CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Abstract

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT

“…Our preliminary underlying mechanism suggests that CAR19 and CAR22 T cells sequentially infused had consistent biological contributions, transcriptional patterns, and clinical relevance with the response or resistance to CAR-T cell therapy (unpublished data) . However, the dual CAR targeting strategy includes co-administration or co-transduction of two separate CAR T-cells, T cells transduction using a bicistronic plasmid encoding both CARs, or utilization of a tandem CAR 36 . Novel dual-targeting approaches are being actively examined in preclinical and clinical studies, and the optimal strategy remains undefined and comparatively assessed for clinical benefits 31 , 36 , 37 .…”

“…However, the dual CAR targeting strategy includes co-administration or co-transduction of two separate CAR T-cells, T cells transduction using a bicistronic plasmid encoding both CARs, or utilization of a tandem CAR 36 . Novel dual-targeting approaches are being actively examined in preclinical and clinical studies, and the optimal strategy remains undefined and comparatively assessed for clinical benefits 31 , 36 , 37 .…”

CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies

“…In the case of B-ALL, CD19 and CD22 dual CAR-T cells were evaluated in clinical trials (NCT03233854, NCT03289455). Despite the promising results from in vitro and in vivo studies [ 245 ], relapses were observed in approximately 50% of the patients [ 246 , 247 ].…”

Car T Cell Therapy. A New Milestone in the Treatment of B Cell Lymphomas

“…mantle cell lymphoma (NCT 04234061) and TRAN-SCEND FL (NCT04245839) is investigating CAR-T therapies in follicular lymphoma. Also, the TRAN- NCT04007029); 3) T-cell engineering with only one vector encoding both CARs (bicistronic CAR-T) (38). The latter strategy may lead to a less expensive and more homogeneous product and is therefore regarded as a very promising approach.…”