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

T细胞介导的免疫毒素靶向基因治疗头颈部鳞癌的研究进展 摘要 头颈部鳞状细胞癌（HNSCC）是第六常见的癌症 在全球范围内，每年有超过50万例新确诊病例。化疗，靶向 FDA已经批准免疫疗法用于HNSCC治疗。而 少数患者经历了显著的持久和有利的临床反应， 大多数患者不能获得持久的临床应答。因此，替代方案， 迫切需要改进有益的反应。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，通常由一个 靶向肿瘤抗原和毒素的抗体（例如，白喉毒素（DT），可杀死肿瘤 细胞RIT已被证明是非常有效的治疗一些造血 恶性肿瘤。然而，RIT是一种高度免疫原性和毒性很强的蛋白质，阻止了其使用 作为实体瘤的有效治疗，包括HNSCC。在以前的研究中，我们 产生了靶向EGFR的人源化RIT DT 390-HuBiscFv 806（hDT 806），并证实了 hDT 806治疗HNSCC和胶质瘤的疗效。在这个提案中，我们将开发一种新的 克服目前RIT应用于治疗HNSCC的关键局限性的方法 有两个具体目标。目的1：消除全身免疫原性并减少RIT诱导的 毒性，我们将设计合成Notch T细胞来递送hDT 806，特异性靶向 过表达EGFR的HNSCC肿瘤细胞。目的2：我们将确定hDT 806的功效 在免疫缺陷和免疫活性小鼠中杀死肿瘤细胞和毒性。的 有效和安全地实施RIT的科学原理的验证将提供坚实的理论基础 随后的研究项目补助金（R 01）申请使用RIT作为治疗剂， 复发性或转移性HNSCC，其治疗选择仍然非常有限。

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.