Project Grant K08CA286765

LEVERAGING SMALL MOLECULE INHIBITORS TO IMPROVE CD19 CAR T CELL IMMUNOTHERAPY FOR KMT2A-REARRANGED ALL - PROJECT SUMMARY/ABSTRACT THIS K08 MENTORED CAREER DEVELOPMENT AWARD PROPOSAL DETAILS A RESEARCH AND TRAINING PLAN THAT IS DESIGNED TO FACILITATE THE CAREER DEVELOPMENT AND TRANSITION OF LISA NISWANDER, MD PHD TO AN INDEPENDENT PHYSICIAN-SCIENTIST INVESTIGATOR. DR. NISWANDER IS A PEDIATRIC ONCOLOGIST AND AN INSTRUCTOR OF PEDIATRICS AT THE CHILDREN'S HOSPITAL OF PHILADELPHIA (CHOP) AND UNIVERSITY OF PENNSYLVANIA (PENN). HER LONG-TERM GOAL IS TO LEAD AN NIH-FUNDED RESEARCH PROGRAM FOCUSED ON THE PRECLINICAL DEVELOPMENT AND EARLY BENCH-TO-BEDSIDE TRANSLATION OF TARGETED THERAPIES AND IMMUNOTHERAPIES TO IMPROVE OUTCOMES FOR CHILDREN WITH LEUKEMIA. DURING THE 5-YEAR AWARD PERIOD, CRITICAL TECHNICAL AND SCIENTIFIC TRAINING WILL BE ACQUIRED IN T CELL AND CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL IMMUNOBIOLOGY, SINGLE CELL TRANSCRIPTOMICS, EARLY-PHASE CLINICAL TRIAL DESIGN, LEADERSHIP, AND SCIENTIFIC COMMUNICATION. UNDER THE PRIMARY MENTORSHIP OF DR. SARAH TASIAN, A LEADER IN THE DEVELOPMENT OF MOLECULARLY- TARGETED AND CAR T CELL THERAPIES FOR HIGH-RISK PEDIATRIC LEUKEMIAS, AND CO-MENTORSHIP OF DR. MARTIN CARROLL, AN EXPERT IN ACUTE LEUKEMIA SIGNALING, IN TANDEM WITH A COMPLEMENTARY ADVISORY COMMITTEE OF SENIOR SCIENTISTS, THIS SCIENTIFIC RESEARCH PROGRAM AND TRAINING PLAN WILL BE BOLSTERED BY THE RESOURCE-RICH ENVIRONMENT AT CHOP/PENN. DESPITE HIGH CURE RATES IN MOST CHILDREN WITH B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL), INFANTS WITH B-ALL HAVE DISMAL OUTCOMES. MOST CASES OF INFANT B-ALL ARE CHARACTERIZED BY KMT2A REARRANGEMENTS (KMT2A-R) WITH RESULTING FUSION PROTEINS THAT COMPLEX WITH CRITICAL ADAPTOR PROTEIN MENIN TO DRIVE LEUKEMOGENESIS AND/OR BY FREQUENT ACTIVATING RAS PATHWAY MUTATIONS. PROMISING PRECLINICAL AND EARLY CLINICAL EFFORTS HAVE FOCUSED ON SMALL MOLECULE DISRUPTION OF KMT2A-MENIN BINDING (MENIN-I) AND ON MEK INHIBITOR (MEK-I) BLOCKADE OF RAS SIGNALING. CD19-DIRECTED CAR T CELL IMMUNOTHERAPY (CD19CART) HAS ACHIEVED HIGH RESPONSE RATES IN CHILDREN WITH B- ALL, INCLUDING INFANTS WITH KMT2A-R ALL. HOWEVER, AT LEAST 50% OF THESE PATIENTS WILL ULTIMATELY RELAPSE. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT COMBINING CD19CART WITH PHARMACOLOGIC DISRUPTION OF SPECIFIC KMT2A-R ALL BIOLOGIC VULNERABILITIES, INCLUDING MENIN-BINDING OR ABERRANT RAS SIGNALING, WILL IMPROVE TREATMENT EFFICACY AND LONG-TERM REMISSION IN KMT2A-R ALL. TO TEST THIS HYPOTHESIS, THE COMBINATORIAL STRATEGY OF MENIN- I (AIM 1) AND MEK-I (AIM 2) WITH CD19CART AGAINST KMT2A-R ALL WILL BE INVESTIGATED. THE EFFECTS OF THESE DUAL APPROACHES WILL BE ELUCIDATED FOR BOTH ANTI-LEUKEMIA THERAPEUTIC ACTIVITY AND FOR CD19CART FUNCTIONALITY AND PERSISTENCE. SUCCESSFUL COMPLETION OF THIS CAREER DEVELOPMENT AWARD WILL IDENTIFY PROMISING CO-THERAPEUTIC STRATEGIES WITH CD19CART POISED FOR RAPID CLINICAL TRANSLATION FOR CHILDREN WITH KMT2A-R ALL. THESE RESEARCH AND TRAINING EFFORTS WILL ALSO PROPEL DR. NISWANDER'S TRANSITION TO INDEPENDENCE BY ESTABLISHING A ROBUST SCIENTIFIC PIPELINE FOR FUTURE INVESTIGATION OF TARGETED INHIBITORS WITH IMMUNOTHERAPIES IN PEDIATRIC LEUKEMIAS.