WASHINGTON --- Immune-system T cells have been reprogrammed into regenerative stem cell-like memory (TSCM) cells that are long-lived, highly active "super immune cells" with strong antitumor activity, according to new research from Georgetown Lombardi Comprehensive Cancer Center.
The reprogramming involves a novel approach the researchers developed that inhibits the activity of proteins known as MEK1/2. Currently, several MEK inhibitors are used to effectively treat melanoma, but this study demonstrates that MEK inhibitors don't just target certain types of cancer cells, but rather, more broadly, reprogram T cells to fight many types of cancer.
The finding appears November 23, 2020, in Nature Immunology.
"Although immunotherapies have improved survival for cancer patients over recent years, survival rates remain sub-optimal. Therefore, there is an urgent need to develop novel, more effective anti-cancer immunotherapies," says Samir N. Khleif, MD, director of The Jeannie and Tony Loop Immuno-Oncology Laboratory and head of the team that conducted this research. "Our research shows that using drugs that have already been approved for human use may significantly enhance currently available immune therapeutic approaches, thereby leading to better and more durable anti-cancer responses."
The researchers performed experiments with human cells in the lab and then confirmed the effects of such an approach in mice. The investigators were able to not only identify a novel strategy to reprogram T cells into TSCM cells by using MEK1/2 inhibition, they were able to identify a novel molecular mechanism by which the TSCMs were induced.
The scientists found that reprograming T cells into TSCM can significantly improve T cell therapies for cancer patients. T cell therapy is a process that is widely used in specific cancers and in clinical trials, where immune-system T cells are separated out from a patient's blood, engineered and expanded with special tumor-targeting capabilities and infused back into the patient to fight cancer. In their experiments, human T cells were reprogrammed with MEK inhibitors into TSCM; additionally, when treating mice with MEK inhibitors, the reprogramming of T cells was also found to induce effective TSCMs.
"Stem cell research has played a vital role this century in enhancing the progress against many diseases. Recent public and private support for stem cell therapy is very gratifying," says Khleif. "Having stem cell research-specific funding from both governmental and private funders will greatly help accelerate the development of this under-utilized area of research."
Now that MEK inhibitors have been shown to enhance an anti-tumor immune response, the researchers are starting to look into designing clinical trials to test their research approach in cancer patients. "Our approach is quite novel and we're anxious to see it put to use in the clinical arena as soon as possible," concludes Khleif.
###
In addition to Khleif, authors of the manuscript at Lombardi include Vivek Verma?, Nazli Jafarzadeh, Subhadip Kundu, Zhinuo Jiang?, Fatmah Alolaqi, Pankaj Gaur, Mikayel Mkrtichyan, Jose Lopez, Rahul Nandre, and Seema Gupta?. Other authors include Shannon Boi? and Benjamin Youngblood Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN; Yiping Fan, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN; Peng Zeng, Paulo C. Rodriguez, and Shamim Ahmad, Georgia Cancer Center, Augusta University, Augusta, GA; Simon T. Barry, Viia E. Valge-Archer and Paul D. Smith, Bioscience, Early Oncology, AstraZeneca, Cambridge, UK; and Jacques Banchereau?, The Jackson Laboratory for Genomic Medicine, Farmington, CT.
Khleif and Verma are named inventors on the patent application titled "Induced Stem Memory T-cells and Methods of Use Thereof" that relates to this research.
Khleif would like to acknowledge Tony and Jeannie Loop for their generous and ongoing support of his research. Additionally funding for this work provided by NIH grants R01-CA237311 01A1, R01-CA184185, R01-CA233512 and P30-CA076292 and a Florida Department of Health grant no. 20B04.
About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute (NCI) as a comprehensive cancer center. A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington D.C. area. It serves as the research engine for MedStar Health, Georgetown University's clinical partner. Georgetown Lombardi is also an NCI recognized consortium with John Theurer Cancer Center/Hackensack Meridian Health in Bergen County, New Jersey. The consortium reflects an integrated cancer research enterprise with scientists and physician-researchers from both locations. Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic, translational and clinical research, patient care, community education and outreach to service communities throughout the Washington region, while its consortium member John Theurer Cancer Center/Hackensack Meridian Health serves communities in northern New Jersey. Georgetown Lombardi is a member of the NCI Community Oncology Research Program (UG1CA239758). Georgetown Lombardi is supported in part by a National Cancer Institute Cancer Center Support Grant (P30CA051008). Connect with Georgetown Lombardi on Facebook (Facebook.com/Georgetown Lombardi) and Twitter (@LombardiCancer).
Journal
Nature Immunology