In our original studies, we first described the ability to generate MHC class I restricted CD4+ T cells by retrovirally transduced normal T cells with MHC class I restricted TCR genes. We subsequently showed that if the TCR had sufficient affinity, the resulting MHC class 1 restricted CD4+ T cells could recognize physiologic levels of antigen expressed by tumor cells. Therefore, these novels T cells could augment the anti-tumor immune response by helping to prime the host immune response in tumor lesions. They could also promote the persistence and function of adoptively transferred CD8+ T cells. However, nothing is known about the biology of TCR transduced CD4+ T cells in vivo and their impact on the CD8+ T cells in vitro or in vivo. We have preliminary data that shows this novel population actually inhibits CD8+ T cell priming which would be contrary to their desired function. The goal of this project is to acquire a better understanding ofthe role of MHC class 1 restricted CD4+ T cells in anti-tumor immunity. Our central hypothesis is that MHC class I restricted, TCR transduced CD4+ T cells can be made to augment the antitumor immune response by CD8+ T cells. We predict this will occur by inducing them to become potent Th cells capable of licensing DC to prime CD8+ T cells in vitro. We further predict that MHC class I restricted, TCR transduced CD4+ T cells can be made promote the persistence and function of TCR transduced CD8+ T cells in vivo. These hypotheses/predictions will be tested using a combination of mouse and human CD4+ T cells transduced to express the TIL 13831 TCR. These TCR transduced CD4+ T cells, which recognize the tyrosinase:368-376 epitope presented by HLA-A2, will be compared to their normal mouse or human counterparts for their ability secrete cytokines, license DC to prime/activate naive and TCR transduced CD8+ T cells, and mediate tumor regression in vivo.
This Project will study the biology of TCR transduced cells that are engineered to be MHC class I restricted. This novel T cell population could help activate the host immune response against tumor antigens and maintain the persistence of adoptively transferred CD8+ T cells in vivo. Using a combination of mouse and human models, we will determine how to apply the biology we learn to improve the effectiveness of TCR transduced T cells in cancer patients.
|Moore, Tamson; Wagner, Courtney Regan; Scurti, Gina M et al. (2018) Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. Cancer Immunol Immunother 67:311-325|
|Johnson, C Bryce; May, Bennett R; Riesenberg, Brian P et al. (2018) Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8+ T Cells. Cancer Res 78:3067-3074|
|Spear, Timothy T; Wang, Yuan; Smith Jr, Thomas W et al. (2018) Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells. Mol Ther 26:996-1007|
|Wrangle, John M; Velcheti, Vamsidhar; Patel, Manish R et al. (2018) ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol 19:694-704|
|Spear, Timothy T; Foley, Kendra C; Garrett-Mayer, Elizabeth et al. (2018) TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence. J Leukoc Biol 103:973-983|
|Riley, Timothy P; Hellman, Lance M; Gee, Marvin H et al. (2018) T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability. Nat Chem Biol 14:934-942|
|Nelson, Alexander; Cunha, Christina; Nishimura, Michael I et al. (2018) Activated human Foxp3+ regulatory T cells produce membrane-bound TNF. Cytokine 111:454-459|
|Knochelmann, Hannah M; Smith, Aubrey S; Dwyer, Connor J et al. (2018) CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies. Front Immunol 9:1740|
|Wrangle, John M; Patterson, Alicia; Johnson, C Bryce et al. (2018) IL-2 and Beyond in Cancer Immunotherapy. J Interferon Cytokine Res 38:45-68|
|Scheffel, Matthew J; Scurti, Gina; Wyatt, Megan M et al. (2018) N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner. Cancer Immunol Immunother 67:691-702|
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