Abstract
BackgroundDespite the impressive complete remission (CR) induced by CD19 CAR-T cell therapy in B-ALL, the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse.MethodsWe here report the design of a bispecific CAR simultaneous targeting of CD19 and CD22. We performed a phase 1 trial of bispecific CAR T cell therapy in patients with relapsed/refractory precursor B-ALL at a dose that ranged from 1.7 × 106 to 3 × 106 CAR T cells per kilogram of body weight.ResultsWe demonstrate bispecific CD19/CD22 CAR T cells could trigger robust cytolytic activity against target cells. MRD-negative CR was achieved in 6 out of 6 enrolled patients. Autologous CD19/CD22 CAR T cells proliferated in vivo and were detected in the blood, bone marrow, and cerebrospinal fluid. No neurotoxicity occurred in any of the 6 patients treated. Of note, one patient had a relapse with blast cells that no longer expressed CD19 and exhibited diminished CD22 site density approximately 5 months after treatment.ConclusionIn brief, autologous CD19/CD22 CAR T cell therapy is feasible and safe and mediates potent anti-leukemic activity in patients with relapsed/refractory B-ALL. Furthermore, the emergence of target antigen loss and expression downregulation highlights the critical need to anticipate antigen escape. Our study demonstrates the reliability of bispecific CD19/CD22 CAR T cell therapy in inducing remission in adult patients with relapsed/refractory B-ALL.Trial registrationClinicalTrials.gov identifier: NCT03185494.
Highlights
Despite the impressive complete remission (CR) induced by CD19 chimeric antigen receptor (CAR)-T cell therapy in B cell acute lymphoblastic leukemia (B-ALL), the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia
In vitro validation of bispecific CD19/CD22 CAR T cells Second-generation CD19/CD22 CARs were constructed by taking the standard three-domain CAR architecture and incorporating two single-chain variable fragments connected in tandem via an EAAAK linker (Fig. 1a)
We found that T cells transduced with the CD19/CD22 CAR vector yielded strong induction of cytokines in the presence of tumor target that is similar in magnitude (Fig. 1c)
Summary
Despite the impressive complete remission (CR) induced by CD19 CAR-T cell therapy in B-ALL, the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse. Despite the great successes with CAR T cell therapy in leukemia that have been published previously by our group and others [3,4,5,6,7], up to 60% of relapses after CD19 CAR T cell therapy are characterized by CD19 antigen loss, which involves several different mechanisms [8,9,10]. One approach to overcoming antigen loss following CAR T cell therapy is to simultaneously target more than one antigen on cancer cells, an approach that is compelling for B-ALL, given that anti-CD22 CAR T cells have demonstrated clinical efficacy [11]. Preclinical data supporting the multitargeted approaches include tandem anti-CD19-CD20 CAR constructs; combinatorial anti-CD19 and anti-CD123 strategies, targeting both CD19 and CD22; and several clinical trials utilizing strategies are underway
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