Tandem CAR T Cells Targeting CD19 and CD22 Is a Safe and Highly Efficacious Treatment for Relapse/ Refractory ALL Patients

Background: CAR-T immunotherapy has shown remarkable promising results for relapsed/ refractory (R/R) acute lymphoblastic leukemia (ALL). However, CD19-targeted CAR T cell therapy for R/R ALL has a relapse rate of approximately 50% at 1 year after CART therapy, and the most common mechanism of relapse is due to CD19 antigen loss or decreased target expression on the surfaces of the lymphoblastic leukemia cells. Potential approaches to overcome this challenge include engineering CAR T cells to achieve multispecificity and to respond to lower expression levels of target antigens by dual target CAR T strategies.

Objective: In order to evaluate the efficacy and safety of CD19/CD22 dual target CAR T cells for R/R ALL patients to determine if targeting multiple antigens can prevent treatment failure and improve response rates and durability of response.

Method: A novel CAR T cells with tandem targeting CD19 and CD22 antigens and a third generation CAR construct of CD28 and OX40 co-stimulatory domains were administered to 23 patients with R/R ALL with a median age of 24(6-56)years. High-risk patients were enrolled in this cohort, including 10 with BCR-ABL+ALL (6 of 10 with T 315I mutation), 4 with TP53 mutation, 2 with Ph-like ALL and 3 with relapsed ALL post allo-HSCT. The patients received a single infusion of CAR T cells with dose escalation schedule:10%--30%--60%. The median infusion dose of CAR T cells was 1 (0.5- 2.5) ×10⁷cells/kg.

Results: The median follow-up was 9 (3.5-20) months. The day 28 CR/CRi rate was 100% with21/22 (95.5%) molecular remission. Six-month OS was 94.4% and RFS was 76.9%. One-year OS was 57.2% and RFS was 67.3%. One-year OS of high tumor burden (BM blast> 30%)(15/22) and low tumor burden(BM blast≤30%)(7/22) was 47.5% and 75% respectively (p>0.05). The 1-year OS of the CAR T- to- allo-HSCT group(14/22) was better than that of the non-transplant group(8/22) (OS 72.9% vs. 26.7%, p = 0.116). The cumulative relapse rate of 6 months and 1 year were 23.1% and 32.7% respectively. The overall incidence of CRS were 91% included 22.7%grade III CRS ,4.5% grade IV CRS and 0% severe CRES. Only one patient presented MAH syndrome and was cured with low dose dexamethasone. There was no CAR T-related death.

Conclusions: The tandem CD19/CD22 dual target CAR T cells therapy is a safe and high efficacy treatment for R/R ALL patients. It is possible that multi-targeted CAR-T cell therapy may overcome this resistance mechanism and improve clinical outcomes.