Recent clinical trials conducted at the Surgery Branch of the National Cancer Institute (NCI) has have found that adoptive transfer of autologous tumor reactive T cells into patients preconditioned with nonmyeloablative chemotherapy leads to significant durable objective clinical responses. T cells used in these studies were TIL harvested from melanoma lesions. There are two key problems that have limited its use outside the NCI. First, many patients don't have suitable tumors TIL harvest. Second, it is difficult to isolate and expand tumor reactive T cells to therapeutic numbers for most patients. New approaches for adoptive T cell transfer are needed if this approach will make it beyond the experimental stage. We published the first report demonstrating that it was feasible to redirect the reactivity of normal PBL-derived T cells using retroviral vectors encoding TCR genes isolated from a MART-1 reactive T cell clone. This opened the possibility of providing any patient with a source of autologous tumor-reactive T cells capable of recognizing any antigen so long as a TCR was available which could recognize that antigen. This MART-1 reactive TCR was the first used to treat patients with TCR gene modified T cells demonstrating the feasibility and safety of using TCR gene modified T cells in humans. However, this trial and three others had fewer objective clinical response compared to TIL suggesting TCR gene modified T cells are less effective that TIL. Based on these trials, it is clear there are critical differences between these two cells types. Over the years, the field of TCR gene transfer has focused on TCR affinity, TCR pairing, and TCR expression. The biology of T cells engineered with viral vectors has largely been unexplored. We therefore hypothesize that TCR gene modified T cells are fundamentally different than """"""""normal"""""""" T cells in how they respond to environmental factors. We further hypothesize that a better understanding of how TCR transduced T cells are impacted by lymphopenia, T cell help, activation-induced cell death (AICD), costimulation, and immune suppression will lead to better TCR transduced T cells for patient treatment. Based on these hypotheses, we developed this Program to improve the function of TCR gene modified T cells through a series of laboratory comparing TCR transduced T cells to normal T cells bearing the same TCR. When complimented with clinical trials, our highly integrated Program will advance the field of TCR gene transfer leading to their improved therapeutic efficacy not only for patients with melanoma but for patients with other malignancies and chronic viral infections.

Public Health Relevance

The goal of this integrated and collaborative Program is to gain a better understanding of the biology of TCR gene modified T cells to enhance their therapeutic efficacy in vivo. Projects in this Program will study how lymphopenia, antigen stimulation, T cell help, cosfimulafion, and suppression influence the persistence and function of adoptively transferred TCR gene modified T cells. These studies will be conducted in mouse melanoma models and clinical trials in melanoma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154778-02
Application #
8336841
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Song, Min-Kyung H
Project Start
2011-09-21
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$3,493,020
Indirect Cost
$705,117
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
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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