CD19/CD22 CAR-T (Josep Carreras Leukaemia Research Institute)

Despite recent advances, B cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge. Hematopoietic stem cell transplantation (HSCT) provides a potential cure but is hindered by various limitations. Emerging immunotherapies, including chimeric antigen receptor T cell (CAR-T) therapy and blinatumomab, have shown potential as bridging strategies to HSCT in relapsed/refractory (R/R) patients.

This retrospective study was conducted at Tongji Hospital from March 2017 to March 2023 and involved 36 R/R B-ALL patients who underwent HSCT. Prior to transplantation, 27 patients received CD19/CD22 CAR-T therapy, while 9 received blinatumomab. The outcomes assessed included overall survival (OS), progression-free survival (PFS), graft-versus-host disease-free and relapse-free survival (GRFS), and non-relapse mortality (NRM), with comparisons between treatment groups. Hematopoietic reconstitution and transplant-related complications were also evaluated.

The median follow-up time was 28.07 months (range: 2.29-92.21 months). The 2-year OS, PFS, GRFS, and NRM rates of the entire cohort were 76.54%, 54.97%, 40.12%, and 9.93%, respectively. In the CAR-T and blinatumomab treatment groups before transplantation, the 2-year OS rates were 73.89% and 88.89% (P = 0.862), the PFS rates were 59.03% and 44.44% (P = 0.501), the GRFS rates were 47.86% and 13.89% (P = 0.083), and the NRM rates were 8.52% and 11.11% (P = 0.713), respectively. The safety profiles were similar, with no significant differences observed in hematopoietic reconstitution, infection, incidence of grade II-IV acute graft-versus-host disease (GVHD), or chronic GVHD incidence between the CAR-T and blinatumomab groups.

CAR-T and blinatumomab therapies demonstrate comparable safety and efficacy as bridging treatments to HSCT in patients with R/R B-ALL. Further studies are needed to optimize these treatment strategies.

CAR-T therapies targeting either CD19 or CD22 have shown significant promise for treating relapsed or refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, a common limitation is the high frequency of antigen loss, which leads to r/r B-ALL progression. To overcome progression caused by antigen loss, bi-specific CAR-T immunotherapies targeting both CD19 and CD22 may offer enhanced efficacy in eliminating r/r B-ALL and preventing relapse by hindering leukemia cell proliferation. In this study, we present both pre-clinical and clinical findings from an ongoing trial (NCT04303520) assessing the therapeutic efficacy of the CD19-CD22 bi-specific CAR-T therapy for r/r B-ALL patients. Pre-clinical data from animal models reveal that CD19-CD22 CAR-T cells effectively induce cytotoxicity, thus suppressing B-ALL cell proliferation. Notably, this dual-targeted approach outperforms single-target CAR-T treatments. From the Phase I trial encompassing 35 participants, 37.1% (13 out of 35 patients) experienced cytokine release syndrome, with only a single case of Grade III   severity. Importantly, no neurotoxicity episodes were recorded post CD19-CD22 CAR-T administration. Common adverse events included hematological, gastrointestinal, and nutrition-related disturbances. B-ALL patients undergoing stem cell transplantation in tandem with CAR-T therapy exhibited a pronounced improvement in overall survival compared to those treated solely with CAR-T. The median overall survival duration was 21.49 ± 4.4 months (95% CI: 14.31–31.40 months), meanwhile one-year PFS and OS are 0.37 (95% CI, 0.21–0.49) and 0.62 (95% CI: 0.52–0.71), respectively. Clinical monitoring did not identify significant side effects associated with the CD19-CD22 regimen. To monitor the inflammation-associated factors accompanying CAR-T therapy, the peak value of CAR DNA copies was reached around Day 10, accompanied by a similar trend in the levels of inflammatory factors, including IFN-γ, Granzyme B, IL-6, and CRP. Collectively, our data advocate for the potential role of bi-specific CD19-CD22 CAR-T therapy in addressing r/r B-ALL. Trial registration number ClinicalTrials.gov (No. NCT04303520).