Reversing the effects of the tumor microenvironment using chimeric cytokine receptors
The present invention concerns compositions and methods related to approaches to render ineffective Th1 T cells resistant to the inhibitory cytokine milieu present in a cancer microenvironment. In particular embodiments, tumor-specific T cells are modified to employ a chimeric receptor that binds inhibitory/suppressive cytokines and converts their intracellular consequences to a Th1 immunostimulaotyr/activating signal. In specific embodiments, the T cells employ a chimeric antigen receptor having exodomains for IL10, IL13 and/or IL4 fused with the signal transducing endodomains for IL2 and/or IL7.
1. An immune system cell comprising a chimeric cytokine receptor comprising a cytokine-binding exodomain and a signal transducing endodomain, wherein the exodomain is selected from the group consisting of interleukin (IL)10 receptor exodomain, IL13 receptor exodomain, transforming growth factor (TGF)beta receptor exodomain, IL6 receptor exodomain, IL8 receptor exodomain, and a combination thereof, and wherein the endodomain is selected from the group consisting of IL2 receptor endodomain, IL7 receptor endodomain, IL15 receptor endodomain, and a combination thereof,
or wherein the exodomain is IL4 receptor exodomain and the endodomain is IL7 receptor endodomain.
2. The cell of claim 1 , wherein the cell is selected from the group consisting of primary T cell, T lymphocyte, and natural killer (NK) cell.
3. The cell of claim 2 , wherein the T lymphocyte is a naturally occurring tumor antigen-specific cytotoxic T lymphocyte.
4. The cell of claim 1 , wherein the cell targets a tumor associated antigen selected from the group consisting of carcinoembryonic antigen (CEA), Mucin (MUC)1, Mucin 5 Subtypes A And C (MUC5AC), MUC6, telomerase, Preferentially Expressed Antigen In Melanoma (PRAME), Melanoma Antigen Gene (MAGE)A, synovial sarcoma, X (SSX)2/4, New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO), and Survivin.