Precision Combinatorial Immunotherapeutic Targeting of Cytokine Receptor Kinase Signaling in CRLF2-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% relapse risk and experience significant leukemia-associated mortality. Approximately 50% 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% 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% of patients with relapsed/refractory ALL. However, emerging data indicates that up to 50% 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 Phlike ALL PDX models generated by the Tasian laboratory.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1196243
Entities
People
- Sarah K. Tasian
- Terry Fry
Organizations
- Children's Hospital of Philadelphia