Phase 1 Dose Escalation Study of the Anti-CD7 CAR-T Therapy in Relapsed/Refractory T-Cell Acute Leukemia and Lymphoblastic Lymphoma

Introduction Inspired by the successful experience of CAR-T therapy in B-cell malignancies, its introduction to T-cell tumors is being studied. CD7, highly expressed on T-cell tumors, provides a potential target for CAR-T therapy. However, it is also present on normal T and NK cells, leading to possible fratricide of CAR-T during the production and elimination of T and NK cells after infusion. Moreover, CD7 was suggested to express on parts of hematopoietic stem cells (HSC). Thus, apart from the clinical efficacy and safety, the manufacture and hematopoietic toxicity (HPT) are essential topics related with anti-CD7 CAR-T therapies. Here, we reported the preliminary results of phase I clinical trial of anti-CD7 CAR-T (SENL101, dual CD7-nanobodies with 4-1BB co-stimulation domain and CD7 gene unmodified) to address these issues in CD7 + T-cell acute leukemia and lymphoblastic lymphoma (T-ALL and T-LBL) patients. Methods Informed volunteers were screened according to the inclusion and exclusion criteria. Specially, tumors negative for CD4 and CD8, or the tumor load in peripheral blood less than 1% are required. CD4 and CD8 positive selection was employed for T-cell isolation. Lentivirus encoding CAR vector was transduced in CD7 unedited T-cells. The clinical trial was a single-arm, open-label, dose-escalation and predictive study. One day after a 3-day FC chemotherapy, patients were infused with SENL101 at a dose of 1E6, 2E6 or 4E6/ kg. The efficacy, safety and pharmacokinetics of CAR-T were assessed at specified time points. Results As of July 24 th 2023, 7 patients were treated with the specified dose of SENL101, including 5 T-LBL and 2 T-ALL. The average age was 33 years old, and the median prior therapy lines was 3. 28.6% patients experienced HSC transplantation (HSCT). SENL101 was successfully produced in all patients, with an average cell viability of 87.1% and CAR + rate of 92.3%. Complete response (CR) rate was 100% ( Figure 1A). One patient (E006) received HSCT after CR and continued to survive at the present. One case (E002) relapsed at 3-month follow-up, with CAR copy number16740 /ug DNA and CD7 negative in T and NK cells. Notably, 1 patient (E003) developed B-cell lymphoproliferative disease, with primary disease well controlled. The other 4 patients were in CR or hemogram incomplete-recovered CR (CRi), with the longest remission of 9 months. Unfortunately, 2 patients (E005 and E008) died of sepsis at day 116 and 137. CAR-T expanded robustly in all cases, with a median peak value of 701600 copies/ ug DNA reached at day 14. The median survival of CAR-T in vivo was 133 days. As the removal of CAR-T, the CD7 + T and NK cells recovered. The cytokine release syndrome (CRS) happened in 6 cases, with 5 grade 1-2 CRS and 1 grade 3 CRS. No immune effector cell-associated neurotoxicity syndrome was observed. All patients occurred grade 4 HPT. At day 28, 28.6% grade 4 leukopenia and 57.1% grade 4 thrombocytopenia persisted ( Figure 1B). Infections were observed in 3 out of 7 cases (including 2 CMV, 1 EBV and 2 sepsis). Other AEs, including transaminase elevation (3/7), malaise (2/7), anorexia (2/7), nausea/vomiting/diarrhea (1/7) and flu like symptoms (1/7) were relieved after treatment. Due to the high infectious rate (2 sepsis) and profound reduction of hemocyte in the 2E6/kg group, 1E6/kg was set as dose of an expanded cohort. Conclusions Withoutinterfering CD7,SENL101 can be well manufactured. The treatment was effective for T-ALL/LBL, with tolerable toxicity at a dose of 1E6 cells/kg. SENL101 expanded robustly but persisted shortly, which on the other hand, contributed to the recovery of CD7 + T and NK cells, thereby reducing the risk of infection. An expanded cohort is warranted to verify the long-term benefit of SENL101 for T-cell malignant patients.