; 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.
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|Chiuzan, Cody; Garrett-Mayer, Elizabeth; Nishimura, Michael (2018) An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials. Stat Biopharm Res 10:185-195|
|Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita et al. (2018) CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab 27:85-100.e8|
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|Foley, Kendra C; Nishimura, Michael I; Moore, Tamson V (2018) Combination immunotherapies implementing adoptive T-cell transfer for advanced-stage melanoma. Melanoma Res 28:171-184|
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