Precision Combinatorial Immunotherapeutic Targeting of Cytokine Receptor Kinase Signaling in CRLF-2 Rearranged ALL
Abstract
Ph-like ALL is a high-risk subset of B-ALL defined by an activated kinase gene expression profile similar to that of BCR-ABL1-rearranged (Ph+) ALL and driven by a diverse range of genetic alterations that activate cytokine receptor signaling pathways. Children, AYAs, and older adults with Ph-like ALL have >60 percent relapse risk and experience significant leukemia-associated mortality. 50 percent of Ph-like ALL cases harbor rearrangements in CRLF2 (CRLF2-R) and frequent concomitant JAK2 point mutations. In addition to patients with Ph-like ALL, CRLF2 rearrangements (usually P2RY8-CRLF2 fusions) with JAK2 point mutations occur in approximately 60 percent of children and AYAs with trisomy 21/Down Syndrome-associated ALL(DS-ALL) and also induce hyperactive JAK/STAT signaling. Children with DS-ALL have substantial toxicity with chemotherapy and inferior clinical outcomes. CD19CART immunotherapy has proven highly successful at inducing remissions in 80-90 percent of patients with relapsed/refractory ALL. Emerging data indicates that up to 50 percent of children and AYAs will relapse, most within a year. As an alternative strategy, the Fry laboratory developed CAR constructs targeting the TSLPR (encoded by CRLF2) and demonstrated potent in vivo activity of T cells transduced with anti-TSLPR CAR constructs (TSLPRCART) in CRLF2-R Ph-like ALL PDX models generated by the Tasian laboratory. Based on our promising preclinical data, a phase 1 clinical trial of TSLPRCART for children and AYAs with relapsed CRLF2/TSLPR-overexpressing ALL will soon open at the NIH. TKIs and CART immunotherapies have the potential to act synergistically in acute leukemias via co-targeting of oncogenic pathways using two distinct approaches: one (CART) targeting a cell surface cytokine receptor protein and the other (TKI) targeting critical receptor-mediated and intracellular kinase signaling pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1196256
Entities
People
- Sarah K. Tasian
- Terry Fry
Organizations
- University of Colorado Boulder