CISH Inactivated TILs in the Treatment of NSCLC

Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma, but also in non-small cell lung cancer (NSCLC). 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 TIL from patients with metastatic NSCLC whose tumors are PD-L1 negative or positive in order to evaluate the safety and efficacy of genetically engineered T cell therapy in the setting of novel checkpoint inhibition .