Saturday, November 23, 2024
11/23/2024
Project Summary Multiple myeloma (MM) is an incurable malignancy of mature plasma cells accounting for 1.8% of new cancer cases annually, and 10% of hematological malignancies. Immune-based therapeutic interventions targeting B- cell maturation antigen (BCMA) lead to high response rates in patients with heavily pretreated disease and, two Chimeric Antigen Receptor (CAR) T-cell products targeting BCMA are FDA-approved. Despite remarkable clinical responses, most patients have disease remissions induced by BCMA CAR-T cell therapy that do not last more than 18 months. Given that, novel treatment approaches are urgently needed and, they rely on the identification of biologically and therapeutically relevant targets. To address this gap of knowledge, we developed a novel integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identified the most highly expressed cell surface proteins. We annotated candidate protein expression in many healthy tissues and validated the expression of promising targets in 31 patient samples with relapsed or refractory MM, as well as in normal hematopoietic stem cells and T cells. Six candidates (SEMA4A, ILT3, CCR1, LRRC8D, FCRL3, IL12RB1) and BCMA presented the most favorable profile in malignant and healthy cells (Di Meo F. et al., Cell Reports Medicine 2023). We hypothesize that our target discovery strategy uncovered novel MM-associated antigens that meet strict criteria of relevant immunotherapeutic targets: a) they are highly and frequently expressed in patients; b) their expression in normal tissues is minimal and c) targeting these antigens impacts critical features of MM biology. In Aim 1, we will define the distribution of antigen expression in MM patients, especially high-risk patients in relapsed disease state. We will precisely measure antigen density (number of molecules per cell) in primary bone marrow malignant plasma cells by flow-cytometry. We will use a unique cohort of 50 MM patients who relapsed or progressed after BCMA CAR T-cell therapy, comparing expression patterns to BCMA. Further, we will use normal tissue arrays from autopsies and surgical specimens and single-cell RNA seq data from BM samples of healthy donors to predict on-target off-tumor toxicity. These studies will define the relevance of lead targets such as SEMA4A to MM patients and identify the role of targeting novel antigens to rescue patients who relapse with a BCMA-resistant or -negative disease. The results will serve to optimize the design of CAR constructs based on quantitative profiling of antigen density in malignant and normal cells. In Aim 2, we will screen several CARs recognizing SEMA4A that we constructed upon an antibody discovery campaign generating novel purified monoclonal antibodies. We will further systematically compare multiple dual-targeting platforms targeting SEMA4A, BCMA and ILT3 in vitro and in vivo. These studies will serve to identify a lead strategy that may prevent antigen escape and maximize the elimination of MM cells.
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