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Genetically engineered CAR natural killer T cells showed strong antitumor activity against neuroblastoma and have proven to be safe, nontoxic, and well-tolerated in trial participants.

CAR NKT Cell Therapy Shows Promise Against Neuroblastoma in Phase 1 Trial

Trial validates localization of NKT cells to tumor sites in humans and points to high in vivo antitumor activity

Baylor College of Medicine
Published:May 15, 2023
|2 min read
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HOUSTON, TX — Researchers at Baylor College of Medicine (Baylor)/Texas Children’s Cancer Center and collaborating institutions report interim results from a first-in-human Phase 1 clinical trial evaluating the safety, antitumor activity, and immunological characteristics of a genetically engineered natural killer T (NKT) cell immunotherapy for neuroblastoma. The study published in Nature Medicine shows the treatment was well tolerated, and researchers observed early evidence of strong antitumor activity.

NKT cells were modified to express a GD2-specific chimeric antigen receptor (GD2 CAR), which enables the immune cells to target a molecule found on the surface of neuroblastoma cells, and interleukin-15 (IL-15), a natural protein that supports NKT-cell survival. In a previous study, the authors reported interim results from the first three children enrolled in this trial.

In the new article, investigators describe the results obtained in 12 patients with stage 4 relapsed neuroblastoma, resistant to other therapies. They found that the therapy was safe for all 12 patients on four dose levels; there were no reported dose-limiting toxicities. Three patients showed an objective response to treatment, including one complete response and two partial responses. Two other patients also showed evidence of antitumor activity such as clearance of bone marrow involvement or reduction of metastatic tumor burden not reaching partial response criteria.

“We are encouraged by the evidence of antitumor activity that has been observed in several patients, particularly since this trial is still in the dose escalation phase,” said Andras Heczey, MD, co-corresponding author and associate professor of pediatrics–oncology at Baylor.

Previous studies from the team have shown that NKT cells can localize to tumor sites in preclinical models. This trial has validated those observations in humans. Additionally, researchers found a correlation between higher antitumor activity and in vivo proliferation of infused CAR NKT cells.

“We cannot always predict the extent of NKT cell expansion in vivo after infusion,” said Leonid Metelitsa, MD, PhD, co-corresponding author and professor of pediatrics–hematology/oncology at Baylor. “In this study, we found the CD62L [L-selectin] biomarker expressed on the infused NKT cells, which we identified in our preclinical work, is predictive of both higher NKT cell in vivo expansion and antitumor activity in patients.” 

Another important finding revealed a regulatory gene in NKT cells that may impact treatment efficacy. Leveraging the multi-omic platform of key collaborator, Immunai, Inc., Baylor researchers found that upregulation of the BTG anti-proliferation factor 1 (BTG1) gene in infused CAR NKT cells is indicative of cell exhaustion and restricts CAR NKT cell functional activity. “This study provides promising initial evidence of antitumor activity of GD2 CAR NKT cells against neuroblastoma. This inspires hope that novel immunotherapeutic strategies, such as the one studied in this trial, will ultimately improve the outcomes for children with neuroblastoma,” said Metelitsa.

Based on the safety profile and promising evidence of antitumor activity, this trial has been expanded to include two higher dose levels for the GD2 CAR NKT cells. Following the completion of these additional cohorts, a Phase 2 trial is planned to assess the antitumor activity of this novel immunotherapeutic.

- This press release was originally published on the Baylor College of Medicine website