Development of T cell-mediated targeted gene delivery of immunotoxin in HNSCC

点击翻译按钮获取中文摘要

Development of T cell-mediated targeted gene delivery of immunotoxin in HNSCC Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with more than 500,000 new cases diagnosed annually. Chemotherapy, targeted treatment, and immunotherapy have been approved by the FDA for HNSCC treatment. While a minority of patients experience dramatic long-lasting and favorable clinical responses, the majority of patients fail to achieve durable clinical response. Thus, alternative options with improved beneficial response are urgently needed. In HNSCC, over 90% of tumors overexpress cell surface EGFR. Recombinant immunotoxin (RIT) is a fused protein often consisting of an antibody that targets a tumor antigen and a toxin (e.g., diphtheria toxin [DT]) that kills tumor cells. RIT has been shown to be extremely effective for the treatment of some hematopoietic malignancies. However, RIT is a highly immunogenic and very toxic protein, preventing its use as an effective treatment for solid tumors, including HNSCC. In our previous studies, we produced a humanized RIT DT390-HuBiscFv806 (hDT806) targeting EGFR and demonstrated the efficacy of hDT806 in treating HNSCC and glioma. In this proposal, we will develop a novel approach to overcome the critical limitations of the current RIT application for treating HNSCC with two specific aims. Aim 1: to eliminate systemic immunogenicity and reduce RIT-induced toxicity, we will engineer synthetic Notch T cells to deliver hDT806, specifically targeting HNSCC tumor cells that overexpress EGFR. Aim 2: we will determine the efficacy of hDT806 for killing tumor cells and toxicity in immunodeficient and immunocompetent mice. The validation of scientific principles to effectively and safely deliver RIT will provide a solid rationale for a subsequent research project grant (R01) application to use RIT as a therapeutic agent in recurrent or metastatic HNSCC for which treatment options remain extremely limited.