Humanized CD19 CAR-T Cell Combined with Multiple Combination Treatments in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Purpose: To study the efficacy and side effects of humanized anti-CD19-CAR T-cell combined with multiple combination treatments in relapsed/refractory B-cell non-Hodgkin lymphoma.

Methods: Thirty-eight relapsed/refractory B-cell non-Hodgkin lymphoma patients were enrolled in a clinical trial of anti-CD19 chimeric antigen receptor (CAR) modified T-cell expressing humanized anti-CD19 scFv and 4-1BB-CD3ζ costimulatory-activation domains therapy (ChiCTR1800018059) at the Department of Hematology in Tianjin First Center Hospital (Tianjin, China). Except for anti-CD19-CAR T-cell therapy, all the patients received multiple combination treatments before or at the same time of CAR-T cell therapy. The multiple combination treatments included anti-CD22-CAR T-cell, Programmed death 1 (PD-1) inhibitor, Bruton's tyrosine kinase (BTK) inhibitors, Lenalidomide, Advance high-dose chemotherapy and Radiotherapy. Patients were evaluated 2 months after the infusion. The side effects were observed in all the process of the combination treatments. Cytokine release syndrome (CRS) was graded according to the ASBMT Consensus Criteria.

Results: The median time from infusion to cutoff day was 7 months (Range: 1 to 16 months). There were 37 patients included in the evaluation of the efficacy and side effects (Except for one patient with high tumor burden died of CRS 7 days after the infusion). The best overall response rate (ORR) was 75.6% (28/37). The complete response (CR) rate was 45.9% (17/37), the partail response (PR) rate was 29.7% (11/37), the stable disease (SD) rate was16.2% (6/37) and the disease progression (PD) rate was 8.1% (3/37). The grade of cytokine release syndrome (CRS) was Grade 1: 25/38, Grade 2: 9/38, Grade 3: 3/38, Grade 4: 0/38 and Grade 5: 1/38. Two patients died from disease progression within 60 days after infusion. One patient with high tumor burden who achieved PR at 14 days died from intestinal perforation after 25 days of infusion. The combination treatments of anti-CD22-CAR T-cell (4/38), treatment dose or 1/2 treatment dose of PD-1 inhibitor (5/38) or BTK inhibitors (3/38) therapy improved the curative effect of humanized anti-CD19-CAR T-cell therapy. Advance high-dose chemotherapy for patients (9/38) with high tumor burden before the anti-CD19-CAR T-cell therapy achived a satisfactory ORR (5/9) and Grade 1-2 CRS. No patients died from the advance and intensive chemotherapy. There were 6 patients with refractory lymphoma received radiotherapy before they enrolled in the anti-CD19-CAR T-cell therapy. There were 5 patients achived CR or PR except for one patient with high tumor burden died of CRS 7 days after the infusion (the IL-6 level was more than 1000 U/mL at day 3). But the side effects were significant in these 6 patients (Grade 1: 0/6, Grade 2: 2/6, Grade 3: 3/6, Grade 4: 0/6, Grade 5: 1/6). There was no efficacy improvement from the combination treatments of lenalidomide (14/38, 3 patients received advance high-dose chemotherapy meanwhile among the 14 patients), and the side effects were not significant.

Conclusions: The multiple combination treatments combined with humanized anti-CD19-CAR T-cell therapy could improve the efficacy without increase side effects obviously.