Dual-targeting ‘the next step’ for CAR T-cell therapy in advanced non-Hodgkin lymphoma
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A bispecific chimeric antigen receptor T-cell therapy continues to show promising efficacy for patients with relapsed or refractory B-cell non-Hodgkin lymphoma, results of a phase 1/phase 2 trial suggest.
The autologous, gene-edited, bispecific lentiviral CAR T cells (LV20.19 CAR; MB-CART2019, Miltenyi Biotec) — which use a more rapid manufacturing process than commercially available CAR-T — target both CD20 and CD19 on the surface of B-cell malignancies.
Findings presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR showed a 90% overall response rate among patients who received a single infusion of LV20.19 CAR.
Background and methodology
Nirav N. Shah, MD, MSHP, associate professor of hematology and medical oncology at Medical College of Wisconsin and member of the Healio | Cell Therapy Next Peer Perspective Board, previously reported phase 1 results of LV20.19 CAR at the 2019 ASCO Annual Meeting.
The investigational cell therapy “demonstrated exciting clinical responses,” Shah told Healio at the time, adding that additional study via a larger phase 2 trial was necessary to confirm the results.
The current phase 1/phase 2 trial includes several changes to the study’s methodology.
Shah and colleagues enrolled 29 patients (median age, 64 years; range, 41-78; 76% male) in the updated trial, designed to evaluate LV20.19 CAR for patients with relapsed or refractory B-cell non-Hodgkin lymphoma using a new CAR T-cell expansion method and variable manufacturing length ranging from 8 days to 12 days.
“There are preclinical and clinical data that show that using [interleukin]-7 and IL-15 for cell expansion can improve the CAR T-cell product by increasing the number of T cells with central memory and stem cell memory phenotypes, which is important for CAR T-cell persistence and could help mitigate disease relapse,” Shah told Healio.
Disease types represented in the trial included diffuse large B-cell lymphoma (n = 16), mantle cell lymphoma (n = 10) and follicular lymphoma (n = 3). Study participants received a median four lines (range, 2-11) of previous therapy.
The study included enhanced-dose preinfusion lymphodepletion and a phase 2 cohort of patients with mantle cell lymphoma for a disease-specific assessment of the treatment’s efficacy.
Onsite manufacturing of the CAR T cells using the CliniMACS Prodigy (Miltenyi Biotec) production system resulted in the infusion of fresh, noncryopreserved cell products for 26 of 29 patients.
Key findings
Researchers reported a 90% overall response rate across all study groups based on evaluation 28 days after CAR-T infusion.
Ninety percent of patients in the 8-day manufacturing group responded to therapy, with 70% experiencing complete responses.
Seventy-eight percent of patients in the 12-day manufacturing group responded to therapy, with 22% experiencing complete responses.
Treatment with LV19.20 CAR resulted in a 60% ORR among patients with mantle cell lymphoma in the phase 2 cohort. Forty percent of patients in the group achieved complete response.
Twenty patients had minimal residual disease (MRD) assessed between day 28 and day 60 after infusion. Seventy-five percent of these patients were MRD-negative based on results from a commercially available assay, investigators noted.
Median PFS and OS had not been reached.
Cytokine release syndrome occurred in 90% of patients; however, only one patient experienced high-grade (grade 3) CRS. Median time to CRS was 1 day.
Investigators observed higher CRS rates among patients in the phase 1/1B 8-day manufacturing group compared with those in the 12-day group (100% vs. 73%; P = .045).
Twenty-eight percent of patients developed immune effector cell-associated neurotoxicity syndrome (ICANS) after CAR-T infusion, including three patients (10%) who had grade 3 ICANS.
One patient had dose-limiting toxicity attributed to prolonged grade 3 ICANS and grade 4 acute kidney injury.
Two patients experienced nonrelapse mortality events outside the dose-limiting toxicity period attributed to complications from infection.
Clinical implications
Early data from the study suggest that shorter manufacturing time increases percentage of T cells with central memory and stem cell memory phenotype, which may have a positive effect on outcomes, Shah said.
“The key takeaway is that using IL-7 and IL-15 does lead to a faster platform that allows us to shorten manufacturing down to 8 days for the majority of patients,” he added.
Further evaluation of LV20.19 CAR is underway via a multicenter phase 2 trial as third-line therapy for patients with DLBCL. This study uses a centralized manufacturing process rather than the onsite one reported by Shah and colleagues.
The goal of the research is approval of LV20.19 CAR for commercial use by the FDA, Shah said.
“If the construct is approved, we are hopeful that we can do future research showing that the approved vector can be manufactured onsite, which we have been doing for the last 5 years,” he told Healio.
“This dual-targeted CAR is one of the furthest along in terms of clinical development,” Shah added. “We have shown that dual targeting is effective and potentially the next step for CAR T-cell therapy.”
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Shah NN, et al. Abstract 11. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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