Currently, four CAR T-cell therapies have been approved by the FDA to treat a range of hematological malignancies. However, treating solid tumors has been a challenge and several ongoing studies are striving to overcome it. At the virtual AACR conference, a few such studies were presented.
Identification of Transcription Factors Contributing to CAR-T Cell Dysfunction
The inefficacy of CAR-T against solid tumors is attributed to the fact that CAR-T cells become dysfunctional when they enter the tumor microenvironment. To investigate this, Dr. Charly Good and her coworkers at the University of Pennsylvania developed a model to identify factors contributing to the dysfunction of CAR T in solid tumors. Her model uses healthy donor-derived CAR T cells and exposes them to pancreatic tumor cells for long periods of time.
Dr. Charly R. Good, University of Pennsylvania
After chronic exposure, CAR T cells had reduced growth, and a reduced ability to kill tumor cells. These cells show induction of Natural Killer (NK) cells receptors and markers of CAR T exhaustion. By analyzing the gene expression signatures of the exhaust populations, Dr. Good also identified several transcription factors that could lead to changes in CAR T exhaustion. Only two transcription factors, ID3, and SOX4, were expressed in the chronically exposed cells, which could suggest that ID3 and SOX4 are mediating the CAR T dysfunction. Future experiments will determine if targeting these factors can prevent or overcome exhaustion.
Giving a “rest” Period to CAR-T Cells Reinvigorates Them to Fight Cancer
Dr. Evan Weber, a postdoctoral fellow at Stanford, presented his work developing CAR T cells that be turn off and on to overcome exhaustion. He engineered T cells that express CAR linked to a destabilizing domain. When a stabilizing drug is present, this modified CAR is expressed on the surface of the cells. However, in the absence of the drug, the CAR is not expressed. CAR T cells that are always active become exhausted and lose anti-tumor capabilities. However, giving CAR T cells a period of “rest” reinvigorated them. These cells showed transcriptional and epigenetic changes that closely resembled CAR T cells that were not exposed to chronic CAR signaling and better at killing cancer tumor cells.
Dr. Evan Weber, Stanford University
To verify this observation, dasatinib, a kinase inhibitor that leads to “rest” of CAR T cells, was used to treat the cells in vitro and in vivo. These cells showed a decrease in exhaustion-associated genes and restored ability to kill tumor cells. Together, these observations suggest that temporarily suppressing the expression of CAR in cells, could lead to better efficacy of CAR T cell therapies.
Developing a Dual-targeted Fine-tuned Immune Restoring (DFIR) CAR-T for Kidney Cancer
Dr. Yufei Wang from Dana-Farber Cancer Institute presented her work developing a dual-targeting fine-tuned immune restoring (DFIR) CAR T cell therapy against clear cell renal cell carcinoma (ccRCC). Her approach was to engineer cells with 3 crucial characteristics:
- They target both CAIX and CD70.
- They become active only in the presence of cells that highly express these receptors.
- Release checkpoint inhibitors to reactivate the immune response.
Dr. Yufei Wang, Dana-Farber Cancer Institute
She showed that her modified cells could kill ccRCC that expressed one or both receptors targeted. Additionally, her cells were fine-tuned to target only cells with high levels of CAIX, and as a result, on-target off-tumor toxicity was reduced. In an in vivo model of ccRCC, her CAR T cells armed with an anti-PD-L1 antibody were better at reducing tumor size, tumor weight, and it reduced genes associated with exhaustion. Together these observations make a compelling case to use these DFIR CAR T cells to treat ccRCC.
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