Manipulating T-cells and tumor antigens to improve endogenous and immunotherapy response against cancer.
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[EMBARGOED UNTIL 12/01/2026] Despite many recent advancements in the development of treatments, cancer has remained the second leading cause of death globally for the past 75 years, accounting for over 9.7 million deaths annually. The inherent complexity and multifaceted nature of cancer pose significant challenges to advancing cancer treatment strategies. Cancer cells exploit various mechanisms to create a heterogeneous and immunosuppressive tumor microenvironment (TME) that evades immune surveillance, including the downregulation of tumor antigens and the production and recruitment of immunosuppressive immune cells, which further compromises the effectiveness of immunotherapeutic strategies. Cancer treatment strategies that boost both endogenous immune surveillance and empower the immune system to fight and target cancer cells are of significant need. This dissertation examines the potential of manipulating T-cell functionality and antigenic strength of tumor antigens to enhance the effectiveness of endogenous immune surveillance and therapy-mediated tumor immunity. We hypothesized that empowering immune cell functioning by controlled alteration of the T cell activation and tumor immunogenicity threshold would improve immune response against cancer cells. To this end, we tested anti-mouse and anti-human CD3ε Fab fragments strictly controlled for monovalence (Mono-Fabs) previously shown to co-potentiate T cell activation and effector function in response to T cell receptor (TCR)/antigen stimulation. We found that anti-CD3ε Fabs delivered anti-tumor effects in mice subcutaneously injected with the Yale University Mouse Melanoma (YUMM) tumor model. Using YUMM sub-lines, we dissected the impact of inherent tumor immunogenicity on the therapeutic effects of anti-CD3ε Mono-Fabs. We found anti-CD3ε Mono-Fabs enhanced anti-tumor effects of clinically proven anti-CTLA-4 and anti-PD-1 mAbs that function by immune checkpoint inhibition (ICI) in a manner dependent on tumor immunogenicity. Interestingly, anti-CD3ε Mono-Fabs displayed this beneficial effect without enhancing immunotoxicity associated with the use of ICI mAbs. Clinical translation of the novel anti-CD3ε Mono-Fabs may address the current therapeutic needs of various cancer patients who are considered ineligible to receive ICI-based therapies due to concerns about their immunotoxicity. While empowering immune cells with ICI mAbs has yielded improved clinical outcomes in a subset of patients, suboptimal responses prevail in most patients, primarily attributed to inadequate tumor immunogenicity and limited immune cell infiltration within the TME of certain cancer types, including “cold” tumors. We propose an immune-evoking strategy aimed at augmenting the immunogenicity of "cold" tumors to enhance both intra-tumoral immunogenicity and the efficacy of immune-targeted therapies. Comparing immunologically cold or hot variants of the melanoma model, YUMM showed enhanced endogenous tumor immunity with significant tumor rejection capability of hotter over colder melanoma variants. We observed that endogenous anti-tumor responses were above those achieved with combined T cell-based immunotherapies upon experimental comparison. In addition, we obtained empirical evidence that endogenous anti-tumor responses against more immunogenic tumor variants result in the generation of long-lasting memory T cells that can protect against less immunogenic but related variants. Although unexplored here, it is conceivable that extracting less immunogenic tumors and expanding their immunogenicity can be used as an immunizing agent to generate potent and long-lasting anti-tumor immune responses against original tumors that are less immunogen
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Ph. D.