CD22 CAR T-cell Therapy Effective After CD19 CAR Therapy Failure in Children With B-ALL

A novel chimeric antigen receptor (CAR) T-cell therapy specific for CD22 was safe and provided high response rates for pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) who had failed chemotherapy and/or a CD19-targeted CAR T-cell treatment, according to early findings reported at the 2018 EHA Congress.

In 15 efficacy-evaluable patients with relapsed or refractory B-ALL, the objective response rate was 86.7% at 30 days’ post-infusion. Eighty percent of patients achieved complete remission (CR) or CR with incomplete count recovery (CRi). Partial remission was achieved in 6.7% of patients. The 6-month progression-free survival (PFS) rate was 91.7% in responding patients. Additionally, the procedure was well-tolerated with cytokine release syndrome (CRS) of mild to medium severity (grade 0 to 2) reported in all patients following the immunotherapy.

Lead investigator Jing Pan, MD, Beijing Boren Hospital, Beijing, China, underscored the need for new therapies in relapsed or refractory B-ALL, due to the high rate of relapse within 1 year following treatment, including with anti-CD19 CAR T-cell therapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT).

“All heavily treated children with relapsed or refractory B-ALL will die with current therapies,” she stated. However, she noted, that with the CD22 CAR T-cell therapy, “No patient, not even those who had received prior allo-HSCT, had severe side effects or died during CD22 CAR-T therapy.”

The need for new therapies after the development of resistance to CD19-directed CAR T-cell therapy prompted Pan and colleagues to evaluate the efficacy and safety of a CAR T-cell directed to CD22, a marker found on mature B cells that has been identified as a resistance mechanism to current CD19-targeted therapies.

Their study enrolled 15 pediatric patients with relapsed or refractory B-ALL between July 6, 2017, and January 8, 2018, at the Beijing Boren Hospital. The median age of patients was 8 years (range, 2-18) and the median time since diagnosis was 21 months (range, 5-84). All patients were refractory to chemotherapy and 14 had relapsed or had no response to CD19 CAR T-cell therapy. Four patients had relapsed following allo-HSCT but had not received prior CAR T-cell therapy.

At baseline, all patients tested positive for CD22 expression on leukemia cells. One patient was found to have weak CD19 expression, possibly leading to a lack of response to prior anti-CD19 therapy. Eleven patients entered the trial with hematologic relapse with 42% bone marrow blast cells (range, 5%-95.5%). Two patients were minimal residual disease-positive by flow-cytometry (FCM-MRD) and 2 patients had developed extramedullary diseases (EMDs) at study entry.

The patients were monitored for CAR T cell expansion after infusion, which revealed that peak expansion of CD3+ cells ranged from 3.2% to 71.7% by day 11 (±1.8 days). At the 30-day assessment, all but 2 patients had shown response to the CAR T-cell therapy. The two patients who did not respond, continued to have strong CD22 expression.

Of those with hematologic relapse at baseline, 10 of 11 achieved a CR or CRi, with 9 achieving FCM-MRD negativity (82%). One of the 2 MRD-positive patients converted to an MRD-negative response with the CD22 CAR T cell infusion. Additionally, 1 of the 2 patients with EMDs achieved a CR and the other achieved a PR.

With a median follow-up of 108 day, 6 patients had gone on to receive subsequent allo-HSCT. Of those achieving a CR/CRi, 11 continued to be progression-free at the analysis. The one relapsing patient had relapsed at 50 days.

“CD22-directed CAR-T cell therapy brings hope to patients with relapse or refractory B-ALL who have failed CD19 CAR-T cell therapy,” Pan said.

Severe CRS (grade 3/4) was not reported in the study, with most events being grade 1 and just 3 patients having grade 2 events. Grade 1 neurotoxicity was experienced by 2 patients. Overall, there was no significant difference in CRS found between patients who received and did not receive prior allo-HSCT (P = .41).

Further analysis from the study is ongoing. FCM-MRD scans had been conducted at months 1 and 3, Pan noted, with longer observation needed to determine the long-term outcomes.

Pan J, Deng B, Liu S, et al. Efficacy and safety of CD22-directed CAR-T cell therapy in 15 pediatric refractory or relapsed B acute lymphoblastic leukemia patients. Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S832.

<<< 2018 European Hematology Association Congress

The cells used in the trial were manufactured using a lentiviral vector to transduce a CAR derived from a humanized CD22 antibody. The CAR T-cell therapy was also engineered to have a 4-1BB costimulatory domain and a CD3-zeta signaling domain. The manufacturing process, which use peripheral blood mononuclear cells, took 7 to 8 days following leukapheresis, according to the investigators. The agent was administered at a median dose of 8.2 × 10⁵/kg in non-transplanted patients and at a median of 0.9 × 10⁵/kg for previously transplanted patients.