CD7-Directed CAR T-Cell Therapy WU-CART-007 Is Safe in R/R T-ALL/LBL

The off-the-shelf, allogeneic, CD7-targeted CAR T-cell therapy WU-CART-007 (W-T7) had a manageable safety profile and elicited preliminary efficacy signals in patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL), according to findings from the phase 2 portion of the phase 1/2 WU-CART-007 1001 trial (NCT04984356) presented at the 2024 EHA Congress.

Among all evaluable patients in the study (n = 26), the rate of grade 3 or higher treatment-related adverse effects was 61.5%. A total of 88.5% of patients in the overall population had cytokine release syndrome (CRS); most instances (69.2%) were grade 1/2, and grade 3 and 4 CRS occurred in 11.5% and 7% of patients, respectively. In the 2 patients who experienced grade 4 CRS, the events were manageable with supportive care and completely resolved within 7 and 13 days, respectively.

“Although we’ve made a lot of progress in frontline therapy by optimizing frontline regimens, the problem is the relapse rate is still high,” lead study author Ibrahim T. Aldoss, MD, said in the presentation. “For relapsed disease, options are very limited, and it remains a disease with unmet needs. While CAR T-cell therapies have been effective in treating B-cell leukemias, there are specific challenges that exist when targeting T-cell disease.”

Aldoss is an associate professor in the Division of Leukemia in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

W-T7 is a dual-edited, second-generation, CD7-targeted CAR T-cell therapy that addresses some of the limitations of targeting T-cell malignancies with other CAR T-cell products. For instance, since malignant and healthy T cells share the same antigen, CAR T-cell products derived from patients can be contaminated by malignant T cells. However, allogeneic CAR T-cell products derived from healthy donors could eliminate this risk. Furthermore, the use of allogeneic T cells increases the risk of graft-vs-host disease (GVHD). However, W-T7 undergoes T-cell receptor gene deletion, which mitigates this risk. Moreover, CAR T-cell fratricide is possible with the use of many CD7-positive CAR T-cell products. However, W-T7 undergoes CD7 deletion to prevent this issue.

WU-CART-007 1001 is a global, first-in-human trial investigating single-agent W-T7 in patients with relapsed/refractory T-ALL/LBL. This study enrolled patients at least 12 years of age with evidence of relapsed/refractory T-ALL/LBL per World Health Organization (WHO) classification with bone marrow with at least 5% lymphoblasts, or evidence of extramedullary disease. Eligible patients needed to have an ECOG performance status of 0 or 1. Patients who had previously received any investigational drug or approved therapy needed to undergo a wash-out period of 5 half-lives from their last dose of therapy.

Relapsed/refractory disease was defined as meeting at least 1 of the following criteria:

• Primary refractory: Not achieving complete response (CR) after induction chemotherapy.
• Early relapse: Relapsed disease within 12 months of initial diagnosis.
• Late relapse: Relapsed disease after 12 months of initial diagnosis and progression on re-induction therapy after disease recurrence.
• Relapsed/refractory disease after allogeneic transplant.

Patients were excluded if they had received prior treatment with any CD7-directed therapy; toxicities from prior anticancer therapy that did not resolve to baseline levels or CTCAE grade 1 or lower, except for alopecia and nausea; active or latent hepatitis B, active hepatitis C, or any uncontrolled infection at screening; or active grade 2 or higher acute or extensive chronic GVHD requiring systemic immunosuppression.

Phase 1 of the trial was a dose-escalation portion in which patients received lymphodepleting conditioning chemotherapy consisting of fludarabine at 30 mg/m² plus cyclophosphamide at 500 mg/m² on days –5, –4, and –3. Patients in this phase received W-T7 at 1 of 4 dose levels: 100 x 10⁶ (dose level 1), 300 x 10⁶ (dose level 2), 600 x 10⁶ (dose level 3), or 900 x 10⁶ (dose level 4) CAR-positive T cells, followed by W-T7 infusion at day 1 and disease assessment at day 28. The primary objectives of the phase 1 portion were safety, dose-limiting toxicities, determination of the maximum tolerated dose or maximum administered dose, and definition of the recommended phase 2 dose (RP2D).

Data from the phase 1 dose-escalation portion were presented at the 2023 ASH Annual Meeting.

In the phase 2 cohort-expansion portion, patients received enhanced lymphodepletion conditioning chemotherapy with fludarabine at 30 mg/m² on days –6, –5, –4, and –3, plus cyclophosphamide at 1000 mg/m² on days 5, –4, and –3. On day 1, patients received the RP2D of W-T7, and disease assessment occurred on day 28. The primary objective of this phase was to evaluate the composite CR (CRc) of W-T7. A key secondary objective was duration of response (DOR).

In the phase 2 portion (n = 13), patients had a median age of 30 years (range, 14-47). Thirty-eight percent of patients were female, and 15% had primary induction failure. Patients had received a median of 3 prior lines of therapy (range, 2-6), 38% of patients had received prior hematopoietic stem cell transplant (HSCT), and the median baseline percentage of bone marrow blasts was 67% (range, 5%-95%).

