Background:T-ALL/LBL are highly aggressive hematologic cancers with high rates of relapse and mortality in both children and adults. Cluster of differentiation (CD) 7 is expressed in over 95% of T-ALL/LBL patients and limited effective treatment options are available for these patients. WT-7 is an allogeneic, fratricide-resistant genetically modified T cell transduced with a 2nd generation 4-1BB-CD3z chimeric antigen receptor (CAR) targeting human CD7. In a global first-in-human, phase 1/2 single-agent study of WT-7, 28 patients with R/R T-ALL/LBL were treated with WT-7 at varying dose levels (Aldoss, et al, EHA 2024). Patients ≥12 years old were included. The recommended phase 2 dose (RP2D) was 900M WT-7 cells following an enhanced lymphodepletion (eLD) regimen consisting of fludarabine 30mg/m2/day for four days and cyclophosphamide 1gm/m2/day for 3 days. WT-7 demonstrated an acceptable safety profile as well as dose-dependent anti-tumor activity at the RP2D, with 1) an overall response rate (ORR) of 91%, 2) a composite complete response (CRc) rate of 73%, MRDneg 83% (n=8 with available sample for MRD testing) 3) a median duration of response (DOR) not reached (95%CI: 1.8, NE) with follow up of up to 9.9 months, and 4) CAR-T cell expansion peaking on day 10 (median 237,827 copies/µg of DNA) and persisting to day 90, with no development of anti-HLA or anti-CAR antibodies. WT-7 has the potential to address a significant unmet medical need for patients with CD7 positive R/R T-ALL/LBL, as patients who relapse have a poor prognosis. Methods:WUC007-03, a single-agent, multicenter study, will evaluate patients 1 year of age and older with R/R T-ALL/LBL. The primary endpoint is CRc during the 3 months after WT-7 administration. CRc rate is defined as the proportion of patients that achieve a complete remission (CR) + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi). Secondary endpoints include DOR, percentage of patients who achieve best overall response (BOR) of CR or CRh at Month 6 without stem cell transplant (SCT) between WT-7 infusion and Month 6 response assessment, and percentage of patients who achieve CR, CRh or CRi and then proceed to SCT while in remission before Month 6 response assessment. Response assessments will take place on Day 28 (±3days), and at Months 3, 6, 12, and 24 (±14 days) by bone marrow (BM) aspirate and biopsy, and computerized tomography (CT)/PET, if applicable. Undetectable MRD disease is defined as <0.1% blasts in BM. MRD threshold is based on the Children's Oncology Group risk classification schema for T-ALL where patients with an end-of-consolidation MRD ≥0.1% are considered very high risk for relapse. After evaluation of safety in R/R T-ALL/LBL patients (n~30), patients in CR with detectable MRD may be enrolled to evaluate MRD conversion rate to undetectable, and hematological relapse-free survival (NCT06514794). Eligibility: Patients ≥ 1 year old with evidence of T-ALL or T-LBL, as defined by the World Health Organization (WHO) classification, and R/R disease (≥5% blasts in the BM and/or evidence of extramedullary disease (EMD)) will be eligible for this study. For potential exploratory cohort, patients with detectable MRD disease (0.1-5% blasts in the BM as determined by a central flow-based assay) following first induction and consolidation, will also be eligible for this study following confirmation of safety in the R/R cohort. Treatment: Enrollment will begin with a safety lead-in in the R/R cohort at a reduced dose of 600M cells with eLD. The purpose of this safety lead-in will be to 1) confirm that the safety data demonstrated in the Phase 1/2 trial is comparable for pediatric patients ages 1-11, and 2) validate the prior safety data in patients 12 years and older. Following this safety lead-in, all patients enrolled in the study will receive a single dose of the RP2D of 900M WT-7 on Day 0 following eLD conditioning. Enrollment: Enrollment will take place at 19 sites globally and is targeted to begin by the end of 2024.
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