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 #
7R01CA104947-06
Application #
8426777
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2007-07-01
Project End
2014-04-30
Budget Start
2012-06-18
Budget End
2014-04-30
Support Year
6
Fiscal Year
2011
Total Cost
$72,521
Indirect Cost
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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
Campoli, Michael; Fitzpatrick, James E; High, Whitney et al. (2012) HLA antigen expression in melanocytic lesions: is acquisition of HLA antigen expression a biomarker of atypical (dysplastic) melanocytes? J Am Acad Dermatol 66:911-6, 916.e1-8
Kirkwood, John M; Butterfield, Lisa H; Tarhini, Ahmad A et al. (2012) Immunotherapy of cancer in 2012. CA Cancer J Clin 62:309-35
Mehrotra, Shikhar; Al-Khami, Amir A; Klarquist, Jared et al. (2012) A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice. J Immunol 189:1627-38

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