Mouse study shows tumors tamed by T cells targeting two different antigens

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TanCAR T cells—so called because they can bind, in tandem, the chimeric antigen receptor (CAR) and both the antigens it targets, HER2 and IL13Ra2—have shown intriguing potential to give oncologists better control over brain tumors.

The researchers behind the preclinical study, published July 18 in the Journal of Clinical Investigation, found that these TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 “in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.”

Pediatric oncologists Meenakshi Hegde, MD, Nabil Ahmed, MD, of Baylor College of Medicine and colleagues built upon prior research establishing that, in preclinical models of glioblastoma, antigen escape can allow tumors to recur after treatment with CAR T cells targeting only one tumor antigen.

Given the heterogeneous expression of antigens on glioblastomas, they hypothesized that a bispecific CAR molecule would reduce antigen escape and boost T cells’ antitumor activity.

To test the theory with a mouse model, they created a CAR that joins the two antigens.

“We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently,” the authors write. “TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy and improved animal survival.”

In a press release from Baylor, the researchers also describe their use of a new molecular-imaging technology, stimulation emission depletion (STED) microscopy.

“With STED we were amazed to see that when TanCAR T cells and glioblastoma cells touch each other, they make a concentrated disc of the surface molecules, an immunological synapse,” Ahmed explains. “Once CARs bring the glioblastoma surface antigens together, this triggers activation inside the T cells that leads to the death of glioblastoma cells. Simply bringing HER2 and IL13Rα2 together leads the cancer cells to their demise.”

The journal has posted the full study, and Baylor’s news office has published a nicely detailed article on the research.