The identification of T cell antigens expressed by human tumors has led to the clinical trials designed to boost the host immune response against their tumors (reviewed by 1-4). Cancer vaccine strategies include antigenic peptides, peptide loaded dendritic cells, recombinant adenoviruses, vaccinia viruses, and plasmid DNA. Despite evidence of vaccination, very few clinical responses have been reported. Furthermore, those patients which had a clinical response generally have no evidence of vaccination. We have recently described a TCR gene transfer a treatment strategy designed to provide a source of autologous tumor reactive T cell to any patient regardless of their immune status. The primary goal of this proposal is to determine TCR gene modified T cells can be safely administered and have anti-tumor efficacy using an animal model for human melanoma. We will also determine how TCR affinity, tumor antigen vaccines, and IL-2 impacts on the safety and efficacy of TCR gene modified T cells in vivo. In addition to safety and efficacy, we will use using sensitive PCR assays we developed to address relevant questions regarding the fate of adoptively transferred T cells in tumor bearing mice which are not easily addressed in cancer patients. The successful completion of the proposed studies will enable us to design better immunotherapy treatment strategies for patients with advanced cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104947-05
Application #
8055517
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2007-07-01
Project End
2011-07-02
Budget Start
2011-05-01
Budget End
2011-07-02
Support Year
5
Fiscal Year
2011
Total Cost
$211,935
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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
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
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
Spear, Timothy T; Wang, Yuan; Foley, Kendra C et al. (2017) Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells. Cancer Immunol Immunother 66:1411-1424
Foley, Kendra C; Spear, Timothy T; Murray, David C et al. (2017) HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer. Mol Ther Oncolytics 5:105-115
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
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
Kesarwani, Pravin; Al-Khami, Amir A; Scurti, Gina et al. (2014) Promoting thiol expression increases the durability of antitumor T-cell functions. Cancer Res 74:6036-6047
Mosenson, Jeffrey A; Zloza, Andrew; Nieland, John D et al. (2013) Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Sci Transl Med 5:174ra28
Wastowski, Isabela J; Simoes, Renata T; Yaghi, Layale et al. (2013) Human leukocyte antigen-G is frequently expressed in glioblastoma and may be induced in vitro by combined 5-aza-2'-deoxycytidine and interferon-ýý treatments: results from a multicentric study. Am J Pathol 182:540-52

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