Immunotherapy for Neuroblastoma Using Off-the-Shelf Engineered NKT Cells
Abstract
Neuroblastoma (NB) is the second most common solid tumor in children, and less than half of those with high-risk disease survive long-term with currently available therapies. Therefore, there is an urgent need for new and effective therapies that do not cause toxic side-effects. We use a unique type of immune cell known as the natural killer T (NKT) cell as a platform for developing novel immunotherapies to treat such high-risk NB cases. NKTs inherently home to tumor sites, and their presence in primary tumors is associated with favorable outcomes in NB patients. We modify NKT cells to express an engineered protein–a chimeric antigen receptor (CAR)–that endows the NKT with a sensor to detect tumor cells expressing a specific cancer antigen and, once detected, activates the NKT to orchestrate an antitumor response. We have recently shown in an ongoing phase I clinical trial that CAR-NKTs specific for a NB antigen known as GD2 ganglioside can expand in patients, localize to tumor sites, and mediate regression of bone metastatic lesions. Here, we propose work that will further improve the efficacy of this GD2-specific CAR-NKT immunotherapy by: (1) fine-tuning the CAR construct, (2) improving the therapeutic window for CAR-NKTs once inside the patient, and (3) optimizing the conditions in which the cells are grown prior to treatment. To fine-tune the CAR, we will focus on the component of the construct responsible for activating the NKT, selecting a candidate domain that mediates the strongest activation. To address the second aim, we will further modify the optimized CAR construct such that it will reduce the visibility of the NKT to the receiving patient’s immune system. This will extend the longevity of CAR-NKTs once inside the patient by limiting or delaying immune rejection. Crucially, this will also allow for off-the-shelf CAR-NKT treatments grown from healthy donors, reducing the time-to-treatment and improving the consistency and quality of the therapeutic product. Finally, we will test new culture conditions for growing NKTs that have the most promise for potent antitumor activity in patients. The goal of these studies is to refine our existing CAR-NKT immunotherapy from multiple angles at once to improve the clinical outlook for a greater number of NB patients with relapsed and refractory disease. The ability to use NKTs from healthy donors to generate off-the-shelf therapeutic products is likely to improve the overall product quality and clinical experience. In the long-term, we hope to develop a safe, widely used, and readily available new therapy for children with NB and eventually modify it to reach patients with other solid tumors. This work serves to benefit active-duty Service Members, Veterans, and other military beneficiaries most immediately by improving a direly needed therapy for a challenging pediatric cancer that may impact the children of military families. Looking forward, this therapy has great promise for treating other solid tumors and may directly benefit affected Service Members in the future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110344
Entities
People
- Leaonid Metelitsa
Organizations
- Baylor College of Medicine
- United States Army