D2C7 CAR specifically targets tumor-associated EGFR and is effective against peripheral and intracranial cancers 3321

Abstract Description Tumor heterogeneity is a major impedance for the success of chimeric antigen receptor (CAR) T cells. Tumor specific antigens (TSAs), such as EGFRvIII in glioblastoma (GBM), are rarely present on all tumor cells in a given tumor, leaving a proportion of tumor cells resistant to CAR therapy. One potential solution is to target a tumor-associated antigen (TAA) that is more widely expressed, with the drawback that this antigen might be shared with healthy tissues. EGFR is amplified in a number of cancers, making it an attractive therapeutic target. However, EGFR is expressed on many peripheral tissues but not on normal brain, limiting EGFR therapies to intracranial (IC) cancers. Here, we adapted the EGFR/EGFRvIII dual-targeting D2C7scFv into a CAR. We proposed that IC delivery of D2C7 CAR would be required to prevent systemic toxicity. IC-delivered D2C7 CAR were effective against multiple IC tumor models, including GBM, medulloblastoma, and brain metastases. Intriguingly, we found that D2C7 CAR did not kill keratinocytes despite their high expression of EGFR. These findings suggest that D2C7 CAR recognizes a tumor-specific EGFR epitope. One major implication of this finding is that D2C7 CAR can be used to safely treat any tumor characterized by EGFR amplification. Indeed, systemic administration of D2C7 CAR was effective in a subcutaneous model of EGFR-amplified lung cancer. In summary, D2C7 CAR is safe and effective against multiple EGFR-amplified IC and peripheral cancers. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)