In an update of a phase I trial of anti-CD22 chimeric antigen receptor (CAR) T-cell therapy in children and young adults with relapsed or refractory CD22-positive B-cell malignancies reported in the Journal of Clinical Oncology, Shah et al described findings in cohorts receiving treatment at doses manufactured using CD4/CD8 T-cell selection of the apheresis product.
As stated by the investigators, “We modified selection procedures of the apheresis product to systematically improve the consistency and reduce inherent interpatient variability of the starting material. This minor modification enhanced manufacturing feasibility but led to a direct increase in inflammatory toxicities, which prompted dose de-escalation with preserved efficacy at a dose that we previously declared as suboptimal.”
Key Findings
In the entire trial, 58 patients received CD22-targeted CAR T-cell infusions at five dose levels, including two dose levels using T-cell selected product. Overall, 51 (87.9%) patents had received prior CD19-targeted therapy.
Among all 58 patients, cytokine release syndrome occurred in 50 (86.2%) and was grade 1 or 2 in 45 (90%). Neurologic toxicity was observed in 19 (32.8%) and was grade 1 or 2 in all but 1 patient.
Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)–like manifestations were observed in 19 patients (32.8%). HLH/MAS-directed treatment included anakinra alone, anakinra plus corticosteroids, or corticosteroids alone.
Among 7 patients treated at the higher T-cell–selected product dose level (1 x 106 CAR T cells per kg), HLH/MAS-like manifestations occurred in 5, compared with 3 of 18 in a cohort treated at a non–T-cell–selected product dose level of 1 x 106/kg. Symptomatic coagulopathy occurred in four of seven patients in the higher dose level group.
These findings prompted de-escalation of T-cell selected product dose level to 3 x 105/kg in a cohort of 25 patients, which was associated with reduced incidence of HLH/MAS-like features (11 patients) and coagulopathy (2 patients) without apparent reduction in efficacy. Complete remission was observed in 6 (85.7%) of 7 patients in the higher-dose cohort compared with 19 (76.0%) of 25 patients in the de-escalated dose cohort.
Among all 58 patients in the trial, the complete remission rate was 70% and median overall survival was 13.4 months (95% confidence interval [CI] =7.7–20.3 months). Among patients with a complete response, median relapse-free survival was 6.0 months (95% CI = 4.1–6.5 months).
A total of 13 patients proceeded to stem cell transplantation.
The investigators concluded: “In the largest experience of CD22 CAR T cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.”
Nirali N. Shah, MD, MHSc, of the Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institutes of Health Clinical Center, a grant from Stand Up To Cancer–St. Baldrick’s Pediatric Dream Team, and a Cooperative Research and Development Agreement with Juno Therapeutics. For full disclosures of the study authors, visit ascopubs.org.
