Allogeneic CAR-T induces high response rates in non-Hodgkin lymphoma, B-cell ALL
An enhanced lymphodepletion regimen followed by chimeric antigen receptor T-cell therapy induced response among patients with relapsed or refractory B-cell malignancies, according to results presented at ASH Annual Meeting and Exposition.
The nonrandomized, multicenter phase 1/phase 2 study evaluated PBCAR0191 (Precision BioSciences) after enhanced lymphodepletion for patients with non-Hodgkin lymphoma or B-cell acute lymphoblastic leukemia.
PBCAR019 is an allogeneic, gene-edited, CD19-directed CAR T-cell therapy derived from healthy donor T cells.
The investigational agent uses proprietary ARCUS gene editing to simultaneously knock out a T cell’s endogenous T-cell receptor to prevent graft-versus-host disease and insert a CAR expression cassette.
Initial participants in a phase 1 dose-escalation study underwent a standard lymphodepletion regimen with fludarabine and cyclophosphamide that resulted in poor CAR T-cell expansion and persistence, Bijal D. Shah, MD, associate professor in the department of malignant hematology at Moffitt Cancer Center, said during a presentation.
“We accordingly sought to explore the impact of an enhanced lymphodepletion regimen to improve CAR T-cell kinetics and clinical outcomes,” Shah said.
The enhanced lymphodepletion regimen increased the dose of fludarabine to 30 mg/m2 per day for 4 days, compared with 3 days in the standard regimen. The investigators also doubled the dose of cyclophosphamide to 1,000 mg/m2 per day for 3 days.
After enhanced lymphodepletion, study participants received PBCAR0191 at a dose of 3 × 106 cells/kg.
“Enhanced lymphodepletion was associated with a significant increase in the expansion of CAR-positive cells,” Shah said.
This included an approximately 21-fold increase in peak expansion of CAR T cells compared with standard lymphodepletion.
At ASH, Shah presented results from 22 adults with relapsed or refractory non-Hodgkin lymphoma (n = 17; median age, 59 years; range, 34-76) or B-cell ALL (n = 5; median age, 50 years; range, 26-56) who underwent enhanced lymphodepletion followed by PBCAR0191.
Study patients had received a median five prior lines of therapy. Four patients (24%) with non-Hodgkin lymphoma received previous CD19-directed autologous CAR T-cell therapy, as did one patient (20%) with B-cell ALL.
Researchers reported overall response rates of 71% in the entire cohort, 69% among those with non-Hodgkin lymphoma and 80% among those with B-cell ALL.
Results showed complete response rates of 62% in the entire cohort, 56% among those with non-Hodgkin lymphoma and 80% among those with B-cell ALL.
All study participants who received prior CD19-directed CAR T-cell therapy responded to therapy. Those who received prior CAR-T appeared more likely to achieve complete response than non-recipients (80% vs. 56%).
Sixty-five percent of patients with non-Hodgkin lymphoma and 80% of those with B-cell ALL experienced grade 1 or grade 2 cytokine release syndrome. No cases of grade 3 or higher CRS occurred.
One patient with non-Hodgkin lymphoma developed grade 3 immune effector cell-associated neurotoxicity syndrome.
Forty-one percent of patients with non-Hodgkin lymphoma and 80% of those with B-cell ALL developed grade 3 or higher infections. No cases of graft-versus-host disease occurred.
“Enhanced lymphodepletion mitigated PBCAR0191 rejection and markedly improved peak cell expansion and persistence, with predictable toxicity,” Shah said. “Despite the use of PBCAR0191 in a heavily pretreated population, we are seeing some extended remissions.”
The results among patients who received prior autologous CAR T-cell therapy are encouraging, Shah said. Three of those five patients had a longer duration of response after receiving PBCAR0191, which could signal its ability to serve as an effective bridging therapy to autologous hematopoietic stem cell transplant.
“The overall and [complete response] rates for PBCAR0191 appear comparable with what has been observed with autologous CAR T-cell therapy, although durability in this heavily pretreated population may be lower,” Shah concluded.
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Shah BD, et al. Abstract 302. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.