Optimized Tandem CAR T-Cell Therapy Targeted CD19/CD20 Appears Feasible in B-NHL

Optimized tandem CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy induced potent and durable anti-tumor responses as treatment of patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) with good control of cytokine release syndrome (CRS) and CAR T-related encephalopathy syndrome, according to a phase 1/2 clinical trial presented in a poster at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

After a median of 13.5 months of follow-up (IQR, 33.2-3.3), 84% of patients had an objective response, and 74% had a complete response (CR). The duration of overall response rate (ORR) at 6 months was 94% and 74% at 12 months.

Both the median progression-free and overall survivals had not been reached for patients at the time of data cut-off. At 6 months, the progression-free survival rate was 76%, and at 12 months, it was 59%.

Sixty-two patients experienced CRS (71%), which was grade 1 or 2 in 61% of patients and grade 3 or greater in 10%. The median time to the onset of CRS after infusion was 1 day (range, 1-5). The median duration of CRS was 6 days (range, 1-9). Investigators also noted that the median time to the onset of grade 3 CRS was 1 day (range, 1-2).

The most common adverse events within 1 month of the IV infusion were leukopenia, pyrexia, and anorexia. Only 2 patients (2%) experienced CAR T-cell-related encephalopathy syndrome of grade 3 severity.

Three treatment-related deaths occurred in the study, 2 due to pulmonary infection and 1 due to deposition of CAR T cells in pulmonary alveoli.

Ninety-nine patients were screened for the study, of which 87 received the infusion and 74 were followed for at least 3 months before the data cutoff date. Patients underwent leukapheresis and conditioning chemotherapy, which was followed by a single intravenous infusion of tandem CD19/20 CAR T cells on day 0 at a dose of 0.5x106x106 per kg of body weight.

The majority of patients in the study were under the age of 60 years (82%) and female (53%). Overall, 62% of patients had an ECOG performance status of 0 or 1 versus 38% who had a 2. Upon study entry, 85% had stage III or IV disease and 15% had stage I or II. Patients were diagnosed with either diffuse large B-cell lymphoma (66%), follicular lymphoma (15%), transformed follicular lymphoma (7%), primary mediastinal B-cell lymphoma (6%) or other (6%).

Fifty-six percent of patients had 3 to 5 prior lines of anti-neoplastic therapy, while 27% had 2 or less and 17% had 6 or more. The majority of patients had a lesion diameter less than 10 cm (78%) and had tumor burden SPD of 100 cm2 or more (55%). Eighty percent of the patients were refractory, 20% had relapsed to second-line or later therapy, 14% became refractory after stem cell transplant, and 10% had relapsed after a prior CD19 CAR-T cell therapy.

To be eligible for the study, patients had to be between the ages of 16 and 70 years, and they could not have received prior anti-CD20 monoclonal antibody and anthracycline treatment. Patients had to have an ECOG performance status of 0 to 2 with a life expectancy greater than 3 months and adequate organ function to enroll in the study. Patients also had to have measurable disease according to the IWG Response Criteria for Malignant Lymphoma.

Patients who had a CR with no evidence of disease were ineligible to enroll. If they had definite involvement of the gastrointestinal tract, negative tumor puncture detection in both CD19 and CD20, or had serious uncontrolled medical disorders or active infections, they also could not enroll. Patients were also excluded from the study if they were deemed unsuitable for the trial based on clinical judgement or were pregnant or lactating.

CD19-targeted CAR T cells have been highly effective in the treatment landscape of hematologic malignancies, but the recurrence rate appears high, which is a major obstacle to durable remissions with this therapy. This study aimed to evaluate the safety and tolerability of intravenous tandem CD19/20 CAR T cells among patients with relapsed/refractory NHL.

Secondary objectives of this study also included assessment of efficacy of the study treatment defined by ORR and evaluation of the duration of overall response, progression-free and overall survival. An exploratory objective of the study was to determine in vivo expansion and persistence of the Tandem CD19/CD20 CAR T cells.

The rationale for this study was to address the high recurrence rate observed with CAR T-cell therapy, which often prevents durable remission after treatment. Overall the optimized tandem CAR T treatment appeared feasible in patients with B-NHL. Although many of the patients in the study had heavy tumor burden, were in poor physical condition, or had highly aggressive characteristics, they were still able to achieve a satisfactory ORR and CR rate with the tandem CD19/CD20 CAR-engineered T-cell therapy.

_Reference

_{Ja-Jing Z, Yao W, Zhi-Qiang Wu, et al. Safety and Efficacy of Optimized Tandem CD19/CD20 CAR-Engineered T Cells in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. J Clin Oncol. 38: 2020 (suppl; abstr 3034). doi: 10.1200/JCO.2020.38.15_suppl.3034}