Sam McCachren

BME PhD Defense Presentation

Date: 2023-05-15
Time: 2:00 p.m. - 4:00 p.m.
Location / Meeting Link: Emory Clinic Building B Room B5701 / https://zoom.us/j/91034990756

Committee Members:
Melissa Kemp, Ph.D. (Advisor); Madhav Dhodapkar, M.D. (Advisor); Gabe Kwong, Ph.D.; Max Cooper, M.D.; Kavita Dhodapkar, M.D.; Julie Babensee, Ph.D.


Title: Investigation of the Bone Marrow Tumor Immune Microenvironment and Immune Cell Redirection in Multiple Myeloma

Abstract:
Multiple myeloma (MM), a malignant neoplasm of plasma cells (PCs) that reside in the bone marrow (BM), is the second most common primary hematological malignancy and is currently incurable. MM is universally preceded by an unresectable asymptomatic precursor state, monoclonal gammopathy of undetermined significance (MGUS), which provides a valuable opportunity to study premalignancy and malignant transformation. This dissertation aims both to increase our understanding of the BM tumor immune microenvironment in MGUS and MM (and applying similar analyses to the BM of pediatric leukemia), as well as to improve immune cell redirection via exploration of a novel chimeric antigen receptor (CAR) T cell to treat MM. To better understand immune correlates of malignancy and disease progression in MGUS and MM, mass cytometry and single-cell RNA sequencing were leveraged to compare the BMs of healthy donors and patients with MGUS or MM. Notably, T cells shifted toward a more terminally differentiated/exhausted-like phenotype over disease course. In MGUS, T cells with a stem-like/resident-like phenotype were enriched, suggesting that this population has a role in disease control. The presence of these T cells also correlated with enrichment of immune activating myeloid populations, while MM had more immune-suppressive myeloid phenotypes, further implicating loss of immune surveillance in disease progression, and identifying potential targets for reinvigorating anti-tumor immunity. Complementary analyses were applied to the BM of patients with pediatric leukemias. Interestingly, T cells in these patients also exhibited similar dysfunctional, exhausted-like phenotypes to those seen in MM, despite the traditional perception of pediatric malignancy being less immunogenic due to lower mutation burden and fewer neoantigens. Notably, T cell populations to correlated with disease risk, properties of the tumor, and survival, emphasizing the importance of the immune system in these malignancies and arguing for incorporation of immune phenotypes into current risk metrics and treatment approaches. T cell redirection via anti-BCMA CARs has shown promising activity in MM, but exploration of additional targets for T cell redirection is necessary. Prior research involving sea lamprey revealed a variable lymphocyte receptor (VLR – the antibody equivalent in the lamprey immune system) that specifically binds a multimeric configuration of CD38 specifically expressed on PCs but not on other CD38-expressing hematopoietic cells. The final portion of this dissertation explores a CAR T cell with this VLR (named MM3) as its binding domain to target malignant PCs in MM. MM3 was observed to specifically bind malignant PCs from MM and other PC malignancies. The MM3 CAR T cell was demonstrated to have strong, specific in vitro activity and killing against cell lines susceptible to MM3 binding, as well as showing ability to kill malignant PCs from MM patient BM. Importantly, the MM3 CAR T cell did not kill activated T cells despite high CD38 expression, overcoming a major current hurdle for traditional CD38-directed CAR T cells. MM3 CAR T cells also showed promising in vivo activity in a mouse xenograft model. Therefore, the MM3 CAR T cell is a promising novel method for T cell redirection for MM and other PC malignancies.