Improving CAR-T cell therapy with more sensitive tumor detection

CAR-T cell therapy, which involves engineering a patient’s own T cells to target and kill cancer cells with specific antigens, has shown strong results in blood disorders. But many patients still progress or relapse after initial remission, as tumor cells expressing low levels of the biomarker may go undetected by treatment.

In search of ways to enhance CAR-T therapy, scientists at Fred Hutchinson Cancer Research Center took a page from natural T-cell receptors (TCRs) to design new chimeric antigen receptors (CARs) with improved antigen sensitivity. According to the results published in Science Signaling, the novel CAR-T cells showed superior anti-tumor activities in mouse models of lymphoma, leukemia and breast cancer.

The researchers believe that the new technology could be incorporated into existing CAR structures to create better CAR-T treatments that can eliminate tumor cells with low levels of target antigens. Fred Hutch is now seeking business partners to take the work forward.

CAR was originally designed to mimic TCR signalling. CARs fuse antibody fragments that can recognize cell surface tumor-associated antigens with elements that provide TCR-like signals to trigger T-cell activation. But CAR requires at least 100-fold more surface tumor-associated antigens to launch robust signalling.

For the study, the Fred Hutch team compared signaling in CAR-T cells with that of natural TCRs. They found that some key T-cell signaling proteins, including the CD3 protein complex that makes up the T-cell co-receptor in the CAR, did not undergo some structural changes as part of the cell-signaling process that activates the CAR. .

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With the insight, the researchers designed two new types of CARs that contain the CD3-epsilon or growth factor receptor-bound protein 2 domains. In laboratory dishes, T cells with novel CARs showed increased antigen sensitivity with a higher level of activation than those with native CARs.

The team also tested whether the novel CAR design could better control tumor cells with low antigen expression in living animals. In mice with mantle cell lymphoma expressing low levels of ROR1, CAR-T cells designed with the two novel CARs provided the most effective anti-tumor responses and the longest survival time, even though conventional The improvements in CAR-T cells were not statistically significant. , the team reported.

In a mouse model of breast cancer in which ROR1 expression was also low, the researchers found that conventional CAR-T cells did not show anti-tumor effects. In contrast, mice receiving the two new CAR-T constructs had a significantly lower tumor burden than those receiving the old CAR-T.

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Fred Hutch has a known history of being a pioneer in CAR-T research. CAR-T specialist Juno Therapeutics, now part of Bristol Myers Squibb, was a spinoff of Fred Hutch. The company’s new FDA-approved CD19-targeted CAR-T therapy, Breyanzi, was developed with pioneering CAR technology at Fred Hutch.

In April, Sanofi made an upfront payment of $160 million to buy another Fred Hutch spinout, Tidal Therapeutics. The startup is working on using nanoparticles to deliver mRNA to immune cells inside the body, so that they can be reprogrammed to fight cancer. This may allow the creation of tumor-specific CARs without taking out T cells from patients for modification.

The Fred Hutch researchers behind the new paper suggest that their discovery could expand the CAR-T field even further.

“Our study provides important insights on how to design the next generation of CAR-T cells that may provide lasting remission from cancer,” study co-corresponding author Alex Salter said in a statement.

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