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.