A new CAR T cell strategy is highly effective against small cell lung cancer in preclinical trials.Roswell Park Comprehensive Cancer Center

BUFFALO, NY — A novel approach to chimeric antigen receptor T cell (CAR T) therapy shows great promise for small cell lung cancer (SCLC) in preclinical studies. This finding covers new ground in our understanding of how CAR T can be used against solid tumor cancers and supports further research in cancer patients.

Renier Brengens, MD, PhDKatherine Anne Gioia Endowed Chair in Cancer Medicine, Associate Director of the Roswell Park Comprehensive Cancer Center, served as the principal investigator of the study.recently It was published It was published in the Journal of Clinical Investigation. This study was a collaboration with researchers at Memorial Sloan Kettering Cancer Center and Weill his Cornell Medical School.

SCLC accounts for 15% of all lung cancers. At the time of diagnosis, her two-thirds of patients have metastatic disease. This means the cancer has spread to other parts of the body. This is one reason why median overall survival is only 13 months. Tumors may initially respond to chemotherapy, but in most cases the cancer recurs, highlighting the need for newer and more effective treatments.

CAR T-cell therapy, also called “living medicine,” reconstitutes the patient’s own T-cells, which are part of the immune system that can attach to and destroy cancer cells. But that is only possible if a specific type of receptor on the surface of the T cell matches a specific antigen or protein on the surface of the cancer cell. To ensure proper matching, T cells are isolated from the patient’s blood, sent to a laboratory, and transduced into CAR T cells by inserting a gene antigen. It then expands the CAR T cells back into the patient and launches an attack.

The efficacy of CAR-T cell therapy has so far been limited to hematologic malignancies. Since 2017, the U.S. Food and Drug Administration has approved six of his CAR T-cell products to treat these types of cancer, but the same therapeutic approach has plateaued in patients with solid tumors.

“First-generation CAR T cells have yet to show significant progress in solid tumors,” said Dr. Brentjens. He and his colleagues believe that:‘This is because the tumor microenvironment (TME) (blood vessels, normal cells, and other elements that surround tumor cells) suppresses the immune system, leaving T cells exhausted and unable to defend against cancer cells.

To overcome this problem, researchers have come up with two attack strategies. First, they developed CAR T cells that can home to delta-like ligand 3 (DLL3), an antigen found on the surface of SCLC tumor cells. We then took it a step further and upgraded to an ‘armored CAR’ T cell that could express another molecule. In this case, interleukin-18 (IL-18) is a protein encoded by the IL-18 gene that regulates immune system responses. disease.

In both xenograft and murine models of SCLC, IL-18-secreting CAR T cells targeting DLL3 significantly increased antitumor activity, and IL-18, the other two interleukins evaluated during the study, significantly increased antitumor activity. showed a stronger response than 12 and IL-16. IL-18 also alleviated T cell depletion, proliferated DLL3 CAR T cells, made them survive longer, and generated more T cells capable of ‘remembering’ the DLL3 antigen, thus continuing to target it for destruction in the future. is ready. At the same time, IL-18 further activated tumor-infiltrating lymphocytes (TILs), immune cells that invade tumors to kill them.

“Inserting the IL-18 gene into these T cells significantly improved tumor eradication,” said Dr. Brentjens. Indeed, in a xenograft SCLC animal model, this strategy completely destroyed his H82 tumor, a model representing recurrent SCLC. The researchers also noted that survival was significantly improved when his IL-18-secreting CAR T cells were combined with immunotherapies called immune checkpoint inhibitors.

DLL3 is expressed in many neuroendocrine cancers (including lung, prostate, breast, pancreas, high-grade intestinal cancer, low-grade glioma, and neuroblastoma). Targeting CAR T cells may provide new therapeutic options for these diseases. .

“This is the next generation of CAR T cells,” explains Dr. Brentjens. “Now that we have shown this technology to be effective, we hope to undertake clinical-stage studies to assess how effective this approach is in cancer patients.”

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