Mathematics Models of Tumor-Immune Interactions And Immunotherapy

Abstract

Immunotherapy is rapidly becoming a standard treatment in cancer, alongside surgery,chemotherapy, and radiotherapy. As T cells are key players in anti-tumor immune response, strategies to modify T cells and then re-inject them to enhance anti-cancer immunity are at the forefront of cancer immunotherapy. Engineered T cell receptor (TCR)-expressing T (TCR-T) cells are intended to drive strong anti-tumor responses upon recognition of the specific cancer antigen, resulting in rapid expansion in the number of TCR-T cells and enhanced cytotoxic functions, causing cancer cell death. However, although TCR-T cell therapy against cancers has shown promising results, it remains challenging to predict which patients will benefit from such therapy. In this dissertation, we look specifically at TCR-T cell therapy, explore the mechanisms by which this living product grows and changes inside the body, explore how and why this process differs so dramatically between patients, and explore how quantity and quality must be optimized for maximal effectiveness of this therapy. We developed two ordinary differential equation models: one focusing on TCR-T cell therapy for cervical cancer, and another that expands this framework to evaluate TCR-T cell therapy as a dynamic system involving effector TCR-T cells, regulatory T cells (Tregs), and “non-cancer-killing” TCR-T cells. Our results provide a plausible mechanistic explanation for the wide variability in clinical responses to TCR-T cell therapy and suggest strategies to enhance patient outcomes, particularly for highly heterogeneous patient populations. Specifically, our findings indicate the existence of an optimal dosage window for TCR-T cells, dependent on the initial tumor size, to achieve successful cancer elimination. Furthermore, we demonstrate that a significant proportion of TCR-T cells within the tumor microenvironment (TME) are ”noncancer- killing” cells, such as exhausted T cells, contributing little or no direct cytotoxicity. We also identify two critical factors influencing tumor regression: the reversal of the immunosuppressive TME following Treg depletion and the increased presence of effector TCR-T cells with antitumor activity. Finally, we show that parameters such as enhancing the cytotoxicity of effector TCR-T cells and increasing their numbers are crucial in determining treatment outcomes.