In the current proposal we will use our recently developed mouse models of MM (Larrayoz et al, Nature Medicine 2023) carrying a new set of humanized therapeutic targets (BCMA and GPRC5D in MM cells and CD3 in T cells), with the aim of testing bi-specific antibodies in clinical use that otherwise cannot be tested against … Continued

This project aims to target the loss of the tumor suppressor TENT5C in multiple myeloma (MM). The primary goal is to investigate the effect of pathway-specific inhibitors in MM patients with biallelic TENT5C abnormalities. Additionally, the project seeks to identify novel synthetic lethality pathways associated with the loss of TENT5C in MM. Preliminary data suggest … Continued

This project aims to molecularly characterize and target Protein Kinase D2 (PRKD2) in t(4;14) multiple myeloma (MM), a high-risk subgroup of MM with poor outcomes. Specific aims include validating the functional role of PRKD2 in MM cells through transcriptomic and epigenomic studies, and evaluating the therapeutic potential of targeting PRKD2 and its downstream pathways using … Continued

This project aims to develop an optimized dual-targeted tandem VH-only fully-human CAR for the treatment of multiple myeloma, aiming to achieve durable remissions. Specific aims include analyzing factors associated with CAR T cell manufacturing success, predicting CAR T cell expansion post-infusion, correlating T cell composition with side effects, identifying markers for treatment response and resistance, … Continued

The project focuses on developing a novel CAR-T cell therapy aimed at treating multiple myeloma by utilizing advanced gene editing technologies to engineer a universal CAR-T cell product targeting SLAMF7 and BCMA. The approach involves strategic gene modifications to enhance the therapy’s compatibility and effectiveness while minimizing immune rejection and reducing the risk of adverse … Continued

This project aims to dissect chimeric antigen receptor (CAR) T cell therapy in myeloma patients at a single-cell resolution to understand the factors influencing treatment success. Specific aims include analyzing factors associated with CAR T cell manufacturing success and failures, predicting CAR T cell expansion post-infusion, correlating T cell composition with side effects, identifying markers … Continued

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 … Continued

The specific aims of this research focus on understanding the role of inflammatory mesenchymal stromal cells (iMSC) and bone marrow inflammation in multiple myeloma (MM) development and treatment response. Aim 1 aims to investigate the effect of novel treatments, including bispecific T cell engagers, on normalizing bone marrow inflammation and iMSC presence. Aim 2 seeks … Continued

The specific aims of this proposed study aim to enhance CAR T cell therapy for multiple myeloma by addressing the mechanisms of resistance and improving persistence of CAR T cells armored with BCL-xL. Aim 1 seeks to determine the role of MM cell death ligands in the resistance of BCL-xL armored CARs to activation-induced cell … Continued