TMOD-01. THE ROLE OF PERSISTENCE, PROLIFERATION, AND TUMOR CELL KILLING EFFICIENCY IN DETERMINING RESPONSE TO CAR T-CELL THERAPY IN GLIOBLASTOMA: A MATHEMATICAL MODEL AND ANALYSIS

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a promising emerging area of immunotherapy for the treatment of recurrent glioblastoma. In this therapy, T-cells are genetically modified to target tumor-specific antigens. Efficacy of CAR T-cell therapy depends on several factors, including CAR T-cell proliferation, persistence, and tumor cell killing capacity. Here we use a mathematical model to investigate the role of these three factors in determining response of recurrent GBM to this novel immunotherapy. Additionally, the impact of dosing and scheduling of CAR T-cell infusions on the therapeutic response is explored. We model the interaction between the two cell populations (cancer cells and CAR T-cells) using an ordinary differential equation based formalism. The growth and death of cancer cells are simulated as rates of proliferation and interaction between cancer cells and CAR T-cells, respectively. Biological data was used to parameterize the model. Analysis of the dynamics of interaction between cancer cells and CAR T-cells was performed to determine the maximum efficacy of a single and multiple doses of CAR T-cells. Our mathematical model and analysis shows that a critical parameter for the success of CAR T-cell therapy is the ratio of cancer cell proliferation to the killing capacity of the CAR T-cells. We quantify the dose level of CAR T-cells required to eliminate the cancer cell population. Furthermore, we use the mathematical model to predict the time to progression for specific dose levels, which may help in optimizing and scheduling multiple doses of CAR T-cell monotherapy. We compare the mathematical results with patient data from an ongoing dose-escalation study (NCT02208362) using central memory derived IL13Rα2-targeted CAR T-cell therapy for recurrent glioblastoma.