Driving two chimeric antigen receptors (CARs) in a row to reduce antigen escape in B-cell acute lymphocytic leukaemia

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 have led to unprecedented complete remission rates of 70–98% in relapsed and refractory B-cell acute lymphocytic leukaemia. However, up to 50% of patients experience a disease relapse. 1 Myers RM Jacoby E Pulsipher MA et al. INSPIRED Symposium part 1: clinical variables associated with improved outcomes for children and young adults treated with chimeric antigen receptor T cells for B cell acute lymphoblastic leukemia. Transplant Cell Ther. 2023; (published online July 20.)https://doi.org/10.1016/j.jtct.2023.07.016 Summary Full Text Full Text PDF Scopus (0) Google Scholar Given that antigen escape is a major contributor to relapse or lack of response after single-antigen targeted CARs, 2 Maude SL Laetsch TW Buechner J et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018; 378: 439-448 Crossref PubMed Scopus (3089) Google Scholar it has been hypothesised that multi-antigen targeting could overcome escape, thereby improving remission durability. Clinical experience with CARs targeting both CD19 and CD22 is amassing rapidly. 3 Ghorashian S Lucchini G Richardson R et al. CD19/CD22 targeting with co-transduced CAR T-cells to prevent antigen negative relapse after CAR T-cell therapy of B-ALL. Blood. 2023; (published online Aug 30.)https://doi.org/10.1182/blood.2023020621 Crossref PubMed Scopus (0) Google Scholar , 4 Wang T Tang Y Cai J et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial. J Clin Oncol. 2023; 41: 1670-1683 Crossref PubMed Scopus (16) Google Scholar , 5 Spiegel JY Patel S Muffly L et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021; 27: 1419-1431 Crossref PubMed Scopus (202) Google Scholar , 6 Shalabi H Qin H Su A et al. CD19/22 CAR T-cells in children and young adults with B-ALL: phase I results and development of a novel bicistronic CAR. Blood. 2022; 140: 451-463 Crossref PubMed Scopus (34) Google Scholar Despite this, an optimal dual-targeting approach has not been established. Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 studyThis sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. Full-Text PDF