Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B cell lymphoma

Abstract

Chimeric antigen receptor T (CAR T) cells targeting CD19 have achieved breakthroughs in the treatment of hematological malignancies, such as relapsed/refractory non-Hodgkin lymphoma (r/rNHL); however, high rates of treatment failure and recurrence after CAR T cell therapy are considerable obstacles to overcome. In this study, we designed a series of tandem CARs (TanCARs) and found that TanCAR7 T cells not only showed dual antigen targeting of both CD19 and CD20 but also formed superior and stable immunological synapse (IS) structures, which may be related to their robust antitumor activity. In an open-label, single-arm phase I/IIa trial (ClinicalTrials.gov number NCT03097770), we enrolled 33 patients with r/rNHL, and a total of 28 patients received an infusion after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of TanCAR7 T cells. Efficacy, progression-free survival and overall survival were evaluated as secondary objectives. Cytokine release syndrome (CRS) occurred in 14 patients (50%), with 36% grade 1 or 2 and 14% grade 3. No cases of CAR T cell-related encephalopathy syndrome (CRES) of grade 3 or higher were confirmed in any patient. One patient died from a treatment-associated severe pulmonary infection. The overall response rate was 79% (95% confidence interval [CI], 60 to 92), and the complete response rate was 71%. The progression-free survival rate at 12 months was 64% (95% CI, 43 to 79). In this study, TanCAR7 T cells elicited a potent and durable antitumor response but not grade 3 or higher CRES in patients with r/rNHL.

Challenges and Clinical Strategies of CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Overview and Developments

“…In addition, poor T-cell persistence is also a relatively common situation and contributes to a proportion of relapses. It is worth noting that membrane binding location, linker length between the heavy and light chains and other spatial considerations are all important for the efficacy and safety of CAR T-cells, which is more complex in the incorporation of multiple scFvs ( 51 , 173 , 174 ). More basic studies are required to optimize the structure of multitargeting CARs in pursuit of better clinical outcomes.…”

Clinical development of CAR T cell therapy in China: 2020 update

“…Expressing dualtargeted CAR molecules (tandem CARs) is another combination strategy. In 2020, Tong et al 41 found that optimized tandem CAR T-19/20 cells could form a more stable immunological synapse, leading to better antitumor function. The dual-targeted CAR T cells were then tested in R/R NHL patients, and a total of 28 patients received CAR T-19/20 treatment.…”

Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma

“…Grade 3 CRS occurred in 14% of patients and 17% required tocilizumab for management. There were no three quarter grade neurological toxicities [ 36 ]. An update of this study was provided in abstract form in June 2020 which reported on outcomes of 87 patients.…”