Chimeric antigen receptors with mutated cd28 costimulatory domains

Abstract

Disclosed herein are chimeric antigen receptor (CAR) polypeptides, which can be used with adoptive cell transfer to target and kill cancers, that comprise a co-stimulatory signaling region having a mutated form of a cytoplasmic domain of CD28 that enhances CAR-T cell function, e.g. by reducing CAR-T cell exhaustion. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, which are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a tumor associated antigen-expressing cancer that involvesadoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 529,919, filed July 7, 2017, the entire contents of which are hereby incorporated by reference. [0003] sequence listing [0004] This application contains a Sequence Listing filed electronically as an ASCII.txt file named "320803_2160_Sequence Listing_ST25" created on July 7, 2018. The contents of the Sequence Listing are incorporated herein in their entirety. Background technique [0005] Surgery, radiation therapy, and chemotherapy have become standard approaches to treating cancers including leukemias, solid tumors, and metastases. As an adjunct to conventional cancer treatment, immunotherapies (sometimes called biotherapies, biotherapeutics, or biologic response modifier therapies) that directly or indirectly use the body's immune system to shrink or eradicate cancer have been studied. The human immune system is believed to be an untapped re...

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However, poor CAR T cell persistence and excessive T cell activation lead to relapse and severe toxicity, respectively, suggesting a critical need for understanding CAR T cell biology (Gangadhar, T.C. and R.H. Vonderheide, Nat Rev Clin Oncol, 2014.11(2 ):91-9)

Furthermore, relapse and toxicity were seen in all second-generation CARs, suggesting that adding a co-stimulatory domain to CARs improves efficacy but at the expense of biological complications

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