A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma

Abstract

BackgroundThe use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL.MethodsWe performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed.ResultsFrom August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (Cmax) values than other patients. Responders had higher Cmax and area under the curve values than non-responders. Tumour burden and Cmax were potentially associated with the severity of CRS.ConclusionsThis study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Biology and Treatment of Richter Transformation

“…A bispecific CD37/CD19 CAR-T product is being developed to assess safety and efficacy in preclinical B-cell tumor models. Bispecific CD19/22 CAR-T cells have been already explored in non-Hodgkin lymphomas (NCT03196830), showing promising results (ORR 79.3%, CR 34.5% with 12-month PFS and OS of 40 and 63%, respectively) ( 125 ). The employment of CD19 CAR-NK cells in B-cell malignancies is also being explored in different ongoing phase 1 trials (i.e., NCT04887012, NCT04639739, NCT04796675, and NCT05020678), and novel targets for CAR-NK cells are object of study (i.e., CAR70/IL15-transduced NK cells in NCT05092451).…”

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma

“…The costimulatory domain of all CARs was 4-1BB. Prior to this report, our center reported the protocol for manufacturing CAR-T cells and the construct designs for the CARs ( 17 ). Patients received lymphodepleting chemotherapy with FC (fludarabine 30 mg/m 2 d-5 to d-3, cyclophosphamide 300 mg/m 2 d-5 to d-3) or SEAM (250 mg/m 2 Me-CCNU d-10, etoposide 100 mg/m 2 every 12 h d-9 to d-6, cytarabine every 12 h d-9 to d-6, hematopoietic stem cell infusion d-2).…”

Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies

“…When comparing clinical outcomes on CD19/CD22 Loop Bi-CAR T-cell therapy with different locations of CD19 scFv and CD22 scFv on CAR in NHL subjects, the PFS in the trial on CAR T cells expressing Bi-CAR with CD19 scFv distal to 4-1BB [31] was longer than the one with CD22 scFv distal to 4-1BB [34], both of which have similar OS. Of note, the transduction efficiency of the CD19/CD22 Loop CAR with CD19 scFv distal to the 4-1BB was lower than the lowest one of the CD19/CD22 Loop CAR with CD22 scFv distal to 4-1BB, indicating that optimization may still be needed.…”

“…Time to maximum expansion is comparable in ALL and NHL between Si-CAR T cells and dual-targeting CAR T cells, ranging from 9 to 14 days. Similarly, maximum expansion of CAR T cells detected by polymerase chain reaction is comparable in NHL between one CD19 Si-CAR T-cell product [1] and two CD19/CD22 Loop Bi-CAR T-cell products [31,34]. Unfortunately, the disclosed data are insufficient to make a full comparison on the maximum expansion of CAR T cells among different dual-targeting CAR T cells and Si-CAR T cells.…”

“…As shown in Figure 2, different dual CAR strategies have been translated into six clinical trials on Tandem Bi-CAR T cells targeting CD19/CD20 [27,28], CD19/CD22 [29,30,64], and BCMA/CD38 [38]; four trials on cocktail/sequential infusion of two separate Si-CAR T cells of targeting CD19 or CD22 [15,16] and BCMA or CD19 [88,89]; three trials on Loop Bi-CAR T cells targeting CD19/CD22 [31,34,90]; two trials on bicistronic Bi-CAR T cells targeting CD19/CD22 [32,70]; and two trials on CD19/CD22 Bi-CAR T cells produced by co-transduction of two separate vectors [14,91]. Because the exact construct (tandem or loop) for DOR and survival of a dual BCMA/CD19 targeted FasT CAR-T GC012F [92] has not been disclosed so far, the trial was not included in this section.…”