Tandem CD19/CD22 Dual Targets CAR-T Cells Therapy Obtains Superior CR Rate Than Single CD19 CAR-T Cells Infusion As Well As Sequential CD19 and CD22 CAR-T Cells Infusion for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Patients

Abstract

Background: CD19 chimeric antigen receptor T (CAR-T) cells therapy has shown great success in B-cell acute lymphoblastic leukemia (B-ALL). To reduce the possibility of relapse due to CD19 antigen loss, sequential CD19/CD22 and tandem CD19/CD22 dual targets CAR-T cells have been developed. However, the optimal combination strategy of target antigens for CAR-T cells is still uncertain. This study was designed to compare the efficacy and safety of single CD19, tandem CD19/CD22 and sequential CD19/CD22 CAR-T cells therapies in relapsed/refractory(R/R) B-ALL patients. Methods: Between March 2016 and August 2020, a total of 200 patients with R/R B-ALL successfully received 230 CAR-T treatments (30 patients received the second CAR-T therapy and 8 patients received the third CAR-T therapy) were screened in this study. Among them, 168 patients received single CD19 CAR-T therapy, 49 patients received tandem CD19/CD22 CAR-T therapy, and 13 patients received sequential CD19/CD22 CAR-T therapy. ALL patients enrolled in the CD19 CAR-T clinical trials (NCT03919240) or CD19/CD22 CAR-T clinical trials (NCT03614858). Results: The baseline characteristics of patients were similar among the three groups. The complete remission (CR) rates were 82.7% (139/168) in patients who received CD19 CAR-T therapy, 95.9% (47/49) in patients who received tandem CD19/CD22 CAR-T therapy, and 69.2% (9/13) in patients who received sequential CD19/CD22 CAR-T therapy (P=0.012). Tandem CD19/CD22 CAR-T therapy remained one of the significant favorable factors in multivariate logistic regression analysis of CR rate in all patients (hazard ratio, 0.081; 95% CI, 0.010-0.671). Furthermore, minimal residual disease (MRD)-negative CR rates were 66.7%, 81.6% and 61.5%, respectively (P=0.092). There was no significant difference in the incidence of adverse events among the three groups. Severe cytokine release syndrome (CRS, Grade ≥ 3) occurred in 25.0% of patients in CD19 group, 18.4% of patients in tandem CD19/CD22 group, and 23.1% in sequential CD19/CD22 group (P=0.641). There was no significant difference in overall survival (OS) and leukemia-free survival (LFS) among three groups (6-month OS: 83.1%, 90.0% and 88.9%, respectively, P=0.1620; 6-month LFS: 76.2%, 76.2% and 88.9%, respectively, P=0.8179). Univariate and multivariate Cox regression analyses showed that a better LFS related to less frequencies of relapse, lower tumor burden, MRD-negative CR and bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT). Conclusions: Tandem CD19/CD22 dual targets CAR-T cells therapy obtains superior CR rate than single CD19 and sequential CD19/CD22 CAR-T cells therapy. This provides an effective treatment option for R/R B-ALL patients with chemotherapy resistance. Disclosures No relevant conflicts of interest to declare.

Engineered yeast cells simulating CD19+ cancers to control CAR T cell activation

“…Fig. [9][10][11][12][13][14]. Specifically, SCASA yeast cells could improve the isolation of responses from distorting natural effects of human cell-to-cell interactions, such as rapid and extensive CAR-dependent NALM6 antigen down-modulation forming a CD19 low population 32,50,51 , and the cytotoxic sensitivity of NALM6 imposing a selective pressure bias and loss of CD19+ cells (Fig.…”

“…Since 2017, six FDA approvals on the use of CARs for hematological cancers have been registered 5 . These include anti-CD19 CAR T cells for relapsed or refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) with clinical trials and real-world studies showing complete remission (CR) in 70-96% of patients [7][8][9][10][11][12][13][14][15][16] .…”

“…However, while remission rates are encouraging, 14-57% of r/r B-ALL patients obtaining CR from anti-CD19 CAR T cell immunotherapy eventually experience relapse [7][8][9][10][11][12][13][14][15][16] . Indeed, the field of CAR T is still emerging, and major challenges need to be mitigated to further improve their safety and efficacy, including mitigation of inhibitory immunosuppression, severe toxicity, CAR T cell trafficking, and target antigen escape 5,6,17 .…”

The role of chimeric antigen receptor T cells targeting more than one antigen in the treatment of B‐cell malignancies

“…70 The Suzhou group designed a different tandem CD19/CD22 product, this one in loop configuration, for the treatment of patients with ALL. 71 This study is particularly interesting because the authors compared the outcome of patients with ALL who received CART19 cells versus those who received a sequential administration of CART19 and CART22 cells versus those who received the tandem CD19/CD22 product. 71 This was not a randomised comparison, patients' baseline characteristics were somewhat different and the dose was very different, but the main conclusion was that the tandem CD19/CD22 product achieved better responses and longer survival, particularly when consolidated with an alloHCT.…”

“…71 This study is particularly interesting because the authors compared the outcome of patients with ALL who received CART19 cells versus those who received a sequential administration of CART19 and CART22 cells versus those who received the tandem CD19/CD22 product. 71 This was not a randomised comparison, patients' baseline characteristics were somewhat different and the dose was very different, but the main conclusion was that the tandem CD19/CD22 product achieved better responses and longer survival, particularly when consolidated with an alloHCT. Toxicity was comparable among all three strategies, although the incidence of IEC-HS was higher (3.9%) for the tandem product compared to CART19 cells (0.7%) and sequential administration of CART19 and CART22 cells (0%).…”