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.
Highlights
Immune checkpoint inhibitors (ICIs) that target negative regulatory molecules on T cells have shown clinical efficacy in a subset of patients with multiple types of cancer [1, 2], highlighting the ability of endogenous T cells to eliminate tumors
We evaluated how memory T cell responses elicited by TvaxOVA–LLO/mtIL-12/GM-CSF respond to rechallenge by revaccinating mice on day 28 with TvaxOVA-LLO or Tvax combined with additional inflammatory signals
We found that mtIL-12 on TvaxWT cells enhanced CD8+ T cell priming in Il12r-KO mice but that mtIL-12 on TvaxIL-12Rko cells did not augment priming in WT mice, consistent with an autocrine effect of mtIL-12 on Tvax cells contributing to improved immunogenicity (Figure 5B)
Summary
Immune checkpoint inhibitors (ICIs) that target negative regulatory molecules on T cells have shown clinical efficacy in a subset of patients with multiple types of cancer [1, 2], highlighting the ability of endogenous T cells to eliminate tumors. Even in the tumor types most responsive to ICIs, a majority of the patients do not achieve durable tumor regression after such therapies. This may be due to a deficiency in the breadth and number of tumor-reactive T cells [3] or irreversible dysfunction of these responses [4,5,6], raising the possibility that vaccination to augment preexisting tumor-reactive T cells or elicit new responses might improve outcomes when combined with ICIs. It is acknowledged that cancer vaccines designed to augment T cell responses to cancer-specific self-antigens have had limited success [7].
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