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 8

Human T cells present cancer-derived neoantigens.

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Human T cells present cancer-derived neoantigens. (A) Schematic of piggy...
(A) Schematic of piggyBac transposon construct to engineer human Tvax. MITD, MHC class I tracking domain; pCMV,cytomegalovirus immediate early promoter; T2A, translational skip sequence from thosea asigna virus; WPRE, woodchuck hepatitis virus posttranscriptional regulatory element. (B) Human T cells were transfected with a transposon encoding CMV and tumor neoantigens, and tCD19 and stably transfected cells were measured 7 days later by staining for surface CD19 (top panel). CD19+ cells were enriched by immunomagnetic selection and expanded in culture for 14 days followed by CD19 staining (bottom panel) (C) T cells from HLA-compatible normal donors were transfected with a transposon containing antigen minigenes and then purified and expanded before use as APCs in vitro. Modified T cells presented the respective antigens to a PWP2-specific CD8+ T cell clone derived from a patient with lung adenocarcinoma, a BRAF V600E–specific CD4+ T cell clone derived from a patient with melanoma, and CD8+ T cells specific for the CMV NLV epitope derived from a healthy donor.