Abstract A011: Modeling the coevolution of native and CAR T-cells in large B cell lymphoma reveals a potential biomarker for response to therapy

Abstract

Abstract Application of CD19 targeted Chimeric Antigen Receptor (CAR) T-cell therapy to large B cell lymphoma (LBCL) has yielded unprecedented clinical outcomes in a cancer largely resistant to conventional chemotherapy. This is highlighted in the recent ZUMA-7 trial, where axicabtagene ciloleucel (axi-cel), a CAR T-cell therapy, yielded a complete response (CR) rate in 65% of patients, an improvement over the 32% CR rate when using standard chemotherapy. The ZUMA-7 trial highlights the potential of CAR T-cell therapy to treat traditionally resistant cancers, but work remains to be done to identify biomarkers predictive of response. Operating under the assumption that CAR T not only directly targets CD19+ tumor cells, but also enhances tumor kill by amplifying the native T-cell populations, we hypothesized that neoantigen burden (NAB) may serve as a useful biomarker to make predictions of response to CAR T. We explore this hypothesis by building upon traditional predator-prey mathematical models to simulate the evolution of LBCL under immune predation and treatment with CAR T-cell therapy. More specifically, in our model native T-cells prey upon tumor cells that carry their cognate neoantigen, and each T-cell has variable search rate proportional to the cognate neoantigen’s recognition potential, modeled using a type III functional response. Tumor cells may mutate during division, always gaining a neoantigen, but possibly also losing HLA function, paving the way for immune escape. In addition to modeling the direct killing of tumor by CAR T, we also explore the synergistic effect of CAR T on native T-cells by modeling increased amplification of, and killing by, native T-cells based on interactions with the CAR T-cell population. Preliminary simulations suggest a high NAB can indeed be predictive of CAR T response, although only if the tumor has not evolved an escape mechanism. Indeed, simulations suggest that high NAB can also be a signature of an immune escaped tumor, as neoantigens become neutral traits once the immune system is removed as a selective force. These results suggest that knowledge of a patients’ NAB and immune competency can be used to guide CAR T treatment decisions. Citation Format: Chandler D. Gatenbee, Mark Robertson-Tessi, Maximilian Strobl, Ryan O. Schenck, Bachisio Ziccheddu, Francesco Maura, Frederick Locke, Alexander R.A. Anderson. Modeling the coevolution of native and CAR T-cells in large B cell lymphoma reveals a potential biomarker for response to therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A011.