CAR-natural killer T-cell therapy feasible, safe for advanced neuroblastoma
A modified natural killer T-cell therapy expressing a chimeric antigen receptor and interleukin-15 appeared feasible and safe for children with neuroblastoma, according to interim results of a first-in-human phase 1 trial presented at the virtual American Society of Gene and Cell Therapy Annual Meeting.
Results of the first three patients treated with the investigational, autologous, second-generation, GD2-specific CAR-natural killer T-cell (CAR-NKT) therapy showed acceptable safety, with tumor regression in one patient.
“There are data suggesting that NKT cells are better suited for immunotherapy, in particular for neuroblastoma, mainly because of their ability to control tumor-associated macrophages,” Andras A. Heczey, MD, director of the liver tumor program and assistant professor in the department of pediatrics at Baylor College of Medicine, said during a presentation. “They express a certain set of chemokine receptors that specifically respond to chemokines secreted by neuroblastoma, so they can traffic to tumors better.”
The phase 1 dose-escalation study included patients aged 21 years or younger with relapsed or refractory neuroblastoma. Five patients have been treated to date in the study. The current analysis includes the first three patients — two boys aged 12 years and one boy aged 7 years — who received the lowest-level dose of 3 × 106 cells/m2.
The primary objective of the study was to evaluate the safety of CAR-NKT cells. Secondary objectives included cell persistence and antitumor responses.
Patients underwent lymphodepletion chemotherapy 3 days before receiving an infusion of CAR-NKT cells, with biopsy at 2 weeks and imaging follow-up at 4 weeks after infusion.
The investigators were able to manufacture an autologous CAR-NKT cell product for all three patients in the current analysis. They successfully expanded patient-derived NKT cells to eventually produce enough CAR-NKT cells for treatment within 9 to 17 days; the product had 95.6% median purity (range, 90.4%-97.17%) and 46.9% median CAR expression (range, 20.18%-81.68%).
Results showed CAR-NKT cell infusions appeared safe and resulted in no grade 3 or higher treatment-related toxicities. Most treatment-related toxicities were hematologic, such as anemia and blood cell counts, and were expected because of lymphodepletion, Heczey said.
Patients had manageable cytokine levels, with initially increased interleukin-15 levels that returned close to baseline by week 2 after infusion and interleukin-7 levels that remained close to baseline throughout the study.
All five treated patients showed evidence of cell expansion after infusion; expansion peaked at 3 weeks after infusion in four patients and at 4 weeks in the remaining patient.
Two patients had stable disease at 4 to 6 weeks after infusion, and two experienced clinical disease progression.
The other patient had two metastatic bone lesions before infusion. His right femur lesion experienced compete regression, wheat his large sternum lesion had near complete regression as determined by single-photon emission CT at 4 and 8 weeks after infusion.
“CAR-NKT cells can be manufactured to clinical scale in [good manufacturing practice] conditions,” Heczey said. “Thus far, these NKT cells are safe for infusion ... and we have seen significant tumor regression in at least one patient.” – by Drew Amorosi
Reference:
Heczey A, et al. Abstract 1301. Presented at: ASGCT Annual Meeting; May 11-15, 2020 (virtual meeting).
Disclosure: Heczey reports research support from Kuur Therapeutics and being listed as an inventor on patients licensed by Baylor College of Medicine to Kuur Therapeutics. Please see the abstract for all other researchers’ relevant financial disclosures.
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