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 5

Autocrine effects of mtIL-12 on Tvax cells mediate enhanced immunity of Tvax through IFN-γ.

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Autocrine effects of mtIL-12 on Tvax cells mediate enhanced immunity of ...
(A) Schematic of potential mechanisms whereby IL-12 could augment Tvax priming of CD8+ T cell responses. (B) TvaxOVA cells were engineered with and without mtIL-12 using T cells from WT mice and from mice lacking the IL-12R (Il12r-KO) and then administered to WT or Il12r-KO mice (n = 5 mice/group). OVA-specific CD8+ T cells were measured in the blood 8 days after vaccination by tetramer staining. (C) TvaxOVA cells were constructed with either mtIL-12 or IL-12RCA and administered to WT mice. OVA-specific CD8+ T cell responses were measured in the blood 8 days following vaccination by tetramer staining. (D) TvaxOVA cells from WT or Il12r-KO mice or mice lacking IFN-γ (Ifng-KO) were administered to mice of the same genotype, and OVA-specific T cell responses were measured by tetramer staining 8 days later (n = 10 mice/group). (E) TvaxOVA, TvaxOVA/mtIL-12, or Tvax cells engineered with OVA and constitutively expressing IFN-γ (TvaxOVA/IFN-γ) were administered to WT mice, and OVA-specific CD8+ T cells were measured in the blood on day 8 by tetramer staining (n = 10 mice/group). *P < 0.05 and **P < 0.001, by Mann-Whitney U test.