CTD402, allogeneic anti-CD7 CAR t-cell, in relapsed or refractory (R/R) t-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) - report of clinical outcomes at the recommended phase 2 dose (RP2D)

Abstract Background R/R T-ALL/LBL poses significant therapeutic challenge due to paucity, and limited efficacy, of treatments. CTD402, is a CD7 targeted “off-the-shelf” universal CAR-T product with T cell receptor and human leukocyte antigen class II knockout, and improved resistance to host immune rejection achieved by arming the cells with proprietary ANSWERTM inhibitory ligands. CTD402 is currently being developed for the treatment of T-cell hematologic malignancies and other severe blood disorders with ~100 patients (pts) treated in several Phase I/II trials, conducted across 9 centers in China ( NCT05716113; NCT04620655; NCT05454241; NCT05907603; NCT05923541; NCT05902845; and NCT05895994). Herein we present the data of a cohort of these pts treated at the RP2D. Methods The RP2D of CTD402 is 400 million (M) cells administered on day (D) 0 following standard lymphodepleting chemotherapy (sLD)consisting of fludarabine (30 mg/m²/day) and cyclophosphamide (500 mg/m²/day) from days -5 to -3; this is the starting dosing regimen on the ongoing global clinical study (NCT# 07070219). Results Up to a data cutoff June 30th, 2025, 41 R/R T-ALL/LBL (27 ALL, 13 LBL, 1 MPAL) pts, median age 27 years (range 10-56), were treated at the RP2D. Pts had received a median of 2 prior lines of therapy (range 1-6), 37% were primary induction failure, and 24% had relapsed post allogenic hematopoietic stem cell transplant (allo-HSCT); 56% had high-risk molecular profile including ETP phenotype, RAS/PTEN alterations, NOTCH1/FBXW7WT, or complex karyotype. Baseline disease burden was median bone marrow (BM) blasts of 42% (range 6.5-98.5%), 54% pts had extramedullary (EMD), including 1 pt with CNS leukemia. Post-infusion,78.0% (n=32) pts experienced cytokine release syndrome, mostly mild Grade G 1-2 in 27 (65.9%) and G3 in 5 (12.2%) pts. No pt experienced immune effector cell-associate neurotoxicity or GvHD; Severe treatment-related infections (≥ G3) loccurred in only 5 (12.2%) pts and largely resolved with antibiotic therapy. Cytopenia was the most common AE noted post treatment with neutrophil (ANC) and platelet count recovery to grade ≤2 by D21 and D7 post-infusion, respectively. Lymphopenia nadired on D0 following lymphodepletion, with absolute lymphocyte count (ALC) recovery to G≤2 in 45%, 48.6%, and 70% of responders at D42, D56, and M3, respectively, post-infusion. PK analysis revealed Cmax of median 1.2 ×106copies/μg DNA (range 0.05-8.2x106) occurred at a median Tmax of 10 days, with median AUC0-28of 5,880,936. CTD402 persistence ≥ 28 days was noted in 59% of pts and 71% of responders, with persistence extending ≥ 90 days in some pts. CD7pos T-cells were depleted for the duration of CAR-T persistence with a compensatory increase in CD7neg T-cells by day D21even in the presence of CTD402. Notably, CD7neg T-cells from post-CD7 CAR patients could respond to viral peptides by producing interferon-γ, like T cells from healthy donors, suggesting that these CD7neg T-cells retained immune-protective functions. Among the 39 evaluable pts, complete remission rate (CRR) was 64.1% (n=25, 19 CR, 6 CRi ) with an impressive 91.7% (22/24 in pts evaluated) MRDnegrate. With a median follow up time of 21.2 months (range 0.8-25.5), the median DOR was 9.7 months (95% CI: 5.0 - not reached NR). Among the most challenging groups to treat, high-risk (n=23) or EMD pts (n=22), the CRR was 60.9% (8 CR,6 CRi; MRDneg85.7%) and 59% (10 CR, 3 CRi; MRDneg92.3%), respectively. Twelve (30.8%) pts received consolidative allo-HSCT post-CTD402 in remission (CR/CRi). Median overall survival was significantly higher in pts that received a consolidative transplant in remission vs the pts that did not, NR vs 7.3 (95% CI: 2.7-NR), p=0.0016, respectively. Conclusion CTD402 demonstrated an acceptable safety profile and evidence of anti-leukemic activity with high MRD negative remission rates, and lasting benefits—especially when paired with allo-HSCT, that far exceeds the current standard of care. High response rate in particularly challenging to treat populations, high-risk and EMD positive disease, is particularly promising. This program advances an “off-the-shelf” ready at point of care CAR-T cell therapy in heavily pre-treated patients with R/R T-ALL/LBL. A global Phase 1b/2 study is ongoing and currently enrolling patients (NCT# 07070219).