New treatment target emerges for those who relapse after CAR-T for lymphoma
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A novel chimeric antigen receptor T-cell therapy induced response among adults with advanced large B-cell lymphoma who relapsed after previous CAR-T, study results showed.
All but one of the 20 study participants who achieved an initial complete response to therapy remained in remission as of the cutoff date, according to data presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
“We never thought response rates would be this high,” Matthew Frank, MD, PhD, assistant professor of medicine in the division of blood and marrow transplantation and cellular therapy at Stanford University, told Healio. “It's a very effective and safe CAR-T to give to patients who will largely have an unmet need.”
Background
Researchers at Stanford University developed an investigational autologous CAR T-cell therapy that targets the CD22 protein on the surface of cancer cells. They manufactured the agent onsite in a 12-day process using the CliniMACS Prodigy (Miltenyi Biotec) automated cell processing system.
Prior research conducted by NCI showed CD22 directed CAR-T produced a 70% complete response rate among 58 younger patients with relapsed or refractory B-cell ALL whose disease progressed after prior CD19-directed CAR-T.
“Half of our patients would still relapse after the use of commercial CAR-T, and a common reason for relapse was downregulation or loss of CD19,” Frank said. “By going to an alternative antigen that looked promising among children, we were hopeful to see responses.”
Methodology
Frank and colleagues conducted a phase 1, single-institution, dose-escalation trial that evaluated their novel CD22-targeted CAR T-cell therapy.
The trial included 38 adults (median age, 65 years; range, 25-84; 55% men) with relapsed or refractory large B-cell lymphoma whose disease progressed after previous CD19-directed CAR-T or who had CD19-negative disease.
All but one patient treated during the trial received prior CD19-directed CAR T-cell therapy.
Study participants underwent preconditioning lymphodepletion followed by a single infusion of CD22 CAR T cells at a dose of either 1 × 106 cells/kg (n = 29) or 3 × 106 cells/kg (n = 9).
Feasibility, safety and recommended phase 2 dose served as the study’s primary endpoints. Secondary endpoints included investigator assessed overall response rate, duration of response, PFS, OS and CAR-T-associated toxicity.
Median follow up was 18.4 months (range, 1.5-38.6), with a data cutoff date of Dec. 27, 2022.
Key findings
Thirty-six patients developed cytokine release syndrome. The lone grade 3 event occurred in the higher-dose group. Grade 2 CRS occurred more frequently in the higher-dose group (78% vs. 48%).
Five patients (13%) developed immune effector cell-associated neurotoxicity syndrome. Researchers reported no cases of severe (grade 3 or higher) ICANS during the study.
Five patients — including three of the nine patients who received the higher dose —developed CAR-associated hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory response characterized by extreme hyperferritinemia and multiorgan dysfunction.
Efficacy analysis showed an ORR of 68% and complete response rate of 53% for all treated patients. Fifteen patients (52%) who received the lower dose and five (56%) who received the higher dose achieved complete response.
Researchers reported median PFS of 2.9 months (95% CI, 1.7 to not reached) and median OS of 22.5 months (95% CI, 8.3 to not reached). The lower dose and higher dose exhibited similar efficacy with regard to median PFS (3 months vs. 2.6 months) and median OS (not reached vs. 22.5 months).
Only one of 20 patients who achieved complete response experienced disease relapse as of the study cutoff date.
Investigators chose 1 × 106 cells/kg as the recommended phase 2 dose based on its superior safety profile and similar efficacy compared with the higher dose.
Clinical implications
When the trial first started in 2018, little was known about why some patients relapse after CAR-T. The primary hypothesis — beyond tumor biology — was poor T-cell fitness, Frank said.
“We've kind of blown that [theory] out the water a little bit here, because we're taking the same autologous T cells from patients who have had a prior CAR-T and still seeing a nearly 70% response rate and a 53% complete response rate that looks very durable,” Frank told Healio. “This is a very promising therapy that has a high response rate and a very reasonable safety profile.”
A planned multicenter phase 2 trial of CD22 CAR-T will include patients with large B-cell lymphoma who relapsed after CD19-directed CAR-T. Enrollment is expected to open this summer.
References:
- Frank MJ, et al. Abstract 2. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Feb. 15-19, 2023; Orlando.
- Shah NN, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03279.
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Frank MJ, et al. Abstract 2. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Feb. 15-19, 2023; Orlando.
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