Anti-CD19 immunotherapies, including chimeric antigen receptor (CAR) T cells, have ushered in a new era of treatment for acute lymphoblastic leukaemia (ALL); however, resistance often occurs, typically via loss of CD19. Now, a phase I trial has provided new insights into the safety and efficacy of salvage therapy with anti-CD22 CAR T cells in this setting.

After fludarabine and cyclophosphamide conditioning therapy, 58 patients aged 4–31 years with CD22+ B cell malignancies (56 with ALL) received various doses of anti-CD22 CAR T cells. Of these patients, 88% and 33% had received prior CD19-directed and CD22-directed therapies, respectively. The complete remission (CR) rate was 70%, and the median overall survival was 13.4 months. Among those with a CR, 87.5% had a minimal residual disease-negative response, and median relapse-free survival was 6 months. The response rate was unaffected by prior CD19-targeted therapy or haematopoietic stem cell transplantation, but prior receipt of CD22-targeted therapy was associated with inferior responses. At relapse, most patients had CD22−/dim disease.

Overall, 86% and 33% of patients had cytokine-release syndrome (CRS) and neurological toxicities, respectively, mostly of grade 1–2 (90% and 95%). However, two grade 5 adverse events occurred, one in association with CRS. Notably, haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)-like events occurred only in patients with CRS (38% of this group), with a delayed onset. Treatment of HLH/MAS was required in 14 of 19 patients, with 8 receiving the IL-1 receptor antagonist anakinra, and did not seem to impair CAR T cell activity.

In order to improve the feasibility and consistency of CAR T cell manufacturing, selection of CD4+ T cells and CD8+ T cells was performed for 32 patients (55%). This change increased the rate of HLH/MAS at the target dose of 1 × 106 cells/kg (from 17% to 71%; P = 0.017), despite a similar incidence and severity of CRS. This effect was mitigated to some extent by a dose reduction to 3 × 105 cells/kg (HLH/MAS rate of 44%), without compromising efficacy (CR rate 76%).

These findings reveal a perhaps unique toxicity profile of anti-CD22 CAR T cells. The efficacy data warrant further development of this treatment approach.