ConvAD CART: next-generation BCMA CART cells with modular targeting capacities

Description

The curative potential of BCMA CART cells is still suboptimal, with antigen escape and an unfavorable tumor microenvironment contributing to disease relapse. In this project, we aim to overcome these challenges by enhancing established BCMA CART cells with additional multi-antigen specificity by the generation of Conventional and Adapter Dual CART cells (ConvAD CART cells). Our ConvAD CART cells co-express conventional BCMA-directed CAR constructs (in ide-cel or cilta-cel format) and adapter CAR constructs. The latter mediate modular multi-antigen specificity by recognizing an engineered epitope in the Fc region of P329G-mutated IgG1 ‘adapter’ antibodies. Addition of such adapter antibodies with anti-myeloma specificity thus enables flexible redirection of ConvAD CART cells to a plethora of MM targets in addition to BCMA. To pave the way towards clinical application, we will validate ConvAD CART cells in preclinical models of
heterogeneous MM to assess their ability to counteract antigen escape by co-targeting BCMA with the conventional CAR and SLAMF7 and/or GPRC5D with the adapter CAR system. Further, we aim to explore the potential of ConvAD CART cells to enhance tumor penetration and anti-myeloma function by co-targeting cancer-associated fibroblasts with SLAMF7- or FAP-specific adapters. Additionally, we will evaluate the potential of ConvAD CART cells to induce central nervous on-target, off-tumor toxicity by investigating adapter
antibody penetration through the blood-brain barrier. Overall, we envision to advance ConvAD CART cells as a next-generation MM therapy to reduce relapse rates and improve safety, and eventually take MM patients one step further towards cure.