Compositions and methods for inhibiting T cell exhaustion
Inventors
MacKall, Crystal • Lynn, Rachel • Weber, Evan • Sotillo, Elena
Assignees
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Publication Number
US-12454579-B2
Publication Date
2025-10-28
Expiration Date
Abstract
The present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides T cells that are modified (e.g., genetically and/or functionally) to maintain functionality under conditions in which unmodified T cells display exhaustion. Compositions and methods disclosed herein find use in preventing exhaustion of engineered (e.g., chimeric antigen receptor (CAR) T cells) as well as non-engineered T cells thereby enhancing T cell function (e.g., activity against cancer or infectious disease).
Core Innovation
The invention relates to isolated engineered T cells engineered to express a human c-Jun and an engineered receptor specific for a tumor antigen. The human c-Jun and the engineered receptor are expressed either from separate expression vectors or co-expressed from a single expression vector as separate polypeptides. The engineered receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR), and the engineered T cells exhibit a Th1 cytokine profile.
The document describes reducing T cell exhaustion in chronic antigen settings by maintaining elevated AP-1 activity, including c-Jun, and by reducing AP-1 inhibitory complex members such as JunB, BATF3, IRF4/IRF8, and ATF family members. Exhaustion correlates with reduced AP-1, including c-Fos/c-Jun, in tonic/self-aggregating CAR models, and enforced AP-1/c-Jun expression improves IL-2 production and alters cytokine profiles with Th1 skewing while reducing exhaustion marker expression.
The description further reports that c-Jun re-expression, forced overexpression, or c-Jun-fusion stability control reduces exhaustion markers and improves IL-2 and IFN-gamma production while supporting a central memory phenotype and improved tumor killing/curative activity across leukemia and solid tumor models. The document also reports that knockdown of AP-1 inhibitory members, including JunB and BATF3, increases function in exhausted cells, with therapeutic relevance in cancer and infectious diseases.
Claims Coverage
The independent claims cover an isolated engineered T cell composition with two core inventive features: expression of human c-Jun with a tumor-antigen-specific engineered receptor, and a Th1 cytokine profile. The claims also specify that c-Jun and the engineered receptor are expressed from separate vectors or from a single vector as separate polypeptides, and the engineered receptor is a CAR or engineered TCR.
Engineered T cells expressing human c-Jun and a tumor-antigen-specific receptor
The T cells are engineered to express a human c-Jun and an engineered receptor specific for a tumor antigen, where the engineered receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR).
Separate-vector or single-vector separate-polypeptide co-expression of c-Jun and the engineered receptor
The human c-Jun and the engineered receptor are expressed from separate expression vectors or co-expressed from a single expression vector as separate polypeptides.
Th1 cytokine profile in engineered T cells
The engineered T cells exhibit a Th1 cytokine profile.
Overall, the claims are directed to isolated engineered T cell compositions combining human c-Jun with a tumor-antigen-specific CAR or engineered TCR, with expression arranged via separate vectors or co-expression from a single vector as separate polypeptides, and with a required Th1 cytokine profile.
Stated Advantages
Reduces T cell exhaustion in chronic antigen settings.
Maintains elevated AP-1 activity including c-Jun.
Improves IL-2 production and Th1 skewing cytokine profiles.
Reduces exhaustion marker expression.
Supports memory and central memory phenotypes.
Enhances tumor control and tumor killing in in vivo leukemia and solid tumor models.
Improves function in exhausted cells by reducing AP-1 inhibitory complex members.
Documented Applications
Therapeutic use in cancer using engineered T cells, including CAR T cells and engineered TCR T cells, with reported leukemia and solid tumor models.
Therapeutic relevance in infectious diseases.
Assessment of clinical immunotherapy responsiveness using RECIST and immune-related response criteria (irRC), including handling delayed immunotherapy responses with new lesions and confirmation of progression after a subsequent assessment.
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