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

T细胞介导免疫毒素靶向基因治疗HNSCC的研究进展 摘要 头颈部鳞状细胞癌(HNSCC)是第六大常见癌症 全世界每年新增确诊病例超过50万例。靶向化疗 治疗和免疫疗法已经被FDA批准用于HNSCC的治疗。当一个 少数患者经历了戏剧性的长期和良好的临床反应， 大多数患者未能取得持久的临床疗效。因此，替代选项包括 迫切需要改进有益的应对措施。在HNSCC中，超过90%的肿瘤过度表达 细胞表面EGFR。重组免疫毒素(RIT)是一种融合蛋白，通常由 针对肿瘤抗原和杀死肿瘤的毒素(如白喉毒素[dt])的抗体 细胞。RIT已被证明对某些造血病的治疗非常有效 恶性肿瘤。然而，RIT是一种高度免疫原性和剧毒的蛋白质，使其无法使用 作为实体肿瘤的有效治疗方法，包括HNSCC。在我们之前的研究中，我们 制作了针对EGFR的人源化RIT DT390-HuBiscFv806(HDT806)并演示了 HDT806治疗HNSCC和脑胶质瘤的疗效观察在这个提案中，我们将开发一部小说 克服目前应用RIT治疗HNSCC的关键限制的方法 有两个明确的目标。目的1：消除系统免疫原性，减少RIT诱导 毒性，我们将设计合成Notch T细胞来传递hDT806，特别是靶向 过度表达EGFR的HNSCC肿瘤细胞。目的2：我们将确定hDT806的疗效 对免疫缺陷和免疫活性小鼠的肿瘤细胞的杀伤和毒性。这个 对有效和安全地提供RIT的科学原则的验证将提供坚实的理由 对于随后的研究项目拨款(R01)申请使用RIT作为治疗剂 复发或转移性HNSCC，其治疗选择仍然极其有限。

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.