Improving CAR-T cell therapy with more sensitive tumor identification

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

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

The researchers believe the new technology could be incorporated into existing CAR structures to create better CAR-T therapies that can eliminate tumor cells with low levels of target antigens. Fred Hutch is now looking for commercial partners to advance the work.

CARs were originally designed to mimic TCR signaling. CARs fuse fragments of antibodies that can identify cell surface tumor-associated antigens with elements that provide a TCR-like signal to trigger T-cell activation. But CARs require at least 100-fold more surface tumor-associated antigen to launch robust signaling.

For the study, the Fred Hutch team compared signaling in CAR-T cells with natural TCRs. They found that some key T-cell signaling proteins—including those in the CD3 protein complex that make up the T-cell co-receptor in CARs—didn’t go through certain structural changes as part of the cell-signaling process that activates CARs.

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Armed with the insight, the researchers designed two new types of CARs that incorporate either CD3-epsilon or growth factor receptor-bound protein 2 domains. In lab dishes, the T cells bearing the novel CARs showed enhanced antigen sensitivity with higher levels of activation compared with those with the original CARs.

The team also tested whether the novel CAR designs 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 longest survival times, even though the improvements over traditional CAR-T cells weren’t statistically significant, the team reported.

In a mouse model of breast cancer that also had low ROR1 expression, the researchers found that the traditional CAR-T cells didn’t show an anti-tumor effect. In contrast, mice that received the two novel CAR-T constructs had significantly lower tumor burden than those that got the old CAR-T.

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

In April, Sanofi paid $160 million upfront to buy another Fred Hutch spinout, Tidal Therapeutics. The startup has been working on using nanoparticles to deliver mRNA to immune cells inside the body, with the goal of reprogramming them to fight cancer. This could allow the creation of tumor-specific CARs without having to draw the T cells out from patients for modification.

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

 “Our study provides important insights on how to design next generation CAR-T cells that could provide lasting remissions from cancer,” Alex Salter, the study’s co-corresponding author, said in a statement.