CD22-targeted chimeric antigen receptor-modified T cells for children and adults with relapse of B-cell acute lymphoblastic leukemia after CD19-directed immunotherapy

Background Relapse of B-cell acute lymphoblastic leukemia (B-ALL) with CD19-antigen loss after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has a dismal prognosis. Novel immunotherapeutic strategies for this patient population are urgently needed. Methods We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL. After lymphodepletion, CART22-65s was infused using a 3-day fractionated dosing scheme, allowing for omission of the second and third doses in cases of early cytokine release syndrome (CRS). Results Twenty-two patients, all with relapse after prior CD19-directed immunotherapy, were enrolled. Of 19 infused patients (pediatric, n=17; adult, n=2), 14 (74%) achieved a complete remission (CR), including 4 of 6 (67%) patients refractory to prior inotuzumab. Five of 14 patients in a CR proceeded to consolidative hematopoietic cell transplantation (HCT). With a median follow-up of 38 months, the 12-month relapse-free survival rate was 38.4% (95% CI 19.3% to 76.5%) and overall survival rate was 52.6% (95% CI 34.3% to 80.6%). Two patients received additional CART22-65s treatments for subsequent CD22-positive relapses; one achieved another CR. All CRS (n=17, 89%) and neurotoxicity (n=4, 21%) events after initial infusion were grades 1–2. The only grade 3 CRS/neurotoxicity and the only high-grade immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome occurred in the retreatment setting. In vivo cellular kinetic data revealed robust CART22-65s proliferation by quantitative PCR peaking at a median of 20 days postinfusion, with the cells persisting out to month 42 in one patient who achieved a long-term remission with CART22-65s alone. Conclusions The favorable safety profile and high remission rates in exceedingly refractory B-ALL support the continued development of CART22-65s but also highlight the need to use the product in combination with HCT or other novel strategies. Trial registration numbers NCT02650414 and NCT03620058 .