Modeling, unraveling, and beating acquired resistance to BCMA and GPRC5D targeted agents in multiple myeloma

Description

Acquired therapeutic resistance constitutes a major limitation to achieve a cure for multiple myeloma (MM). In this context, CAR T-cell and bispecific antibodies against BCMA and GPRC5D antigens have shown promising results, but most patients develop acquired resistance and eventually relapse. While acquired BCMA and GPRC5D inactivation leading to resistant disease has been reported following targeted immunotherapy agents, we need a wider and deeper understanding of the immune biology underlying MM refractoriness to efficiently tackle the resistant disease. However, these studies are difficult to be conducted in patient samples, and we lack of experimental MM models accurately reflecting the process of acquired resistance.
We have generated two new transgenic models derived from our MIcγ1 model (reported in Larrayoz et al. Nat Med 2023) carrying humanized BCMA or GPRC5D in MM cells and humanized CD3ε in the immune cells (termed MIcγ1hBCMA/hCD3ε mice or MIcγ1hGPRC5D/hCD3ε mice). The goal in these mice is to test clinical BCMAxCD3 and GPRC5DxCD3 antibodies that otherwise cannot be tested in mouse immunocompetent systems. Sequential samples will be obtained at different timepoints during the development of the acquired state. Data from multiparametric flow cytometry, single-cell RNA sequencing (scRNAseq) coupled with BCR and TCR seq, and whole exome sequencing (WES) in MM and BM immune cells will be obtained. Mouse data will be then integrated with results from similar studies in human refractory MM samples from BCMAxCD3 and GPRC5DxCD3 clinical trials. These analyses will comprehensively unveil the dynamics of acquired refractoriness progressively developed by MM cells within the BM immune niche. Based on this information, functional approaches to overcome resistance will be conducted in experimental models of refractory MM in vivo. The Specific Aims (SA) of this ongoing project of two years are:
• SA1. Develop and characterize experimental models of MM with acquired resistance to BCMAxCD3 and GPRC5DxCD3 bispecific antibodies (Year 1)
• SA2. Determine the mechanistic basis of acquired resistance in MM and BM immune cells by integrating mouse data with results from MM patients with acquired resistance (Year 2)
• SA3. Define pre-clinical therapeutic approaches that selectively and effectively beat BCMA or GPRC5D acquired resistance (Year 2)
We expect that these results will define strategies to prevent or minimize acquired refractoriness to BCMAxCD3 and GPRC5DxCD3, and will open new treatment approaches once resistance to bispecific antibodies has been developed in MM.