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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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 3

Adjuvant inflammatory signals augment T cell immunity induced by Tvax.

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Adjuvant inflammatory signals augment T cell immunity induced by Tvax. (...
(A) Schematic of different immunostimulatory Tvax strategies. (B–D) Tvax cells transduced with antigen only (TvaxOVA-LLO190) or with antigen and additional inflammatory signals were injected i.v. into mice. The frequency of OVA-specific CD8+ T cell responses in the blood measured by tetramer on day 8 (B and C) and weekly for 28 days (D) is shown for each of the different adjuvants. (E) Frequency of OVA-specific T cells in blood after boosting with TvaxOVA-LLO190 on day 28. (F and G) LLO-specific CD4+ T cell responses to were measured by tetramer staining on day 7 after vaccination of mice with Tvax and different adjuvants. (H and I) Splenocytes were incubated with OVA and LLO190 peptides on day 13 after vaccination, and the percentages of polyfunctional CD8+ T cells (H) and CD4+ T cells (I) were measured by intracellular cytokine staining for IFN-γ, TNF-α, and IL-2. (J) Frequency of OVA-specific CD8+ T cells in mice vaccinated with TvaxOVA–LLO190/mtIL-12/GM-CSF or with an identical number of mature DCs pulsed with OVA and LLO190 peptides (n = 4 mice per group). (K) Mice previously primed with TvaxOVA–LLO190/mtIL-12/GM-CSF were boosted on day 28 with TvaxOVA-LLO190 alone or TvaxOVA-LLO190 and different additional inflammatory signals. OVA-specific T cell responses were measured in the blood by tetramer staining 7 days after boosting. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mann-Whitney U test.