All 3 patients treated at dose level 4 had treatment-related grade 1/2 CRS. Among the patients treated with the RP2D in the phase 2 portion, grade 1/2 and grade 3 or higher treatment-related CRS were observed in 69% and 31%, respectively.

Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients, 1 who received dose level 3 in the phase 1 portion and 1 who was treated with the RP2D in the phase 2 portion, whose ICANS was attributed to the study treatment.

Grade 2 hemophagocytic lymphohistiocytosis (HLH) was reported in 2 patients, 1 who received dose level 2 in the phase 1 portion and 1 who was treated with the RP2D in the phase 2 portion. Furthermore, 1 patient in the phase 2 portion had grade 3 or higher treatment-related HLH.

One case of grade 2 GVHD was reported, which occurred in a patient who was treated with the RP2D in the phase 2 portion, and this was attributed to the study treatment.

Prolonged pancytopenia occurred in 2 patients, both of whom were treated with the RP2D in the phase 2 portion. Both instances were attributed to the study treatment. One case was grade 1/2, and 1 case was grade 3, which manifested as prolonged thrombocytopenia and neutropenia.

Grade 5 adverse effects (AEs) occurred in 3 patients. Two of these AEs were not attributed to the study treatment, including 1 in a patient who received dose level 3 in the phase 1 portion and 1 in a patient who was treated with the RP2D in the phase 2 portion. The third grade 5 AE was observed in a patient who was treated with the RP2D in the phase 2 portion, was temporally related to the study treatment, and occurred during disease progression.

At the RP2D, investigators found that W-T7 expansion peaks at day 10 at 223,799 copies per μg of DNA and can be detected out to day 90. No patient developed drug product–specific anti-HLA antibodies, and to date, no anti-drug antibodies have been detected in any patients. Investigators also observed that W-T7 eliminates both malignant and normal CD-positive cells followed by normal T-cell recovery that correlates with declining levels of CAR T cells in the blood. Additionally, although W-T7 initially contained more CD4-positive CAR T-cells than CD8-positive CAR T cells, after infusion, W-T7 evolved into a largely CD8-positive effector memory phenotype.

Among 11 efficacy-evaluable patients who received W-T7 at the RP2D, the overall response rate was 91%, the CRc rate was 73%, and the median DOR was 6.2 months (95% CI, 1.8–not evaluable [NE]). All 3 evaluable patients treated at dose level 1 in the phase 1 portion had progressive disease (PD). Among the 2 evaluable patients treated at dose level 2 in the phase 1 portion, 1 achieved a partial response and 1 achieved a CR. Among the 3 evaluable patients treated at dose level 3 in the phase 1 portion, 2 had PD and 1 achieved a CR. Among the 3 evaluable patients treated at dose level 4 in the phase 1 portion, 1 had PD, 1 achieved CR with incomplete hematologic recovery, and 1 achieved CR.

At a median follow-up of 8.5 months (95% CI, 2.7-NE), 46% of evaluable patients treated at the RP2D remained in continuous remission at 4.3 to 8.6 months. In total, 7 patients—5 of whom received W-T7 at the RP2D—achieved successful transplant with full engraftment.

Based on the findings from WU-CART-007 1001, the phase 2 pivotal WUC007-03 study will further evaluate the agent in patients with T-ALL/LBL. This trial is enrolling patients at least 1 year of age with evidence of relapsed/refractory T-ALL/LBL per WHO classification with bone marrow with at least 5% lymphoblasts, or evidence of extramedullary disease. In the relapsed/refractory cohort, disease will be defined as bone marrow with at least 5% lymphoblasts by morphologic assessment or flow cytometry and evidence of extramedullary disease. Patients in the relapsed/refractory cohort may be primary refractory or have relapsed at any time point, including after allogeneic HSCT. Patients in the minimal residual disease (MRD) cohort must have evidence of MRD, defined as less than 5% blasts but at least 0.01% blasts in the bone marrow per central laboratory flow cytometry assay. Patients in this cohort must also be MRD positive following induction or consolidation therapy, including allogeneic HSCT.

In WUC007-03, patients will receive lymphodepleting chemotherapy consisting of fludarabine at 30 mg/m2 on days –6, –5, –4, and 3– plus cyclophosphamide at 100 mg/m2 on days –5, –4, and –3. On day 0, patients will receive W-T7, and disease assessment will occur on day 28.

The safety lead-in cohort will administer W-T7 at 600 x 106 CAR-positive T cells across 4 cohorts that will enroll at least 3 patients each: patients ages 1 to 11 years with relapsed/refractory disease, patients ages 12 years and older with relapsed/refractory disease, patients ages 1 to 11 years with MRD-positive disease, and patients ages 12 years and older with MRD-positive disease. The relapsed/refractory cohort will enroll up to 52 patients, 50% of whom will be pediatric. The MRD-positive cohort will enroll up to 49 patients, 50% of whom will be pediatric.

Reference

Aldoss I, Ghobadi A, Maude S, et al. WU-CART-007, an allogeneic CAR-T cell targeting CD7, is highly effective against relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S110.