ECM-targeted CAR T-cell therapy for high-grade glioma
Pediatric gliomas have a relative five-year survival rate of below 30%, and represent the greatest cause of cancer-related deaths in pediatric patients. Current treatments such as chemotherapies, radiation, and/or surgery have limited success, as such, immunotherapy may be an ideal treatment option for these patients. Previously, we have created a form of immunotherapy which consists of immune cells known as T cells. These T cells are engineered to express a chimeric antigen receptor (CAR) which has the ability to seek out and kill tumor cells. Unfortunately, CAR T cell therapy has yet to prove successful in pediatric patients with solid tumors. Key factors limiting this success include: a limited array of targetable tumor associated antigens (TAAs), concerns in regard to ‘on target/off cancer toxicity’, and an immunosuppressive tumor micro-environment (TME). While there are concerted efforts to identify unique TAAs or improve existing CAR T cell constructs, we propose taking advantage of the extracellular matrix (ECM) that exists with the TME surrounding the tumor. This environment is unique to the tumors themselves and does not exist within the rest of the patient body. Successfully targeting this environment will effectively decrease toxicity.
To test this model, we propose targeting a major component of the ECM of tumors, the oncofetal splice variant of fibronectin (fibronectin-EDB; FN-EDB), which is not expressed by normal cells. We propose utilizing the single chain variable fragment (scFv) derived from L19, a monoclonal antibody specific to FN-EDB which has shown impressive tumor specificity in early phase clinical trials, to target the ECM and effectively decrease “on target/off target” toxicity. We will couple our FN-EDB environment-targeting T cell with a CAR designed to target another TAA, thus increasing specificity. As we propose to target the unique components of the microenvironment, as well as a TAA, our approach is uniquely specific and has the potential not only to be effective, but also to reduce treatment-related complications. Additionally, this approach could be readily tested in early phase clinical studies. Further, our approach is applicable not only to brain tumors, but to a broad range of solid tumors, as most tumors contain similar components within the microenvironment.