In the past, Mass General Brigham scientists have showed that live cancer cells can be gene edited and engineered to not only target tumor cells directly but also help the immune system find and destroy cancer cells. In a paper appearing in the January 16 issue of the Journal of Clinical Investigation, these researchers now present a new “safety switch” that uses RIPK3, an enzyme that plays a key role in programmed cell death. Their findings indicate that this safety system could enhance therapeutic impact and improve immune activity against tumors.
“Our study shows that a new generation of safety switches hold the promise of improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies,” said corresponding author Khalid Shah, MS, PhD, director of the Center for Stem Cell and Translational Immunotherapy (CSTI) and the vice chair of research in the Department of Neurosurgery at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. Shah is also faculty at Harvard Medical School and Harvard Stem Cell Institute (HSCI). “Our work continues to build on a simple idea: to take cancer cells and transform them into cancer killers and vaccines.”
The safety switches developed by Kok-Siong Chen, PhD, the first author of the study, Khalid Shah and colleagues can be activated to instantly kill the cells after they have served their therapeutic purpose. Many of the safety switches in use today may inadvertently dampen the immune response to cancer cells. In contrast, the RIPK3-driven necroptotic system designed by Shah and his colleagues is designed to stimulate antitumor response while simultaneously inducing cell death. The team showed that, compared to existing safety switches, their new system inhibited tumor growth, improved survival outcomes in mouse models, improved long-term antitumor immunity, and reinvigorated immune cells.
The researchers note that while they tested their safety switch in the context of cancer, their approach could be implemented in cells used in other forms of immunotherapy. Future research could examine their potential use in cell therapies that use T cells, NK cells, stem cells, macrophages and others. The authors also note that future studies are needed to examine immune population dynamics and changes across cell types and intercellular interactions.
“We never lose sight of the patient throughout all of the technical work that we do,” said Shah. “Our goal is to take an innovative but translatable approach so that we can develop effective and safe cell-based therapy that ultimately will have a lasting impact in medicine.”
Authorship: In addition to Chen and Shah, Mass General Brigham authors include Sarah Manoury-Battais, Nobuhiko Kanaya,1Ioulia Vogiatzi, Paulo Borges, Sterre J. Kruize, Yi-Ching Chen, Laura Y. Lin, Filippo Rossignoli, and Natalia Claire Mendonca.
Disclosures: Shah owns equity in and is a member of the Board of Directors of AMASA Therapeutics, a company developing stem cell-based therapies for cancer.
Funding: This work was supported by the National Institutes of Health (grant R01-NS121096).
Paper cited: Last name, First initial et al. “An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety” Journal DOI: 10.1172/JCI181143
