Abstract 1791: Evolutionary dynamics of non-Hodgkin's lymphoma CAR T cell therapy

Abstract

Abstract Non-Hodgkin Lymphoma (NHL) is the most common hematologic malignancy in the United States with an estimated 72,000 new cases (4.3% of all cancer cases) and 20,000 deaths (3.4% of all cancer deaths) in 2017; the median 5-year survival rate is 71%. Despite a possible cure, with front-line chemotherapy, there exist patients that do not response or relapse and develop refractory disease. These patients have a median overall survival of less than seven months. Chimeric antigen receptor (CAR) T-cell therapy for refractory NHL relies on expansion of engineered T- cells that specifically target tumor cells expressing CD19. Here we combine mathematical modeling with statistical data-analysis based on recent results of clinical studies of CAR T-cell dynamics in individual patients. We use statistical and mathematical modeling to elucidate the key mechanisms that drive evolutionary dynamics of anti-CD19 CAR T-cell therapy. To this end, we integrate patient specific tumor burden profiles, inflammatory cytokine profiles, and CAR T cell population dynamics into our model. We find that the success of therapy may depend on dynamic regulation of inflammatory cytokines in the tumor microenvironment, as well as on specific properties of the heterogeneous CAR T-cell population. Relative abundances of juvenile and effector T cells are key factors that drive the duration of treatment response, and the tumor-killing rate of this CD19-specific immunotherapy. Our modeling framework elucidates disease and treatment specific eco-evolutionary dynamical properties, but can also quantify genetically engineered T-cell population properties related to neurological toxicity and long-term homeostatic mechanisms that determine patient survival. Citation Format: Philipp M. Altrock, Gregory Kimmel, Frederick L. Locke. Evolutionary dynamics of non-Hodgkin's lymphoma CAR T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1791.