Mesothelioma is a cancer that can affect the chest or abdomen. CCR researchers have identified an experimental new immunotherapy called mesothelin-directed T cell receptor fusion construct (TRuC) cell therapy. In this image, the omnivorous and hardy koi fish that can live for many years represent the strong, persistent and sturdy TRuC T cells that can attack and effectively shrink solid tumors like mesothelioma (pink and beige mass in the center). Image credit: Erina He, NIH Medical Arts
An experimental immunotherapy called gavocabtagene autoleucel (gavo-cel), in which patients’ T cells are engineered to recognize the mesothelin protein found on one-third of human cancers, has shrunk treatment-resistant solid tumors in the phase I part of an ongoing clinical trial. Raffit Hassan, M.D., Chief of the Thoracic and GI Malignancies Branch and first author of the study, and colleagues reported the phase I results July 27, 2023, in Nature Medicine.
Gavo-cel, developed by scientists at TCR2 Therapeutics, is a type of immunotherapy known as adoptive cell therapy, in which immune cells from a patient are removed from the body, modified and/or multiplied in a lab, and then administered to the patient by infusion to treat their cancer. So far, adoptive cell therapies have been most successful in treating blood cancers, but Hassan and his colleagues hope that T cells engineered to destroy mesothelin-producing cancer cells could be effective against many kinds of solid tumors.
In the new experimental therapy, instructions for therapeutic T cells are encoded in a genetic module called a T cell receptor fusion construct (TRuC), which is designed to trigger a strong attack when a T cell detects mesothelin. The TRuC — a new way of engineering therapeutic T cells — incorporates features that improve the T cells’ abilities to infiltrate tumors and persist in the body after treatment.
In this first clinical test of gavo-cel, TRuC T cells were administered to 32 patients with advanced mesothelioma, ovarian cancer or cholangiocarcinoma (a cancer of the bile duct). Trial participants had received, on average, five prior therapies. Their cancers either did not respond or had become resistant to those earlier treatments.
Twenty percent of the 30 patients who received gavo-cel and were evaluable for tumor response experienced a 30% or greater reduction in tumor size, as determined by post-treatment imaging. Thirteen percent of the patients had durable tumor regression, with the most durable response continuing for a year after the treatment before tumors began to grow again.
“This is one of the very few adoptive cell therapies in solid tumors that has shown objective tumor regressions,” Hassan says. “This is proof of principle that TruC T cells work and we can get responses, even in heavily pretreated patients.”
Seventy-eight percent of participants in the trial experienced cytokine release syndrome, a manageable but potentially dangerous side effect. As phase II of the trial continues, Hassan and colleagues have begun clinical testing of a second-generation mesothelin-targeting TRuC, TC-510. This TRuC is designed to trigger the same mesothelin-targeting immune response as gavo-cel and additionally convert a signal that normally dampens immune activity into an immune activator. Hassan’s team also plans to begin clinical trials of another mesothelin-targeting adoptive cell therapy, using chimeric antigen receptor (CAR) T cells developed in his lab.