Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells Following Autologous HSCT in Patients with B-NHL

Salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) is the standard treatment for the patients with chemotherapy sensitive relapsed or refractory B-NHL. However, more than half of patients will ultimately relapse. To improve long-term remission rate, we administered adoptive T-cell immunotherapy after HSCT. Based on the findings that CD19/CD22 dual antigen targeting have been demonstrated to be a promising approach for overcoming antigen escape relapse, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells following autologous HSCT. We aimed to evaluate its safety and efficacy in patients with relapsed, refractory and high-risk B cell lymphoma. This trial is registered with ChiCTR, number ChiCTR-OPN-16009847.

Between December 2016 and March 2018, 20 patients were enrolled in this clinical trial, with a median age of 33 years (range, 24-61 years). Of these 20 treated patients, 2 had PMBCL, 4 had tFL,14 had DLBCL, 70.0% (14/20) had received at least three previous therapies. 50.0% patients (8/16) harbor a TP53 mutation. At baseline assessment (prior to conditioning), 3 participants had a CR, 8 had a PR, 8 had a PD, 1 had a SD. All patients received bis-chloroethyl nitrosourea, etoposide, Ara-C, and melphalan, CD22 and CD19 CAR T cells were infused 2 to 7 days after stem cell infusion. The median anti-CD22 and anti-CD19 CAR-T cells dose per kilogram of body weight were 4.0× 10⁶ (range, 1.0-10.0×10⁶) and 4.2× 10⁶ (range, 1.8-10.0×10⁶) respectively. Normal HSCT-associated neutrophil engraftment within 20 days in all 20 patients was observed. 11/20 (50.5%) patients experienced cytokine release syndrome and no patient had severe CRS (grade 3-4). Neurologic events occurred in 2 (10.0%) patients. At 3 months, there was a 90.0% remission rate (95% CI ,68.3-98.8) with 85.0 % complete remissions (CRs) and 5.0% partial remissions (PRs) accessed by PET-CT. The duration of responses currently ranges from 3.7 months to19.1 months. All patients (17/20) who achieved CRs are ongoing, and the current median duration of all CRs is 13.2 months.

Our results indicated that patients with relapsed, refractory and high-risk B cell lymphoma who received sequential infusion of anti-CD22 and anti-CD19 CAR-T cell therapy following HSCT had high rates of durable remission, with safety profile. Anti-CD22 and Anti-CD19 CAR-T cell therapy following HSCT may become a useful treatment approach for relapsed , refractory B cell lymphoma and high-risk B cell lymphoma.