Phase 1 TSLPR-CART anti-TSLPR (CRLF2) CAR T-cell therapy in R/R B-ALL

This first-in-human Phase 1, open-label, 3+3 dose-escalation study sponsored by the National Cancer Institute (NCI) tests autologous TSLPR-CART: a patient’s own T cells engineered to express a chimeric antigen receptor that binds TSLPR (the thymic stromal lymphopoietin receptor; encoded by CRLF2) on leukemia blasts, enabling targeted T-cell killing. The CAR product includes a truncated EGFR (tEGFR) “safety/suicide” marker intended to allow pharmacologic elimination of the infused cells if severe toxicity occurs. Participants (adults ≥18) must have recurrent/refractory B-cell acute lymphoblastic leukemia with TSLPR overexpression on flow cytometry (often enriching for CRLF2-rearranged, Ph-like biology), and have failed at least one standard regimen and one salvage regimen. Patients receive fludarabine and cyclophosphamide lymphodepletion (DNA synthesis–inhibiting cytotoxics) followed by a single TSLPR-CART infusion; an expansion cohort treats at the maximum tolerated or highest tested dose to estimate response rate and characterize CAR expansion/persistence. Scientifically, the key angle is antigen-escape mitigation: after CD19 CAR T (and sometimes CD22-directed approaches), relapse can occur via loss of the targeted antigen, so TSLPR offers a distinct, biologically linked surface target in CRLF2-driven disease. Today, adults with multi-relapsed B-ALL often cycle through salvage chemo and targeted immunotherapies (e.g., blinatumomab for CD19, inotuzumab for CD22) and, when feasible, allogeneic transplant; outcomes remain poor for chemotherapy-resistant Ph-like subsets, motivating novel CAR targets.