There is mounting evidence from early stage clinical trials that indicate adoptive immunotherapy can mediate regression of established tumors and many of these regressions can be durable. So far, the source of tumor reactive T cells with the greatest therapeutic potential has been TIL. Unfortunately, TIL requires resection of tumor lesions which is not feasible for all malignancies and even for melanoma patients, many have unresectable disease. To circumvent this obstacle, we demonstrated that the specificity of normal PBL-derived T cells can be redirected using retroviral vectors encoding the TCR alpha and beta genes from the MART-1 reactive T cell clone TIL 5. The resulting TIL 5 TCR transduced T cell cultures could specifically recognize MART-1 peptide loaded T2 cells and HLA-A2, MART-1 melanoma cells. Subsequently, the TIL 5 TCR was the first TCR used to treat melanoma patients with TCR gene modified T ceils. While the number of objective clinical responses were low, this phase I trial and others demonstrated the feasibility of generating TCR transduced T cells for patient treatment and that TCR transduced T cells could be administered safely. Over the past decade, dozens of TCR genes have been cloned and characterized for their ability to engineer T cells to recognize virus infected cells and tumor cells. One area of intense study has been the impact of TCR affinity on antigen recognition. We reported a unique T cell clone (TIL 13S3I), an MHC class I restricted CD4 T cell which recognized the immunodominant epitope from tyrosinase presented by HLA-A2. The TIL 13831 TCR was subsequently cloned and was shown in mouse and human T cells to be able to transfer CDS-independent anti-tumor activity to other effectors. This TIL 13831 TCR had all of the properties consistent with a high affinity TCR. Adoptive transfer of transgenic T cells expressing the TIL 13831 TCR (h3T) and TIL 13S3I TCR transduced mouse T cells can mediate regression of established human and mouse melanoma. These preclinical mouse results and clinical trials using high affinity TCRs support the hypothesis that high affinity TCRs are superior to TCRs with low affinity for TCR gene transfer studies. In this project, our hypotheses are 1) TCR transduced T cells bearing a high affinity TCR that targets tyrosinase can be administered safely to melanoma patients pretreated with non-myeloablative chemotherapy, and 2) factors that lead to improved persistence of TCR transduced T cells will lead to improved therapeutic efficacy in cancer patients. To evaluate these hypotheses, we will first conduct a phase I dose escalation trial of TIL 13S3I TCR transduced T cells followed by phase II trial randomizing patients between TIL 13831 TCR transduced CD8 +/- CD4+ T cells to determine how CD4 T cells impact the persistence and function of TCR transduced CD8 T cells in vivo.

Public Health Relevance

We have shown that eliminating the white blood cells in a tumor bearing mouse leads to a rapid repopulation of dendritic cells capable of activating and enhancing the function of adoptively transferred T cells. In this Project, we will examine the effect of these dendritic cells on TCR transduced T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154778-02
Application #
8555361
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
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
$693,336
Indirect Cost
$78,346
Name
Loyola University Chicago
Department
Type
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Spear, Timothy T; Nagato, Kaoru; Nishimura, Michael I (2016) Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother 65:631-49
Scheffel, Matthew J; Scurti, Gina; Simms, Patricia et al. (2016) Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death. Cancer Res 76:6006-6016
Blevins, Sydney J; Pierce, Brian G; Singh, Nishant K et al. (2016) How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire. Proc Natl Acad Sci U S A 113:E1276-85
Hellman, Lance M; Yin, Liusong; Wang, Yuan et al. (2016) Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide-MHC complexes. J Immunol Methods 432:95-101
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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