Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies

SIMPLE SUMMARY: Approved chimeric antigen receptor (CAR) T cells recognize and bind to only one tumor target (single-targeted CAR T cells, Si-CART) on cancer cells by the special receptor and followed with activation, thus removing cancers from patients. However, cancer cells can resist the treatment of Si-CART by hiding the single target to prevent the recognition and survive, causing recurrence of cancers in patients. Dual-targeting CAR T-cell therapy contains CAR T cells recognizing two targets on cancer cells and can overcome the resistence in cancers to Si-CART. We summarize the latest preclinical and clinical development of dual-targeting CAR T-cell therapies to provide perspectives for optimization and shed light on new hope for patients after the treatment of Si-CART. ABSTRACT: Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy.