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Catherine Nicholas

Health Science, '20


RHAMM splicing in multiple myeloma (MM) and its implications for immunotherapy

Mentor: Kenneth Anderson, PhD (Dana Farber Cancer Institute)

Multiple Myeloma (MM), is a highly heterogeneous clonal disease characterized by an accumulation of malignant plasma cells (PC) in the bone marrow (BM), multiple bone lesions throughout the axial skeleton, and the secretion of high levels of monoclonal immunoglobulins (Ig). Diagnosis of MM requires the presence of CRAB features (increased calcium levels, renal failure, anemia, and bone lesions). Current treatments rely on combinations of proteasomes, immunomodulatory and immunotherapeutic drugs, all of which have helped to increase life expectancy. MM, however, remains the second most common hematological malignancy, with an estimated prevalence of ~12,000 deaths annually in the U.S. MM remains incurable, because current therapy is limited in its ability to target all members of the MM hierarchy of malignant cells. We have a desperate need to identify more selective druggable targets that capture the hierarchy of MM malignant cells. CAR (chimeric antigen receptor)- T cell therapy is a new frontier for MM treatment that has proven successful in a number of patients. CAR-T cell therapy uses autologous T cells to target malignant cells by genetically altering them ex vivo, so that they express the receptors necessary to recognize specific antigen(s) present on tumor cells and induce apoptosis. Despite the success of CAR-T cell therapy, there is still a need to identify new antigen targets because of the high level of genetic heterogeneity; Due to epigenetic changes of malignant cells many patients relapse as a result of the presence of new clones. To enhance current and future immunotherapeutic approaches, we are interrogating different subpopulations of MM patient cell epigenomes at a single cell level, specifically looking alterations in RNA splicing (AS). AS has the potential to produce numerous mis-spliced genes, creating novel disease markers and drug targets; some resulting proteins are likely to contain neoantigens selectively expressed on MM tumor cells. We aim using novel antigen targets as new Bispecific T-Cell Engager (BiTE) in CAR-T therapy. Receptor for hyaluronan-mediated motility (RHAMM) or CD168 has been a promising target for MM immunotherapy because it is overexpressed in MM cells. Overexpression and/or unbalanced splicing of the RHAMM is linked with the mitotic instability in MM and correlates with poor survival in MM patients. Our pilot study identified cell type-specific RHAMM splicing events in different subpopulations of MM bone marrow cells. We suspect that RHAMM variants can be used as a new BiTE in CAR-T Therapy.

Our goal is to identify novel targets, i.e. RHAMM variants to use as BiTES that can be used in tandem with other , currently used BiTES to target malignant clones in myeloma patients. A) Displays the process by which T cells are genetically engineered (modified, proliferated, and infused in Chimeric Antigen Receptor T-Cell therapy) in order to induce cell death in MM tumor cells. Schematics of manufacturing and delivery pipeline of genetically modified T-cell therapy; B) Unbalanced splicing of the RHAMM correlates with poor survival in MM patients, expression ratio (R)=RHAMM splice variant 3/RHAMM FL; C) Confocal Microscopy image of plasma cell during mitosis with multiple poles; D) Genomic instability in MM caused by RHAMM splicing. Source: