Utomilumab may enhance effectiveness of CAR-T for advanced large B-cell lymphoma
Click Here to Manage Email Alerts
The addition of utomilumab after infusion with axicabtagene ciloleucel induced a 75% response rate among adults with relapsed or refractory large B-cell lymphoma, data from the ZUMA-11 trial showed.
Early results from the phase 1 study — presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR — suggest utomilumab (PF-05082566, Pfizer) may enhance the expansion and function of axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences) to improve clinical outcomes.
Background
Axicabtagene ciloleucel — also known as axi-cel — is an autologous, gene-edited, CD19-directed chimeric antigen receptor T-cell therapy. The agent is approved in the United States for adults with relapsed or refractory large B-cell lymphoma who received two or more lines of systemic therapy, or as second-line therapy for adults with early relapse after front-line treatment.
There is still a need to improve outcomes with axi-cel despite a 5-year OS greater than 40% and recent data showing axi-cel significantly improves EFS as second-line therapy, according to Ran Reshef, MD, associate professor of medicine and clinical lead of the CAR-T Cell Program at Columbia University Medical Center.
“It has been hypothesized that dual stimulation may improve CAR T-cell expansion and persistence that would lead to improved clinical outcomes,” Reshef said during a presentation. “Preclinical evidence supports the use of utomilumab as a T-cell costimulatory molecule capable of enhancing axi-cel expansion and function.”
Methodology
ZUMA-11 is a phase 1 dose-escalation study aimed at determining the safety, efficacy and pharmacokinetics of axi-cel plus utomilumab — an investigational 4-1BB agonist monoclonal antibody —for adults with primary refractory large B-cell lymphoma or relapsed or refractory disease after two or more previous lines of therapy.
The study has enrolled 12 patients (median age, 62 years; range 44-77; 58% male) who investigators assigned to one of four cohorts based on escalating utomilumab doses (10 mg, 30 mg, 100 mg or 200 mg).
Patients underwent lymphodepleting chemotherapy, then received a single infusion of axi-cel. They received subsequent IV infusions of utomilumab every 4 weeks for 6 months or until disease progression.
Median follow-up was 26.7 months, with a data cutoff date of Nov. 11, 2021.
Key findings
All patients experienced at least one treatment-related adverse event. The majority (83%) experienced grade 3 or higher adverse events, the most frequent being decreased neutrophil count (67%), anemia (42%) and hypotension (8%).
No grade 5 or dose-limiting toxicities occurred.
Cytokine release syndrome occurred in 11 (92%) patients, with no reports of grade 3 or higher CRS. Six (50%) patients developed neurotoxicity, with no grade 3 or higher cases.
The combination of axi-cel followed by utomilumab induced an objective response in nine (75%) patients. Seven patients (58%) achieved complete response.
All six patients who received 100 mg or more of utomilumab responded to therapy, including four of six patients (67%) who achieved complete response.
Forty-two percent of patients had an ongoing response to therapy as of data cutoff.
Pharmacologic analysis suggested a dose-dependent trend of increasing peak CAR T-cell levels up to 100 mg utomilumab, as well as increased levels of central memory and effector memory T cells.
Clinical implications
The results show a manageable safety profile, especially given the lack of high-grade CRS or neurotoxicity, Reshef said.
This observation, along with the early response rates and cell expansion data, support the need for further study of the investigational regimen, he added.
“The combination of utomilumab with axi-cel is safe ... and shows promising preliminary efficacy,” he said. “Cell expansion data suggest increasing doses of utomilumab may lead to improved CAR T-cell expansion and a predominance of central and effector memory T cells.”
Collapse
Reshef R, et al. Abstract 76. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
Click Here to Manage Email Alerts