CAR-natural killer T-cell therapy shows antitumor activity in advanced neuroblastoma
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A natural killer T-cell therapy expressing a chimeric antigen receptor demonstrated antitumor activity among children with late-stage neuroblastoma, according to updated results of a phase 1 dose-escalation trial.
The latest data on the investigational agent — presented during the virtual American Society of Gene & Cell Therapy Annual Meeting — showed one durable complete remission among the first 11 children treated. The therapy also continued to exhibit a manageable safety profile, according to the researchers.
Data presented at last year’s ASCGT Annual Meeting indicated the cell therapy was safe and feasible for the treatment of younger patients with late-stage neuroblastoma. A year later, the researchers have escalated the cell dose to a fourth level.
“The infusions remain safe, and no dose-limiting toxicities have been detected,” Andras Heczey, MD, assistant professor in the pediatric hematology and oncology section within the department of pediatrics at Baylor College of Medicine, told Healio.
The autologous Valpha24-invariant natural killer T-cell (iNKT) therapy expresses a GD2-targeted CAR that is engineered to express interleukin-15 for improved persistence and efficacy. GD2 is a glycolipid found on the surface membrane of nerve cells.
“In this first-in-human study of genetically engineered NKTs, we demonstrated the feasibility of clinical-scale CAR-NKT manufacturing and found that [they] are safe, expand and persist in peripheral blood, infiltrate tumor tissues, and can induce durable complete remission,” Heczey said.
The dose-escalation study included 11 patients (median age, 7 years; range, 2-12; n = 6 male) with stage IV relapsed or refractory high-risk neuroblastoma.
After lymphodepletion with cyclophosphamide and fludarabine, the children received an infusion of GD2-directed CAR-iNKTs at one of four dose levels: 3 × 106 cells/m2 (n = 3), 1 × 107 cells/m2 (n = 3), 3 × 107 cells/m2 (n = 3) or 1 × 108 cells/m2 (n = 2).
Safety served as the study’s primary endpoint. Secondary endpoints included CAR-iNKT persistence and trafficking and antitumor activity as determined by Curie scores and International Neuroblastoma Response Criteria.
Results showed cytopenias related to lymphodepletion were the most common treatment-related adverse event. Ten patients had grade 4 neutropenia, six developed grade 4 leukopenia and six experienced grade 4 lymphopenia. However, only one patient had a grade 3 infection after therapy.
One patient experienced grade 3 neurotoxicity related to GD2-directed CAR-iNKTs.
Efficacy results showed five patients had progressive disease, four had stable disease, one had a partial response and one achieved complete remission.
Among those with stable disease, one patient had a 30% reduction in Curie score and another experienced clearance of bone marrow metastases.
“We started to document responses to therapy on dose level one, but perhaps the most exciting finding is that one of the children on dose level 4 achieved complete remission, which continued for at least 4 months now,” Heczey told Healio.
Researchers observed expansion of CAR-iNKTs in all 11 patients, with peak expansion occurring between 2 weeks and 4 weeks after infusion.
Laboratory analysis showed a median 1,144 (range, 46-4,903) NKTs and 40 (range, 4-697) CAR-iNKTs detected per milliliter of peripheral blood. Meanwhile, subsequent tumor biopsies showed trafficking of CAR-iNKTs to metastases at all dose levels evaluated.
The prognosis for patients in this study “remains very poor with currently available treatments,” Heczey said, which makes it difficult to compare the efficacy of GD2-directed CAR-iNKTs with commercially available therapies.
“We are continuing to enroll patients and have extended the study for two more dose levels with the goal of increasing the response rate while maintaining the outstanding safety profile,” he told Healio.
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