Precision Combinatorial Immunotherapeutic Targeting of Cytokine Receptor Kinase Signaling in CRLF2-Rearranged ALL
Abstract
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. Furthermore, combining multi-targeted CAR T cells with TKIs is strategically analogous to the paradigm of of non-cross-resistant cytotoxic chemotherapy regimens that is required to achieve cure in children with ALL. The primary hypothesis of this proposal is that durable remissions in patients with CRLF2-R Ph-like ALL or DS-ALL can be achieved using rationally combined immune and molecular kinase therapies that target critical and necessary signaling pathways in malignant cells. The project is divided into the following Aims: Aim 1. Develop combinatorial CAR constructs targeting TSLPR plus CD19 and/or CD22 and test the anti-leukemia efficacy of multi-targeted CARTs against CRLF2-R ALL in children, adults, and DS patients. Aim 2. Determine the preclinical efficacy of multi-specific CARTs and kinase inhibitors against CRLF2-R ALL. Aim 3. To delineate the impact of DS-associated immunodeficiency and aging on the potency of CART generated from of patients with DS-ALL and to determine functionality of autologous T cell transduction for clinical immunotherapy with CARTs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1227416
Entities
People
- Terry Fry
Organizations
- University of Colorado Boulder