Effectors of the Future: Universal Chimeric Antigen Receptor

Abstract

Background: Cellular therapies leveraging genetically engineered immune effector cells have witnessed a remarkable surge in success, particularly evident in the notable high rates of remission induction and durable remissions observed in a substantial proportion of heavily pretreated patients with refractory B-lineage malignancies. A diverse array of effector cells and therapeutic strategies are now at our disposal, representing the culmination of advancements made over the past 3 decades. The swift pace of development in modern genetic diagnostics, the emergence of spatial proteomics, and the expanding capabilities and precision of computational sciences have profoundly enriched our comprehension of tumor biology and the intricate workings of our immune system. Empowered by advancements in synthetic biology and genome editing, we can expedite the development of next-generation immune effector cells tailored for clinical applications, balancing safety with efficacy. Summary: Universal adapter chimeric antigen receptor (CAR) technologies present the most straightforward solution to tackle antigen heterogeneity and antigen evasion mechanisms employed by tumors. Moreover, due to the decoupling of antigen recognition and signaling in adapter CAR technologies, additional effector functions can safely enhance anticancer activity and most importantly, synergistic combination of patient-specific cellular products with off-the-shelf manufactured antibodies promise increased cost-efficiency. The pivotal collaboration between clinical trial units and regulatory institutions holds the key to surmounting contemporary challenges in trial design, potentially paving the way for the exploration of patient-individualized therapies. Key Messages: In this review, we elaborate on the concept of antibody-dependent cellular cytotoxicity mediated by universal adapter CARs and delineate how recent strides in CAR engineering have the potential to furnish a versatile cellular platform, ushering in an era of cancer-adapted, multitargeted immunotherapies employing universal CAR effector cells.