A phase I clinical trial of CAR-NKT cell therapy shows promising results in patients with neuroblastoma


Researchers at Baylor College of Medicine/Texas Children’s Cancer Center and collaborating institutions report interim results from a phase I human clinical trial evaluating the safety, antitumor activity, and immunogenic properties of transgenic natural killer T (NKT) cell immunotherapy for neuroblastoma, Childhood tumor most commonly seen in the adrenal gland. The study was published in Nature medicine It shows that the treatment was well tolerated, and the researchers noted early evidence of potent antitumor activity.

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

In the new article, the researchers describe results obtained in 12 patients with relapsed stage 4 neuroblastoma that was resistant to other treatments. They found that the treatment was safe for all 12 patients at four dose levels; No dose-specific toxicity has been reported. Three patients showed an objective response to treatment, including a 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 that did not reach partial response criteria.

We are encouraged by the evidence of antitumor activity observed in several patients, especially since this trial is still in the dose-escalation phase.”

Dr. Andras Hicksie, co-author and associate professor of pediatrics–hematology-oncology at Baylor

He is also a member of the Center for Advanced Cellular Therapy at Children’s Cancer Center of Texas, Cell and Gene Therapy Center of Baylor and Texas Children’s and Dan L. Duncan Comprehensive Cancer Center of Baylor.

Previous studies from the team showed that NKT cells can localize to tumor sites in preclinical models. This experiment validated those observations in humans. In addition, the researchers found a relationship between higher antitumor activity and the in vivo proliferation of cast CAR-NKT cells.

“We can’t always predict how much NKT cells will expand in vivo after infusion,” said Dr. Leonid Metelitsa, co-author and professor of pediatrics-hematology-oncology at Baylor. “In this study, we found that the biomarker CD62L expressed in stimulating NKT cells, which we identified in our preclinical work, is predictive of higher NKT cell expansion in vivo and antitumor activity in patients.” Metelitsa is also the director of the Center for Advanced Cellular Therapy at The Children’s Cancer Center of Texas and a member of the Cell and Gene Therapy Center at Baylor and Texas Children’s and the Dan L Duncan Comprehensive Cancer Center at Baylor.

Another important finding revealed the presence of a regulatory gene in NKT cells that may affect NKT cells effectiveness treatment. By leveraging the polyatomic platform of key collaborator Immunai, Inc. Baylor researchers found that upregulation of the anti-proliferation factor 1 (BTG1) BTG gene in cast CAR NKT cells signals cell exhaustion and limits CAR NKT cell functional activity. Conversely, engineering reduction of BTG1 expression in CAR NKT cells enhanced their therapeutic activity against neuroblastoma in a mouse model.

Metelitsa said, “This study provides promising preliminary evidence of the antitumor activity of GD2 CAR NKT cells against neuroblastoma. This inspires hope that novel immunotherapy strategies, such as those studied in this trial, will eventually improve outcomes for children with neuroblastoma. nervous.”

Based on the safety profile and promising evidence of antitumor activity, this trial was expanded to include two higher dose levels of GD2 CAR NKT cells. After completion of these additional cohorts, a phase II trial is planned to evaluate the antitumor activity of this novel immunotherapy.

Other contributors to this work include Shen Xu, Amy N. Courtney, Jingwen Tian, ​​Gabriel A. Barrajan, Lingye Gu, Claudia Martinez Amador, Nisha Gateway, Purva Rathi, Michael S Wood, Yanchuan Li, Chunshao Zhang, Thorsten Demberg, Erica J.D. Piero, Andrew C. Scher, Huimin Zhang, Birju Mehta, Sachin G. Thakar, Bambi Greeley, Tao Wang, Brian de Weiss, Antonino Montalbano, Meena Subramaniam, Chenling Xu, Chirag Sachar, Daniel K. Wells and Gianpietro Dutti. The authors are affiliated with the following institutions: Baylor College of Medicine, Texas Children’s Hospital, Cincinnati Children’s Hospital, The Emonay Corporation, and the University of North Carolina at Chapel Hill.

This work was supported by Alex’s Lemonade Stand for Childhood Cancer, the St. Baldrick’s Foundation, American Cancer Society and Athenex, Inc. For a full list of author affiliations and funding for this work, please refer to the publication.


Journal reference:

Hickzy, A.; et al. (2023). Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated interim results from Phase I trial. Nature medicine. doi.org/10.1038/s41591-023-02363-y.


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