P356: phase 1/2 dose-escalation study of anti-cd7 allogenic car-t cell in relapsed or refractory(r/r) t-cell acute lymphoblastic leukemia/lymphoblastic lymphoma(t-all/lbl)

Background: T-ALL/LBL are challenging hematologic cancers with high rates of relapse and mortality in both children and adults. Despite success in B-cell malignancies, development of CAR-T cell therapy for T cell cancers have been complicated by induction of fratricide and high risk of malignant cell contamination of the drug product in the autologous setting. We have previously demonstrated that CRISPR/Cas9 gene-editing to delete CD7 prevented fratricide, and deletion of the T-cell receptor alpha constant (TRAC) enabled the use of healthy donor allogeneic T-cells to manufacture gene edited CD7-targeted CAR-T cells for the treatment of T-ALL/LBL with a reduced risk of graft vs. host disease (GvHD). (Leedom et al. ASH 2021) Aims: WU-CART-007 1001 is a global first-in-human, Phase 1/2 single-agent study to determine the safety, tolerability, expansion kinetics, recommended Phase 2 dose (RP2D), and preliminary efficacy of WU-CART-007 in patients (pts) with R/R T-ALL/LBL. Four dose levels will be evaluated (DL; 100, 300, 600, 900 million (M) cells per infusion) in a 3 + 3 design. Cohort expansion will enroll up to 20 pts treated at the RP2D. All patients receive a 3-day lymphodepletion regimen consisting of fludarabine and cyclophosphamide, followed by a single dose of WU-CART-007. Eligible patients must be ≥18 years old with R/R T-ALL or T-LBL, have adequate organ function, no evidence of uncontrolled infections, GVHD or CNS disease. Patients with prior anti-CD7 therapy are excluded. Response is assessed by bone marrow (BM) aspirate/biopsy, and CT/PET, if applicable, per modified NCCN Guidelines Version 2.2022. Pharmacokinetics are measured by flow cytometry (FACS), and PCR. Herein, we present early results of the dose escalation phase of the study. Methods:Results: As of 30th January 2023, 12 pts (n = 9 T-ALL, n = 3 T-LBL) have received WU-CART-007; 3 in DL1, 3 in DL2, and 6 in DL3. Median age was 32.5 years (range 21-62). All pts were heavily pretreated with a median of 5 prior lines of therapy (range 2 – 8). Seventeen percent (2/12) had received a prior allogeneic or haploidentical HCST. Disease burden at baseline (BL) consisted of extramedullary disease (EMD) in 67% (8/12) of pts, and a median BM blast count of 61.5% (range 43-85%) in pts with BM disease (8/12). Overall WU-CART-007 demonstrated manageable toxicity; treatment-related adverse events of ≥ G3 were observed in 3/12 (25%) pts. Cytokine release syndrome (CRS) was observed in 8/12 (67%) pts. Most (86%; 7/8) pts had G1-2 CRS events; a single G3 CRS event was reported which resolved within 24 hours after receiving tocilizumab, dexamethasone and low dose vasopressors. Grade 1 ICANS was reported in a patient at DL3, which resolved spontaneously. No GvHD, or prolonged T-cell aplasia or pancytopenia have been reported. One unrelated DLT of encephalopathy, secondary to intracranial bleed associated with a Rhizomucor infection, lead to cohort expansion at DL3. The objective response rate (ORR) at ≥ DL2 of evaluable pts is 43% (3/7; 1 CR, 1 MLFS and 1 PR). To date, with a median follow up of 107 days, duration of response extending to 86 days has been reported. Summary/Conclusion: WU-CART-007 has demonstrated an acceptable safety profile and preliminary evidence of anti-leukemic activity. in a subset of patients. This program advances CAR-T cell therapy in heavily pre-treated patients with R/R T-ALL/LBL. Enrollment in this study (NCT04984356) is ongoing. Keywords: T-ALL, CAR-T, Phase I/II, Clinical trial