; Seminal work on the identity of human melanoma associated antigen have led to the development of novel adoptive immunotherapeutic strategies in cancer treatment that involves isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration for inducing anti-tumor immune responses. In an effort to make adoptive immunotherapy more broadly available, strategies to genetically transfer tumor specific immune receptors into patient's autologous T cells via T cell receptor (TCR) gene therapy are being pursued intensely. Successful outcome for adoptive T cell immunotherapy has been linked to persistence of the effector T cell population. However several biological mechanisms may still account for the failure to achieve efficient immune protection. To address various constraints that may arise when using the high affinity TCR for adoptive immunotherapy, we recently developed transgenic mouse model expressing TIL1383I TCR, same human HLA-A2 restricted high affinity TCR reactive to human tyrosinase-derived peptide YMDGTMSQV isolated from a class-l restricted CD4* T cells of tumor infiltrating lymphocytes (TILs) of a patient with metastatic melanoma, that is being used in clinical trials. The transgenic mouse expressing the TIL1383I TCR presents a clinically relevant model, which provides us with a unique opportunity to compare TCR transduced T cells with a normal unmanlpulated population of T cells bearing the same receptor. Therefore, the TIL1383I TCR bearing transgenic mouse (referred as h3T - human TIL derived Tyrosinase TCR) model will be extensively used as a key source of cells for comparisons in experiments proposed by projects 1-4. The mouse core will provide quality-controlled donor mouse cells to projects 1-4 and Core C. In addition the core will maintain breeding colonies of recipient mice, generate additional hST specialty strains, and maintain other specialty strains as needed for individual projects. The centralized operation of mouse maintenance will have the advantages of reduced cost, consistency among projects due to centralized quality control, and ease of use for the investigators. Thus, the aims of this mouse core facility are 1) To provide quality-controlled donor mouse T cells from TIL 13831 TCR bearing h3T transgenic mice, 2) To maintain breeding colonies of mice, which are used as recipient strains, and 3) To develop novel strains of TIL 13831 TCR transgenic mice and maintain breeding colonies of mice that will be specifically utilized by individual Projects in the Program.
We have developed a novel and unique mouse model, which will provide donor cells for adoptive cell therapy to all investigators of this program project. The core will be responsible for breeding, maintenance and quality control of these mice as well as recipient mice and specialty mouse strains. The centralized operation has the advantages of reduced cost, consistency by providing quality control, and ease of use.
|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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