WU-CART-007 (WT-7), an Allogeneic CAR T-Cell Targeting CD7 in Relapsed/Refractory (R/R) T-Cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/LBL): Phase 2 Results

R/R T-ALL/LBL are challenging malignancies to treat with few treatment options and high rates of relapse and mortality. WT-7 is a CD7-targeted CAR T-cell product with CRISPR/Cas9 deletion of CD7 and T-cell receptor alpha constant (TRAC), to prevent fratricide and enable the use of healthy donor allogeneic T-cells (Leedom, et al. ASH 2021). We report time-to-event (TTE) update from the Phase 2 portion of WU-CART-007 1001 (NCT04984356), a Phase 1/2 study of WU-CART-007 in patients (pts) with R/R T-ALL/LBL, and a focus on subgroup analysis of RP2D.

In the Phase 2 portion, pts received a single infusion of 900 million WT-7 cells on Day 1 following enhanced lymphodepleting (eLD) chemotherapy (fludarabine 30 mg/m²/day x 4 days and cyclophosphamide 1000 mg/m²/day x 3 days). Disease response was assessed by a Day 28 bone marrow (BM) assessment and a CT/PET, if applicable. Composite complete remission (CRc) was defined as combination of CR (BM blasts <5% with absolute neutrophil count ≥1,000/μL and platelet count ≥100,000/μL) and CRi (CR with incomplete hematologic recovery), and SUV uptake < than liver/mediastinum for those with extramedullary disease (EMD). Objective response rate (ORR) was defined as CRc plus partial response (PR; reduced uptake compared to baseline in EMD). Duration of response (DOR) is measured from initial response to relapse or death, follow up time is calculated from first dose to death or last follow date, and TTE endpoints are calculated using Kaplan-Meier statistics. Pharmacokinetics were measured by ddPCR andimmunophenotyping. MRD was measured centrally by flow cytometry, threshold >0.01%.

As of 24 Jul 2024, 13 pts were dosed, median age was 23 years (range 14 – 47). Pts were heavily pretreated with a median of 5 lines of therapy (range 1 – 9); 46% (6/13) had prior allogeneic hematopoietic stem cell transplant (allo-HSCT). Disease burden at baseline consisted of EMD in 38.4% (5/13), and a median BM blast percentage of 82.5% (range 5-95%) in pts with BM disease (8/13). Treatment-related adverse events of ≥ Grade (G) 3 were observed in 10/13 (77%) pts. Cytokine Release Syndrome (CRS) occurred in 13/13 (100%) pts; most (69%; 9/13) had G1-2 CRS events; four (31%) pts had G≥3 CRS, which was managed with steroids (75%), tocilizumab (100%), anakinra (25%). A single event of immune effector cell-associated neurotoxicity (G1) was reported in one pt (8%). Severe (≥ G3) infections were observed in 46% (6/13), including sepsis 31% (4/13), opportunistic viral infections, otitis externa, fungal pneumonia in 1 patient (8%) each. One case of G2 graft vs. host disease was reported. Two G5 events occurred: sepsis due to fungal infection on day 13, and an event of multi-organ failure occurred in the setting of G3 CRS and fulminant disease progression on Day 7 post infusion.

ORR and CRc amongst evaluable pts were 91% (10/11) and 73% (8/11; 6 CR, 2 CRi), respectively. Minimum Residual Disease (MRD) data were available for 6 pts who achieved CRc, with 83% (5/6) achieved MRD^neg CR. Five patients received consolidating allo-HSCT. With a follow-up time of up to 9.9 months (m), median DOR has not been reached (95% CI: 0.5, NE; range 0.5-9.1 m); 4 pts remain in continuous CR at 9.1, 8.2, 6.7, and 6.7 m. In 5 pts with EMD disease, a relatively more challenging population, the ORR was 80% (4/5; 2CR/2PR). For pts that achieved PR the decrease in total disease burden ranged from 78.5-95.7% (median 87.7%) by Lugano Criteria.

Expansion of WT-7 cells peaked on Day 10 in the peripheral blood (median 237,827 copies/μg DNA), persisting out to Day 90. No pt tested developed novel anti-HLA or anti-drug antibodies against the CAR construct.

A further analysis exploring the impact of MRD response was performed on all treated patients irrespective of dose level. A time-to-event Kaplan-Meier analysis showed median duration of response for pts with MRD^neg CR/CRi (n=7) was 6.6 m (95%CI: 1.8, NE) vs. 3.7 m (95%CI: 0.5, NE) for those with CR/CRi MRD^pos (n=3). Similar findings were identified for overall survival (OS), for pts that achieved MRD^neg OS was 11.5 m (95%CI: 2.7, NE) vs. 6.1 m (95%CI: 1.4, NE) for MRD^pos pts.

WT-7 has demonstrated evidence of anti-leukemic activity with an acceptable safety profile in heavily pre-treated R/R T-ALL/LBL pts. A follow up study, NCT06514794, in R/R T-ALL/LBL including pediatric pts 1 year of age and older will begin enrolling in late 2024; exploratory MRD^pos cohort may be initiated after safety is confirmed in the R/R setting.