CAR-natural killer T-cell therapy shows antitumor activity in advanced neuroblastoma

Source / Disclosures Published by:

Source:
Heczey A, et al. Summary 198. Presented at: American Society of Gene & Cell Therapy Annual Meeting (virtual meeting); May 11-14, 2021.

Disclosures:
This study was supported by grants and contracts from the Alex’s Lemonade Stand Foundation, American Cancer Society, Cancer Prevention and Research Institute of Texas, Cookies for Kids’ Cancer Foundation, Cure Therapeutics and NIH. Heczey and another researcher report research support from Cure Therapeutics and patents related to CAR design and the NKT cell therapy platform. Cure Therapeutics has obtained a license for the NKT cell therapy platform from Baylor College of Medicine. The other researchers do not report any relevant financial disclosures.

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A natural killer T cell therapy expressing a chimeric antigen receptor showed anti-tumor activity in children with late-stage neuroblastoma, according to updated results from a phase 1 dose-escalation study.

The latest data on the study drug – presented at the American Society of Gene & Cell Therapy Virtual 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.

Heczey A, et al. Summary 198. Presented at: American Society of Gene & Cell Therapy Annual Meeting (virtual meeting); May 11-14, 2021.

Data presented at last year’s ASCGT annual meeting indicated that the cell therapy was safe and feasible for treating younger patients with late-stage neuroblastoma. A year later, the researchers increased 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 Baylor College of Medicine’s department of pediatrics, Healio said.

The autologous Valpha24 invariant natural killer T cell (iNKT) therapy expresses a GD2-targeted CAR designed to express interleukin-15 for enhanced persistence and efficacy. GD2 is a glycolipid found on the surface membrane of nerve cells.

“In this first human study of genetically engineered NKTs, we demonstrated the feasibility of CAR-NKT production on a clinical scale and found that [they] are safe, expand and persist in peripheral blood, infiltrate tumor tissues and can cause lasting complete remission, ”said Heczey.

The dose escalation study included 11 patients (median age, 7 years; range, 2-12; n = 6 men) with stage IV recurrent or refractory high-risk neuroblastoma.

Following lymphodepletion with cyclophosphamide and fludarabine, the children received an infusion of GD2-targeted 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 primary endpoint of the study. Secondary endpoints included CAR-iNKT persistence and human trafficking and anti-tumor activity as determined by Curie scores and International Neuroblastoma Response Criteria.

The results showed that lymphodepletion-related cytopenias were the most common treatment-related adverse reaction. Ten patients had grade 4 neutropenia, six developed grade 4 leucopenia, and six developed grade 4 lymphopenia. Only one patient had a Grade 3 infection after therapy.

One patient experienced Grade 3 neurotoxicity related to GD2-targeted CAR-iNKTs.

Efficacy results showed that 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 had clearance of bone marrow metastases.

“We began to document responses to therapy at dose level one, but perhaps the most exciting finding is that one of the children at dose level 4 achieved complete remission, which has now been going on for at least 4 months,” Heczey told Healio.

Researchers observed extension of CAR-iNKTs in all 11 patients, with peak extension between 2 weeks and 4 weeks after infusion.

Laboratory analysis showed a median of 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 the 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,” said Heczey, making it difficult to compare the efficacy of GD2-targeted CAR-iNKTs with commercially available therapies.

“We will continue to enroll patients and have expanded the trial to two more dose levels with the aim of increasing response rates while maintaining the excellent safety profile,” he told Healio.

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