Antigen modulation places a limit on the longevity of remission after single-antigen focused chimeric antigen receptor (CAR) T-cell therapy, although combinatorial targeting can get around it. For a study, researchers reported on phase 1 dose-escalation research of a new murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies, building on the experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL).

Finding the appropriate dosage and toxicity were the main goals. Response rates and relapse-free survival (RFS) were secondary goals. Laboratory studies, CAR T-cell growth, and cytokine profiling were used as biologic correlates. Twenty B-ALL patients, ranging in age from 5.4 to 34.6 years, received CD19.22.BBζ.

Among the entire cohort, the complete response (CR) rate was 60% (12 of 20), and in CAR-naive patients, it was 71.4% (10 of 14). About 10 (50%) people had cytokine release syndrome (CRS), with only 1 developing neurotoxicity (grade 3) and 3 (15%) having ≥grade 3 CRS. The 6-month RFS and 12-month RFS for those attaining CR were 80.8% (95% CI: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. MSCV-CD19.22.BBζ had less CAR T-cell growth and persistence than EF1α-CD22.BBζ. Laboratory comparisons of EF1α and MSCV promoters were sparked by BB, but they did not turn up any significant differences.

As shown by ex vivo cytokine secretion and the elimination of leukemia, CD19.22.BBζ limited CD22 targeting resulted in the creation of a new bicistronic CD19.28ζ/CD22.BBζ constructs with increased cytokine production against CD22. Further modification of combinatorial antigen targeting helped to address noted drawbacks with the use of CD19.22.BBζ, which has shown to be safe and effective in a substantially pretreated CAYA B-ALL cohort.