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.
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