Recent studies have shown that adoptive T cell transfer (ACT) can be an effective treatment for patients with metastatic cancer. The most common source of antigen reactive T cells for ACT is ex vivo expanded tumor infiltrating lymphocytes (TIL) or antigen stimulated PBL-derived T cells. One ofthe main limitations to treating patients with ACT is the availability of large numbers of antigen reactive autologous T cells. To circumvent this limitation, we first demonstrated that it was possible to redirect the specificity of T cells using retroviral vectors encoding the TCR a and p genes isolated from a tumor-reactive T cell clone. Subsequently, we and others have shown that it is possible to isolate TCR's that recognize a wide variety of tumor and viral antigens. The resulting TCR transduced T cells can secrete cytokines and lyse targets as efficiently as antigen specific T cells. The field was further advanced by the identification of the first high affinity human TCR that could engineer both CD4+ and CD8+ T cells to recognize the physiologic levels of antigen expressed by tumor cells. These studies and others have open the possibility of providing ACT to a large number of patients regardless of their natural ability to generate anti-tumor immunity. In 2006, the first use of TCR transduced T cells was reported in humans. The conclusions from this study were that TCR gene modified T cells can be safely administered to patients and there was evidence of their anti-tumor activity in vivo. Subsequently, three other studies have been published which support the safety of using TCR transduced T cells in cancer patients. In these studies, objective clinical responses were observed at higher frequencies when high affinity TCRs were used. However, the frequency of the clinical responses in patients treated with TCR transduced T cells (12-30%) was substantially less than in patients treated with TIL (~50%). Therefore, there may be fundamental differences between the biology of TCR transduced T cells and TIL which account for the differences in the clinical response rates. What is needed for this Program is a consistent and reproducible source of mouse and human TIL 13831 TCR transduced T cells for use throughout the Program. Therefore, the goal of Core C is to provide Projects 1-4 with high quality TIL 13831 TCR transduced mouse and human T cells for their in vitro and in vivo studies and to generate clinical grade TIL 13831 TCR transduced T cells for the clinical trials in Project 5.
This Core will provide TCR transduced human and mouse T cells for Project 1-5 in the Program. This includes laboratory grade mouse and human T cells for the laboratory studies as well as all of the clinical grade T cells for the clinical trials in Project 5.
|Wang, Yuan; Singh, Nishant K; Spear, Timothy T et al. (2017) How an alloreactive T-cell receptor achieves peptide and MHC specificity. Proc Natl Acad Sci U S A 114:E4792-E4801|
|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|
|Banerjee, Anirban; Thyagarajan, Krishnamurthy; Chatterjee, Shilpak et al. (2016) Lack of p53 Augments Antitumor Functions in Cytolytic T Cells. Cancer Res 76:5229-5240|
|Blevins, Sydney J; Pierce, Brian G; Singh, Nishant K et al. (2016) How structural adaptability exists alongside HLA-A2 bias in the human ?? TCR repertoire. Proc Natl Acad Sci U S A 113:E1276-85|
|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|
|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|
|Spear, Timothy T; Nagato, Kaoru; Nishimura, Michael I (2016) Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother 65:631-49|
|Sandri, Sara; Bobisse, Sara; Moxley, Kelly et al. (2016) Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies. Cancer Res 76:2540-51|
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