A Study of Metastatic Gastrointestinal Cancers Treated With Tumor Infiltrating Lymphocytes in Which the Gene Encoding the Intracellular Immune Checkpoint CISH Is Inhibited Using CRISPR Genetic Engineering

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Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma. Efficacy in more common solid tumors has been demonstrated via the selection of cancer neoantigen-specific TIL. Combination cell surface checkpoint inhibitor therapy has also been employed in an att...

Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma. Efficacy in more common solid tumors has been demonstrated via the selection of cancer neoantigen-specific TIL. Combination cell surface checkpoint inhibitor therapy has also been employed in an attempt to enhance the efficacy of these cell therapies. Genetic engineering of T cells to further increase anti-tumor activity is now possible. CISH (Cytokine-induced SH2 protein) is a novel intra-cellular immune checkpoint and an important negative regulator of T-cell signaling and function. The inhibition of CISH in mouse anti-tumor lymphocytes results in a marked increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. Additionally, data in genetically-engineered, neoantigen-specific human T cells in which CISH was inhibited, showed enhanced TCR functional avidity and increased ability of these T cells to detect cancer specific mutations and mount robust polyfunctional cytokine immune responses against their cognate cancer antigens. Thus, these T cells appear to have a significant advantage in inducing anti-tumor responses compared to wild-type anti-tumor lymphocytes. The researchers have developed and optimized a CRISPR/Cas9 based strategy for precise and efficient genetic engineering in primary human T-cells without sacrificing cell viability or function, allowing for inhibition of a heretofore undruggable intracellular checkpoint. Thus, in this protocol, the researchers propose to inhibit the gene encoding the intracellular checkpoint target CISH in lymphocytes from patients with metastatic cancers that are selected for anti-tumor activity in order to evaluate the safety and efficacy of genetically engineered T cell therapy for solid tumors in the setting of novel checkpoint inhibition.

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