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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154778-04
Application #
8745148
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$201,200
Indirect Cost
$69,831
Name
Loyola University Chicago
Department
Type
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Chiuzan, Cody; Garrett-Mayer, Elizabeth; Nishimura, Michael (2018) An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials. Stat Biopharm Res 10:185-195
Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita et al. (2018) CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab 27:85-100.e8
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Chatterjee, Shilpak; Chakraborty, Paramita; Daenthanasanmak, Anusara et al. (2018) Targeting PIM Kinase with PD1 inhibition Improves Immunotherapeutic Antitumor T-cell Response. Clin Cancer Res :
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
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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

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