Evaluation of therapeutic index of TIP1 targeted beta and alpha radioimmunotherapy - ABSTRACT Lung cancer remains the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for most cases. Current treatment options for metastatic NSCLC, such as chemotherapy and immunotherapy, yield dismal 5-year overall survival rates, especially for patients lacking actionable mutations. Chemotherapy’s non-targeted approach results in significant toxicity, and immunotherapy benefits only a small subset of patients. This underscores an urgent unmet need for novel, more effective therapies to improve survival outcomes for NSCLC patients. Our proposal aims to revolutionize the treatment paradigm for NSCLC by utilizing targeted radiopharmaceutical therapy (TRT) directed against Tax-interacting protein 1 (TIP1), a tumor-associated antigen highly upregulated on NSCLC cells and further enhanced following radiation therapy. Our team’s pioneering work has demonstrated that anti-TIP1 human antibodies selectively target tumor cells, avoiding healthy tissues and delivering payloads with minimal off-target toxicity. By leveraging this unique biology, we propose to radiolabel TIP1-targeted antibodies with potent alpha- and beta-emitting radionuclides, providing precise and powerful tumor control while minimizing systemic toxicity. Alpha and beta particles have distinct properties, including tissue penetration and energy transfer, which we hypothesize will lead to different therapeutic effects when conjugated to TIP1-targeted antibodies. Importantly, we anticipate that alpha-emitting radionuclides will induce higher tumor cell killing while beta-emitters offer better penetration into larger tumors. Additionally, we hypothesize that combining these radionuclides with immune checkpoint inhibitors (ICIs) will create synergistic effects, enhancing antitumor immune responses and overcoming resistance to immunotherapy. In Aim 1, we will systematically compare the therapeutic efficacy and toxicity profiles of 177Lu (β-emitter) versus 212Pb (α-emitter) conjugated anti-TIP1 antibodies in preclinical models. These studies will elucidate the distinct mechanisms by which these radionuclides mediate tumor destruction, including DNA damage, cellular senescence, and apoptosis. We will use patient-derived xenograft (PDX) models to closely mimic the clinical landscape and assess patient-specific responses. In Aim 2, we will investigate the immunomodulatory effects of TRT in combination with immune checkpoint blockade, exploring how α- and βemitters influence the tumor microenvironment. Through advanced single-cell RNA sequencing and flow cytometry, we will uncover how TRT alters immune cell populations and cytokine profiles, potentially enhancing immunotherapy efficacy. Therapeutic efficacy will be tested in immunocompetent mouse models to provide comprehensive insights into clinical translation. This innovative approach has the potential to extend survival and improve quality of life for NSCLC patients, offering a highly targeted therapy with minimal collateral damage. By optimizing the combination of TRT with ICIs, this research could transform the treatment landscape for NSCLC, overcoming the limitations of current therapies and improving outcomes for patients worldwide. We proposed animal models, as an intact circulatory system is needed to understand the biodistribution of the TRTs and whether the antibodies have any adverse effects on healthy organs.
