In a single-institution phase I study reported in the Journal of Clinical Oncology, Jae H. Park, MD, and colleagues found that first-in-human use of a CD19-1XX chimeric antigen receptor (CAR) T-cell therapy with calibrated signaling showed high activity in patients with relapsed or refractory large B-cell lymphoma (LBCL).
Jae H. Park, MD
As stated by the investigators: “We designed a CD19-targeted CAR comprising a calibrated signaling module, termed 1XX, that differs from that of conventional…CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities.”
Study Details
A total of 28 patients were enrolled between July 2020 and November 2022 at Memorial Sloan Kettering Cancer Center, including 16 treated in the dose-escalation cohort and 12 in the dose-expansion cohort. They underwent apheresis and received the novel therapy at four dose levels ranging from 25 to 200 x 106 CAR T cells.
Key Findings
Among all patients, the objective response rate was 82%, with complete responses in 71%. The lowest investigated dose of 25 x 106 CAR T cells was selected for dose expansion. In 16 patients treated at this dose level, an objective response was observed in 88%, with a complete response in 75%.
With a median follow-up of 24 months, 1-year event-free survival was 61% (95% confidence interval [CI] = 45%–82%), with 14 patients remaining in continuous complete response at more than 12 months.
Robust T-cell expansion was observed across all dose levels, with no difference in peak CAR T-cell expansion observed. Persistence of CAR T cells beyond 1 year was observed in 10 patients with ongoing complete response, including 1 patient treated with 25 x 106 CAR T cells who had detectable CAR T cells beyond 2 years.
Among all patients, cytokine-release syndrome was observed in 86% and was grade 3 in one patient (4%; no grade 4 or 5 events). Immune effector cell–associated neurotoxicity syndrome occurred in three patients and was grade 3 in two (7%; no grade 4 or 5 events). Other grade ≥ 3 adverse events included hypotension (4%), generalized edema (4%), sepsis (4%), and atrial fibrillation (4%).
The investigators concluded: “The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses with favorable toxicity profiles and may benefit the treatment of other hematologic malignancies, solid tumors, and autoimmunity.”
Dr. Park, of the Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute and Takeda Pharmaceuticals. For full disclosures of the study authors, visit ascopubs.org.
