CD19 and CD22-directed biespecific CAR for B-cell Acute Lymphoblastic Leukemia

CD19 CAR-T cells have shown impressive rates of clinical response in B-cell acute lymphoblastic leukemia (B-ALL) but CD19- relapses are still common. A combinational targeting of multiple antigens represents a potential strategy to overcome this, so we developed a CAR containing binding domains for CD19 and CD22 in tandem (CD22/CD19 CAR) and we cloned it in a pCCL lentivector. Lentiviral particles were produced and used to transduce primary pre-activated human T cells (anti CD3/CD28 plus IL7 and IL15) and we tested pre-clinically the activity of our CD22/CD19 CAR for B-ALL.

Using CRISPR/Cas9-edited CD19+CD22+, CD19+CD22-, CD19-CD22+ and double KO SEM cells we confirmed in in vitro cytotoxic assays the bispecificity of the CD22/CD19 CAR. In vitro and in vivo cytotoxic assays revealed that CD22/CD19 CAR achieves very similar cytotoxic potency than CD19 CAR but with significantly lower in vitro production of the pro-inflammatory cytokines IL-2, INF-γ and TNF-α which may have major implications in lowering the rates of cytokine release syndrome toxicity. Further experimental work is underway to assess whether the CD22/CD19 CAR can contribute to delay/prevent long-term relapses.

 

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