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 #
5P01CA154778-03
Application #
8744931
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2013-09-04
Project End
2016-08-31
Budget Start
2013-09-04
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$181,225
Indirect Cost
$65,512
Name
Loyola University Chicago
Department
Type
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Banerjee, Anirban; Thyagarajan, Krishnamurthy; Chatterjee, Shilpak et al. (2016) Lack of p53 Augments Antitumor Functions in Cytolytic T Cells. Cancer Res 76:5229-40
Spear, Timothy T; Callender, Glenda G; Roszkowski, Jeffrey J et al. (2016) TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol Immunother 65:293-304
Klarquist, Jared; Eby, Jonathan M; Henning, Steven W et al. (2016) Functional cloning of a gp100-reactive T-cell receptor from vitiligo patient skin. Pigment Cell Melanoma Res 29:379-84
Spear, Timothy T; Riley, Timothy P; Lyons, Gretchen E et al. (2016) Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability. J Leukoc Biol 100:545-57
Rubinstein, Mark P; Su, Ee Wern; Suriano, Samantha et al. (2015) Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8(+) T cells. Cancer Immunol Immunother 64:539-49

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