described in a methylcholanthrene-induced sarcoma, with and without mtIL12 and GM-CSF adjuvants. Alg8- and Lama4-specific T cell responses were measured in the blood on day 7 by tetramer staining. (B) Frequency of Alg8- and Lama4-specific T cells in mice over time and after a booster vaccination on day 42 with Tvax expressing Alg8 and Lama4 only. (C) Expression of CD44 and CD62L on tetramer+ T cells in the blood on day 7 and day 36 following vaccination. (D and E) T cell responses induced by administration of TvaxmtIL-12/GM-CSF modified to express the MC-38 neoantigens Adgpk, Dpagt, or Reps1 (n = 8 mice/group) (D), and Cpne1, Irgq, or Aatf (n = 8 mice/group) (E). Responses were determined by intracellular staining for IFN-γ in CD8+ T cells following stimulation of splenocytes pulsed with peptides for each neoantigen. Controls included responses in unstimulated splenocytes and in splenocytes from mice that were not vaccinated. (F) Mice were injected with TvaxmtIL-12/GM-CSF expressing either Alg8 and Lama4, murine GP100, or human GP100. Spleens were harvested on day13, splenocytes were restimulated with Alg8 or mouse GP100 peptide, and CD8+ T cell responses to each antigen were determined by intracellular staining for IFN-γ. (G) Mice (n = 10 per group) were injected with TvaxAlg8-Lama4–LLO190/mtIL-12/GM-CSF cells from C57BL/6 (syngeneic), B2m–/– (syngeneic B2m), S129 (allogeneic HLA-matched), or BALB/c (allogeneic HLA-mismatched) mice, and Alg8-specific T cell responses were measured in the blood by tetramer staining. *P < 0.0001 and **P < 0.01 for comparisons at all time points, by Mann-Whitney U test. Error bars represent the SEM. stim, stimulation.