Modeling Cancer Immunotherapies through in silico Trials*

Abstract: Immunotherapies are a promising new development in treating breast cancer and specifically triple-negative breast cancer (TNBC). In our research we investigate two types of immunotherapies: Cytotoxic T-cell (CTLs) insertion therapy and Chimeric Antigen Receptor (CAR) T-cell therapy using an agent-based model (ABM) of breast cancer development. In CTL insertion therapy, CTLs - which are one mechanism the immune systems uses to fight cancer - are inserted into the tumor microenvironment. In CAR T-cell therapy, the CAR T-cells have been modified such that they bind to a cancer associated antigen (CAA) and activate signaling domains that lead to cancer cell death. In this research, we expand upon a previously developed agent-based model for triple-negative breast cancer by incorporating immunotherapy, including breast cancer cells, endothelial cells, and T-cells (CTLs or CAR-T). The breast cancer cell module includes TNBC cancer cells, which are influenced by their type (stem or progenitor cell), their state (quiescent, senescent, etc.), their CCR5 status, and hypoxia. The endothelial cell module simulates sprouting angiogenesis, including sprout formation, different cell types (tip, stalk, and phalanx cells), and anastomosis. The CTL therapy module is modeled by inserting a specific number of CTLs in the tumor microenvironment and simulating how they to migrate and kill tumor cells. The CAR T-cell therapy module is modeled by CAR T-cell recruitment through the tumor vasculature with breast cancer cells expressing different amounts of cancer associated antigen. The cancer associated antigen expression determines how likely a tumor cell will be detected and killed by a CAR T-cell. We investigate the treatment effects of inserting different numbers of CTLs into the tumor microenvironment and vary the percentages of antigen expression to determine their overall effect on tumor size in the short and longer terms. Our findings suggest that T-cell therapy is effective in decreasing the size of solid TNBC tumors but in many cases may not be effective at completely eliminating the tumor.

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