Phase I Open-Label Single-Arm Study of Sscart-19 in Adult Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in China
Authors: Kang Liqing , Xue Shengli , Tang Xiaowen , Lou Xiaoyan , Qian Chongsheng , Gong Wenjie , Xu Mingzhu , Zhou Haixia , Yao Zhen , Wang Wei , Li Minghao , Xu Nan , Yu Zhou , Chen Suning , Qiu Huiying , Dai Haiping , Xu Yang , Wu Depei , Yu Lei 
Published: December 2023

Background:
Although CAR-T therapy has shown amazing efficacy in the treatment of hematologic malignancies in recent years, it is also accompanied by high-frequency of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), especially in acute lymphoblastic leukemia patients. Therefore, it is not recommended to enroll patients with active CNS involvement in CAR-T therapy.
ssCART-19 is an autologous CD19-specific chimeric antigen receptor T-cell with short hairpin RNA-IL-6 gene silencing element. ssCART-19 can simultaneously express CAR structure and IL-6 silencing element. CAR structure can recognize and bind CD19 positive tumor cells, enhance T cell amplification, and finally exert T cell killing activity, such as releasing cytokines and perforin. Post-transcriptional expression of short hairpin RNA-IL-6 gene silencing element can recognize mRNA of IL-6, inhibit the expression of endogenous IL-6 in CAR-T cells through RNA interference mechanism, and then reduce the stimulation or activation intensity of downstream immune cells (mainly monocytes), with the control of the overall release intensity of cytokines, it reduces the incidence of severe CRS and ICANS, at the end reduces the clinical risk of CAR-T therapy.
Methods:
The trial of ssCART-19 in adult patients with R/R B-cell ALL (NCT04825496) is a single-arm, open-label Phase 1 study conducted in China. Patients underwent leukapheresis to obtain T cells for ssCART-19 manufacturing. Patients received fractionated infusions split over 3 days (10%; 30%; 60%) after lymphodepleting chemotherapy (3 days fludarabine and cyclophosphamide). Adverse events (AEs) were graded according to CTCAE, v5.0; CRS and ICANS were graded according to ASTCT Consensus Grading. The overall response rate(ORR) of complete response (CR) and CR with incomplete hematological recovery (CRi) within 3 months, duration of remission, relapse-free survival, and OS were assessed as secondary endpoints.
Results :
ssCART-19 was administered at 3 doses levels (DL) of 1×10 6/kg, 5×10 6/kg, or 10×10 6/kg. As of June 30th 2023 data cutoff (the median follow-up 15.9 months), 13 patients enrolled and underwent leukapheresis, 12 patients were received ssCART-19 treatment, 5 patients in DL1, 6 patients in DL2, and 1 patients in DL3. ssCART-19 was manufactured using serum-free culture system and no manufacture failure was reported. All 12 patients diagnosed with B-cell ALL were relapsed (75.0%) and refractory (25.0%) to multiple lines of prior therapy (100.0% patients had received 2 or more therapies). Five patients (41.7%) had more than 50% blasts in the bone marrow.
All 12 patients did not have DLT events within 28 days. The most common ssCART-19-related AEs were transient neutropenia (100.0%), lymphopenia (100.0%), leukopenia (100.0%), anaemia (100.0%) and thrombocytopenia (83.3%). Adverse events of special interest (AESI) were CRS and ICANS. Among the 12 patients, 9 patients (75.0%) developed CRS, and 3 patients (25.0%) were grade 3 CRS. Notably, none of the 12 patients were occurred ICANS. No death cases were reported due to CRS or ICANS.
A 83.3% overall response rate was achieved in efficacy-evaluable patients (n=12), with 7 complete response (CR, 58.3%), and 3 CR with incomplete hematological recovery (CRi,25.0%). The median duration of remission, relapse-free survival and OS have not been reached. Among them, 6 patients were in ongoing remission for over 12 months. Notably, one of the 12 patients (S012) had central nervous system infiltration with grade 2 before ssCART-19 infusion(Figure 1). After ssCART-19 therapy, the patient had no ICANS and got continuous remission. Robust CAR T-cell expansion occurred in all patients with a median time to T max of 12.5 days (range 9-14d), and peak copy number (C max) of 52495 (194-348000) copies/μg DNA.
Conclusions ：
ssCART-19 CAR-T cell therapy can effectively reduce the incidence of severe CRS and ICANS, especially control the occurrence of ICANS. And ssCART-19 achieved a high rate of remission in adult patients with R/R B-cell ALL. The ORR within 3 months were 83.3%. And, ssCART-19 shows good clinical efficacy in the treatment of leukemia patients with central nervous system infiltration. Thus, with the combination of short hairpin RNA-IL-6 gene silencing element, ssCART-19 can greatly improve the safety of CAR-T therapy, especially in central nervous system infiltration patients.