Gene-regulating compositions and methods for improved immunotherapy

Inventors

Benson, Micah • Merkin, Jason J. • Kryukov, Gregory V. • Shenker, Solomon Martin • Schlabach, Michael R. • Tubo, Noah Jacob

Assignees

KSQ Therapeutics Inc

Abstract

The present disclosure provides methods and compositions related to the modification of immune effector cells to increase therapeutic efficacy. In some embodiments, immune effector cells modified to reduce expression of one or more endogenous target genes, or to reduce one or more functions of an endogenous protein to enhance effector functions of the immune cells are provided. In some embodiments, immune effector cells further modified by introduction of transgenes conferring antigen specificity, such as exogenous T cell receptors (TCRs) or chimeric antigen receptors (CARs) are provided. Methods of treating a cell proliferative disorder, such as a cancer, using the modified immune effector cells described herein are also provided.

Core Innovation

The disclosure relates to gene-regulating immunotherapy using modified human tumor infiltrating lymphocytes (TIL) to enhance anti-tumor effector functions. The modified human TIL comprise a modified endogenous ZC3H12A gene, and ZC3H12A protein expression and/or function is reduced relative to unmodified human TIL expressing an unmodified endogenous ZC3H12A gene. Anti-tumor efficacy of the modified TIL is increased relative to anti-tumor efficacy of the unmodified TIL.

The disclosure ties improved efficacy to enhanced effector functions including proliferation, infiltration, persistence, cytotoxicity, resistance to exhaustion, and increased cytokine production including IFNγ, TNFα, and IL-2. It also states that reducing ZC3H12A protein expression and/or function in tumor infiltrating lymphocytes improves anti-tumor effector functions, and that modified cells show increased target-cell lysis.

The document further describes gene-regulating system components for reducing endogenous gene expression and/or function, centered on ZC3H12A inhibition using CRISPR/Cas, zinc-finger systems, siRNA/shRNA, antisense modalities, antibodies, small molecules, or peptides. It also describes optional reduction of additional endogenous target genes across checkpoint and inhibitory pathways and other pathway genes, including NFκB signaling, TGF-β signaling, TCR activation, and apoptosis.

Claims Coverage

The independent claims cover cancer treatment methods administering modified human tumor infiltrating lymphocytes (TIL) with reduced ZC3H12A protein expression and/or function, resulting in increased anti-tumor efficacy. Two inventive features are present: a general modified TIL treatment based on ZC3H12A reduction, and an expanded method specifying a minimum population size with an insertion and deletion (indel) in the ZC3H12A gene.

Overall, the claims focus on administering modified human TIL in which endogenous ZC3H12A protein expression and/or function is reduced, with increased anti-tumor efficacy as the outcome. One independent claim covers the method broadly with ZC3H12A reduction, and the other additionally specifies an indel in the ZC3H12A gene and a minimum administered TIL population quantity.

Stated Advantages

Documented Applications