CD19/22 CAR T-cells in Children and Young Adults with B-ALL: Phase I Results and Development of a Novel Bicistronic CAR

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on the experiences and limitations of a novel MSCV-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ). This phase I dose-escalation trial enrolled children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose-finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives, including CAR T-cell expansion and cytokine profiling, and laboratory investigations, were also analyzed. Twenty patients, ages 5.4-34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12/20) in the full cohort and 71.4% (10/14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing any neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% CI: 42.4-94.9%) and 57.7% (95% CI: 22.1-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared to EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α versus MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pre-treated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations. (Clinicaltrials.gov NCT03448393)

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