Scientists at St. Jude Children’s Research Hospital developed a strategy to improve the ability of engager (ENG) T cells to kill acute myeloid leukemia (AML). The approach showed promise in preclinical models against hard-to-treat relapsed disease. The results were pre-published today in the journal Haematologica.
Despite advances in pediatric leukemia treatment, clinical outcomes remain poor for relapsed AML. Researchers are exploring multiple potential therapies. One approach uses ENG T cells. These cells are immune cells that have been modified to secrete antibodies that bring T cells and cancer cells together, promoting tumor killing. Scientists at St. Jude developed a way to improve on ENG T cells, making the therapy more efficient and effective. They added a co-stimulation system controlled by an activating drug to the ENG construct. Preclinical findings show that the approach increased the anti-AML activity of ENG T cells.
“We’re basically having the T cells express a battery that we can control,” said corresponding author Paulina Velasquez, M.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “ENG T cells secrete a protein that allows the T cells to kill leukemia. In this case, when they also express the controlled battery that we added, we are getting extra mileage out of these cells.”
ENG T cells for AML improve with inducible co-stimulation
Regular ENG T cells quickly become exhausted after encountering tumor cells, ending their therapeutic effect. The St. Jude team found that co-stimulation can counteract exhaustion, making the ENG T cells work better. The team tested inducible co-stimulatory proteins that only function in the presence of a small molecule (drug). The drug gives the researchers more control, even after the ENG T cells are infused into a patient. In addition to preventing exhaustion, this system can serve as an important safety feature because the inducible co-stimulation can be easily curtailed if the drug is stopped.
Velasquez and her team tested whether expression of inducible co-stimulatory proteins that activate MyD88, CD40, or both MyD88 and CD40 immune pathways in ENG T cells improves their antitumor activity. AML-specific ENG T cells in which both signaling pathways were activated outperformed their unmodified counterparts or ENG T cells in which only one of the pathways was active in laboratory studies as well as animal models.
ENG T cells - a promising alternative to treat relapsed AML
At present there are many genetic approaches to render T cells specific for AML. This includes, for example, expression of chimeric antigen receptors (CARs). In contrast to CAR T-cell therapy for acute lymphoblastic leukemia (ALL), the clinical experience with AML-specific CAR T cells has presented challenges.
“Based on the results of our study, ENG T cells that express inducible co-stimulatory proteins, might be a promising alternative to other AML-specific T-cell therapy approaches that are actively being explored,” Velasquez said. “There are currently no clinical trials with ENG T cells, but our study should provide the impetus to explore the safety and efficacy of AML-specific ENG T cells in early phase clinical studies in the future.”
Authors and funding
The study’s first author is Abishek Vaidya, formerly of St. Jude. The other authors are Xiya Wu, Sujuan Huang, Nikhil Hebbar, Unmesha Thanekar, Cheng Cheng and Stephen Gottschalk, of St. Jude; Erin Doherty, Baylor College of Medicine; and Challice L. Bonifant, Johns Hopkins Medicine.
The study was supported by grants from by the National Institutes of Health (P01CA096832 and R50CA211481), National Cancer Institute (P30CA021765), the Leukemia Lymphoma Society (6483-16), the Cancer Prevention Research Institute of Texas (RP160693), St. Baldrick’s Foundation, the Assisi Foundation of Memphis, and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.