Combining CAR-T and BiTE in Models of Glioblastoma Multiforme

Human chimeric antigen receptor (CAR) T cells (CAR-T) expressing the epidermal growth factor receptor variant III (EGFRvIII) antigen can be engineered to also secrete bispecific T-cell engagers (BiTEs) against wild-type EGFR, according to researchers at the American Association for Cancer Research (AACR) Annual Meeting 2019.

While CAR-T cell therapy involving T-cell expression of EGFRvIII, an antigen that is overexpressed in glioblastoma multiforme (GBM), represents a logical approach to the treatment of this disease, clinical studies of GBM treated with CAR-T EGFRvIII therapy have shown evidence of immune escape due, in part, to high levels of expression of wild-type EGFR.  

To to address this problem, EGFRvIII-targeted CAR-T cells were engineered to secrete bispecific T-cell engagers (BiTEs) against wild-type EGFR, a protein that is not expressed in normal brain tissue. Specifically, BiTE therapy involves the engineering of T cells to secrete a fusion protein involving linked fragments from 2 different antibodies, each of which targets either a tumor-associated antigen or a T-cell–specific molecule in order to physically bring a T cell to a tumor cell. 

In addition to demonstrating that CAR-T EGFRvIII cells could be successfully reengineered to secrete BiTEs that are specific to wild-type EGFR, studies performed in mice models of brain tumors, including tumors derived from glioma cell lines or patient-derived glioma neurosphere cultures, yielded extended survival and even prolonged remission in animals following infusion with EGFRvIII-targeted CAR-T cells that secrete wild-type EGFR-specific BiTEs. 

“These results demonstrate that CARs and BiTEs can be combined strategically to mitigate the impact of antigen heterogeneity in GBM, and also provide a unique T-cell–based delivery method for BiTEs to tumors in the brain,” the authors noted in conclusion.

Disclosure: The presenters disclosed financial ties to various pharmaceutical companies. For a full list of disclosures, please see the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2019 meeting by visiting the conference page.

Reference

1. Choi BD, Yu X, Castano AP, et al. BiTE-armored CARs overcome antigen escape in EGFRvIII-targeted therapy for glioblastoma. Presented at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. Abstract LB-066/11. 

This article originally appeared on Cancer Therapy Advisor