Correcting abnormalities in solid tumor vasculature can improve efficacy of CAR T-cell therapy.

A type of immunotherapy called chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of several types of blood cancers but has shown limitations. effectiveness against glioblastoma; The most deadly type of primary brain cancer; and other solid tumors.

New research led by researchers at Massachusetts General Hospital (MGH) and published in Journal of Cancer Immunotherapy March 10, 2023 suggests that drugs that correct abnormalities in solid tumor vasculature can improve the delivery and function of CAR T-cell therapy.

With CAR-T cell therapy, immune cells are taken from a patient’s blood and modified in the laboratory by adding a gene for a receptor that directs the cells to bind to a specific protein on the membrane of cancer cells.

One of the main reasons why CAR-T therapy does not work well against solid tumors is that cells given intravenously are only able to migrate to the invasive edges of the tumor or only in limited areas of the tumor.”

Rakesh K. Jain, Ph.D., senior author, director of the EL Steele Laboratories of Tumor Biology at MGH and the Andrew Werk-Kook Professor of Radiation Oncology at Harvard Medical School

“The tumors also create an immunosuppressive environment around them, protecting them from CAR-T therapy and other anticancer therapies that are given intravenously through the blood supply.”

Jain and colleagues previously showed that “normalizing” tumor blood vessels with agents called antiangiogenic drugs, which were originally developed to prevent new blood vessel growth, can improve the delivery function of the body’s naturally produced, anticancer immune cells.

Therefore, we sought to investigate whether we could improve CAR-T cell infiltration and overcome the resistance mechanisms posed by the abnormal tumor microenvironment by normalizing the vasculature of glioblastomas using an antibody that blocks an important angiogenic molecule called Vascular endothelial growth factoror VEGF,” Jain explains.

Using the latest live imaging images to track the movement of CAR-T cells In real-time tumors, the team found that treatment with an anti-VEGF antibody improved CAR-T cell infiltration into glioblastoma tumors in mice. The treatment also inhibited tumor growth and prolonged survival in mice with glioblastoma.

“Because the anti-VEGF-β antibody; bevacizumab- has been approved for glioblastoma patients and there are several CAR-T therapies being tested in patients, our findings provide a compelling rationale for testing a combination of vascular normalizing agents, such as anti-VEGF antibodies. VEGF, along with current CAR-T therapies,” says Jain.

“In addition, our approach may also lead to improved CAR-T therapy against other solid tumors. Therefore, we plan to expand our research to other tumors.”

Additional study authors include Xinyue Dong, Jun Ren, Zohreh Amoozgar, Somin Lee, Meenal Datta, Sylvie Roberge, Mark Duquette, and Dai Fukumura.

This work was supported by the National Cancer Research Foundation, the Ludwig Center at Harvard Medical School, the Jane Trust, the Neil Albright Research Foundation, and the National Institutes of Health.