Researchers pursue new strategies for CAR-T cell therapy

Volume 8, Issue 1, March 2019

Summary

Preclinical findings suggest innovative methods to reduce severe toxicity and boost response rates.

Saad J. Kenderian, M.B., Ch.B.

Saad J. Kenderian, M.B., Ch.B.

Rosalie M. Sterner

Rosalie M. Sterner

Mayo Clinic researchers have developed two new strategies that may improve the performance of chimeric antigen receptor (CAR)-T cell therapy in treating cancer. They presented results of their preclinical research at the 2018 annual meeting of the American Society of Hematology in San Diego.

Reducing toxicity in CAR-T cell therapy

In one strategy, researchers are working to find ways to reduce potentially serious toxic effects associated with CAR-T cell therapy.

Although CAR-T cell therapy has proved successful in treating certain cancers, severe toxicity in some patients has limited its widespread use, said Rosalie M. Sterner, an M.D.-Ph.D. student at Mayo Clinic who worked in the T Cell Engineering Laboratory of Saad J. Kenderian, M.B., Ch.B., a hematologist at Mayo Clinic in Rochester, Minnesota.

One toxicity associated with CAR-T cell therapy is cytokine release syndrome, in which patients can experience fever, nausea, headache, rash, rapid heartbeat, low blood pressure, difficulty breathing and neurotoxicity, Sterner said. Some patients undergoing CAR-T cell therapy get so sick that they require a stay in a hospital intensive care unit. Deaths related to cytokine release syndrome have been reported.

Sterner and her colleagues have developed a strategy to reduce the severe toxicities associated with CAR-T cell therapy.

The strategy involves using a clinical-grade antibody (lenzilumab) to block the GM-CSF protein, which is produced by CAR-T cells and other cells. "When we blocked the GM-CSF protein, we found that we could reduce toxicities in preclinical models," Sterner said. "We also were able to demonstrate that CAR-T cells worked better after the GM-CSF protein was blocked."

Researchers also used a gene-editing technology, called CRISPR, to generate CAR-T cells that didn't secrete the GM-CSF protein. These modified CAR-T cells were more effective than were regular CAR-T cells, Sterner said.

Based on their findings, the research team is proceeding with a phase II clinical trial of the GM-CSF blocking antibody during CAR-T cell therapy. If the trial results are consistent with earlier findings, the therapy could become a standard of care during CAR-T cell therapy at Mayo Clinic.

This research was published in the journal Blood in February 2019.

Improving response rates for CAR-T cell therapy in B cell lymphoma

Reona (Leo) Sakemura, M.D., Ph.D.

Reona (Leo) Sakemura, M.D., Ph.D.

In CAR-T cell therapy, physicians remove and modify a patient's T cells to recognize and fight cancer, explained Reona (Leo) Sakemura, M.D., Ph.D., a hematologist and a postdoctoral fellow working in Dr. Kenderian's T Cell Engineering Lab. The T cells are then reinfused into the patient, where they seek out and ultimately kill cancer cells.

Response rates to CAR-T cell therapy vary by disease. For example, in B cell acute lymphoblastic leukemia, response rates of more than 90 percent have been seen with CAR-T cell therapy, compared with response rates of 10 to 30 percent for treatment with conventional chemotherapy. In other blood cancers, such as lymphoma and chronic lymphocytic leukemia, the response rates for treatment with CAR-T cell therapy remain low, Dr. Sakemura said.

To improve the effectiveness of CAR-T cell therapy in these cancers, Dr. Sakemura and his colleagues developed a strategy to combine CAR-T cell therapy with a drug that targets a protein called AXL. This protein is present on the cancer cell and within the cancer's environment. The drug, called TP-0903, kills cancer cells, enhances the potency of CAR-T cells in attacking cancer cells, and potentially lowers toxicity associated with CAR-T cell treatment.

While more research and clinical trials are needed, Dr. Sakemura said, "We believe the latter effect may eventually be utilized as an innovative approach to augment the efficacy of CAR-T cell therapy and extend its use to other B cell cancers."

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