THE PURPOSE OF THIS MODIFICATION IS TO EXERCISE THE I-CORP OPTION

青少年粒单核细胞白血病（JMML）是一种罕见的幼儿血液恶性肿瘤，死亡率高。JMML每年占儿童白血病的1-2%;在美国，估计每年诊断出25-50例新病例。JMML主要影响幼儿，最常见于4岁以下儿童。目前，对大多数JMML患者唯一有效的治疗方法是异基因造血干细胞移植（HSCT）。然而，JMML儿童在HSCT后复发是一个显著的风险，因为一旦肿瘤逃逸变异发生，就没有其他可用的治疗方法。40-50%的患者会出现疾病复发。 Gencyte Therapeutics，Inc.提出开发一种逻辑门控精密分子适配器（PMA）系统，用于JMML治疗。这种平台技术可能会降低治疗期间的CAR-T毒性并防止复发。通过概念授予阶段的工作，Gencyte将建立用于JMML治疗的逻辑门控PMA CAR平台，并获得关键的初步概念验证数据，这些数据将使这种潜在的广泛适用的免疫治疗技术进入下一阶段的进一步发展。这些研究将推动CAR靶向治疗的发展，如果成功，将产生一个具有广泛适用性的有前景的治疗平台，可用于临床前和临床开发。 目的1：开发特异性结合表位和PMA的单链抗体，用于肿瘤靶向 目标2.逻辑门控控制的CAR的慢病毒的产生 目的3：制备逻辑门控控制的CAR-T细胞和靶细胞 目的4：通过体外测定评估对数门控PMA CAR系统的JMML肿瘤细胞杀伤效率。

Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy of early childhood with high mortality. JMML accounts for 1-2% of childhood leukemias each year; in the United States, an estimated 25-50 new cases are diagnosed each year. JMML predominately affects young children, most often developing in children under the age of 4. Currently, the only effective treatment for most JMML patients is allogeneic hematopoietic stem cell transplantation (HSCT). However, relapse is a significant risk after HSCT for children with JMML because once tumor escape variants are developed, there are no other treatments available. 40–50% of the patients experience disease recurrence. Gencyte Therapeutics, Inc. proposes developing a logic gate-controlled precision molecular adaptor (PMA) system, for JMML treatment. This proposed platform technology could potentially lower CAR-T toxicity during treatment and prevent relapse. Through the work of concept award phase, Gencyte will have established the logic gated PMA CAR platform for JMML treatment and obtained key preliminary proof-of-concept data that will move this potentially broadly applicable immunotherapy technology toward the further development next phase. These studies will advance CAR-targeted therapies in general and, if successful, yield a promising therapeutic platform with broad applicability that is ready for preclinical and clinical development. Objective 1: Develop scFv antibodies specific to our proprietary binding epitope and PMAs for tumor targeting Objective 2. Generation of lentivirus of logic-gated controlled CAR Objective 3: Preparing logic-gated controlled CAR-T cells and target cells Objective 4: Evaluating the JMML tumor cell killing efficiency of the log-gated PMA CAR system by in vitro assays.