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Chimeric antigen receptor (CAR)-T cell therapy is a sort of immunotherapy that has revolutionized the treatment of many different blood malignancies, but it has only somewhat effective against glioblastoma, the deadliest form of primary brain cancer, and other solid tumors.
A recent study conducted by researchers at Massachusetts General Hospital (MGH) and reported in the Journal for ImmunoTherapy of Cancer on March 10, 2023, reveals that CAR-T cell therapy can be delivered and functioned better when medications are used to treat blood vessel anomalies in solid tumors.
Immune cells used in CAR-T cell immunotherapy are obtained from a patient’s blood and altered in a lab by adding a gene for a receptor that tells the cells to adhere to a certain protein on the membrane of cancer cells.
“One of the main reasons that CAR-T therapy hasn’t worked well against solid tumors is that intravenously administered cells are only capable of migrating to either the invasive edges of a tumor or only in limited areas of the tumor,” says senior author Rakesh K. Jain, Ph.D., director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School.
“Also, tumors create an environment around them that is immunosuppressive, that protects them from CAR-T therapy and other anti-cancer treatments administered intravenously through the blood supply.”
Jain and his colleagues previously demonstrated how agents known as anti-angiogenesis drugs, which were initially created to inhibit the growth of new blood vessels, can “normalize” tumors’ blood vessels and improve the delivery and anti-cancer function of immune cells naturally produced by the body.
“Therefore, we sought to investigate if we could improve CAR-T cell infiltration and overcome resistance mechanisms posed by the abnormal tumor microenvironment by normalizing glioblastoma blood vessels using an antibody that blocks an important angiogenic molecule called vascular endothelial growth factor, or VEGF,” Jain explains.
Using state-of- the-art live imaging to track the movement of CAR-T cells into tumors in real-time, the team found that treatment with an antibody against VEGF improved the infiltration of CAR-T cells into glioblastoma tumors in mice. The treatment also inhibited tumor growth and prolonged survival in mice with glioblastoma.
“Given that an anti-VEGF antibody—bevacizumab—has been approved for glioblastoma patients and that there are several CAR-T therapies being tested in patients, our results provide a compelling rationale for testing the combination of vascular normalizing agents, such as anti-VEGF antibody, with current CAR-T therapies,” says Jain. “In addition, our approach may also improve CAR-T therapy against other solid tumors. Therefore, we plan to extend 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.
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