Active specific and adoptive immunotherapy for cancer centering on cytolytic T lymphocyte (CTL) response have shown encouraging results. These treatment modalities, however, would benefit from the involvement of cognate CD4+ T helper (Th) cells. We have found that CD4+ T cells -- engineered to express a MHC class I- restricted melanoma epitope specific T cell receptor (TCR) that is also used by CTL to recognize the epitope -- synthesize Th1 type cytokines and exhibit cytolytic potential against melanoma cells and surrogate target cells in an epitope specific manner. We propose a comprehensive study of the biology of such MHC class I-restricted TCR engineered CD4 T cells in an anti-melanoma immune response focusing on their role as effector cells and as helper T cells. The central hypothesis is that """"""""considering that help and suppression are two mutually opposed conditions, if one could engage CTL and helper cells recognizing a tumor associated epitope of interest simultaneously through an identical TCR and on the same MHC restricting molecules, the CD4+ T cells would facilitate the generation of a robust and long-lasting CTL response and mitigate Treg activation. Additionally, by exhibiting anti-tumor effector function of their own, they would expand the anti-tumor repertoire"""""""". We propose to test this hypothesis through several specific aims designed with CD4+ T cells engineered to express melanoma epitope (MART-127-35 and Tyrosinase368-376)-specific TCR in in vitro assays, and in HLA- A2.1/Kb transgenic mice employing a chimeric human-mouse TCR consisting of mouse constant regions and human variable regions, in vivo. The biology of the CD4+ Th cells will be assessed through a comprehensive phenotypic and functional characterization in in vitro CTL generation assay, in vitro Treg activation assay, and in adoptive transfers of chimeric TCR engineered T cells into HLA-A2.1/Kb mice bearing A2.1/Kb transgenic B-16 melanoma cells. The proposed research will lead to the development of a new and complementary strategy to active specific and adoptive immunotherapy for cancer. Lay Summary: The proposed research is designed to develop a novel way to engage killer T cells and helper T cells (two important players in the immune system) to work in a collaborative and synergistic manner so as to orchestrate a robust and long-lived cellular immune attack against human cancers - a major cause of death.

Public Health Relevance

""""""""Cancer vaccines"""""""" and adoptive cell therapy for cancer have shown promising results but the two basic approaches need new strategies addressing two major impediments -- the lack of an effective way that would engage cognate CD4 T helper (Th) cells in the treatment and T regulatory (Treg) cell activities. We propose a novel strategy that could address both constraints through the employment of CD4 T cells engineered to express an MHC class I-restricted and tumor epitope specific T cell receptor (TCR) that are also used by cytolytic T cells (CTL) to recognize the tumor antigen. The TCR-engineered CD4 Th cells, therefore, could provide """"""""help"""""""" towards the generation of a robust and long-lived CTL response as well as expand the therapeutic repertoire by mitigating Treg activities (as help and suppression are mutually opposed conditions) and through their own cytolytic potential.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Mccarthy, Susan A
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University of Connecticut
Internal Medicine/Medicine
Schools of Medicine
United States
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Chhabra, Arvind; Mukherji, Bijay (2013) Death receptor-independent activation-induced cell death in human melanoma antigen-specific MHC class I-restricted TCR-engineered CD4 T cells. J Immunol 191:3471-7
Chakraborty, Nitya G; Yadav, Meeta; Dadras, Soheil S et al. (2013) Analyses of T cell-mediated immune response to a human melanoma-associated antigen by the young and the elderly. Hum Immunol 74:640-7
Mukherji, Bijay (2013) Immunology of melanoma. Clin Dermatol 31:156-65
Kaur, Navtej; Naga, Osama S; Norell, Hakan et al. (2011) T cells expanded in presence of IL-15 exhibit increased antioxidant capacity and innate effector molecules. Cytokine 55:307-17
Hegde, Upendra P; Chakraborty, Nitya; Mukherji, Bijay et al. (2011) Metastatic melanoma in the older patient: immunologic insights and treatment outcomes. Expert Rev Pharmacoecon Outcomes Res 11:185-93
Ray, Swagatam; Chhabra, Arvind; Chakraborty, Nitya G et al. (2010) MHC-I-restricted melanoma antigen specific TCR-engineered human CD4+ T cells exhibit multifunctional effector and helper responses, in vitro. Clin Immunol 136:338-47
Ray, Swagatam; Chhabra, Arvind; Mehrotra, Shikhar et al. (2009) Obstacles to and opportunities for more effective peptide-based therapeutic immunization in human melanoma. Clin Dermatol 27:603-13
Chhabra, Arvind; Yang, Lili; Wang, Pin et al. (2008) CD4+CD25- T cells transduced to express MHC class I-restricted epitope-specific TCR synthesize Th1 cytokines and exhibit MHC class I-restricted cytolytic effector function in a human melanoma model. J Immunol 181:1063-70
Chhabra, Arvind; Chakraborty, Nitya G; Mukherji, Bijay (2008) Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-1 27-35. Clin Immunol 126:251-9
Mehrotra, Shikhar; Chhabra, Arvind; Hegde, Upendra et al. (2007) Inhibition of c-Jun N-terminal kinase rescues influenza epitope-specific human cytolytic T lymphocytes from activation-induced cell death. J Leukoc Biol 81:539-47

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