The genetically engineered immune cells successfully target specific cancer cells that may be responsible for the relapse of acute myeloid leukemia (AML), a type of blood cancer, and have been shown to be effective in animal models of the disease, according to a researcher. preclinical study conducted by researchers at Weill Cornell Medicine. The new cell therapy, currently being tested in phase 1 clinical trials, may ultimately help AML patients stay cancer-free.
In the studypublished on April 28 in Nature Communication, the researchers used an approach in which immune cells called T cells are directed to produce proteins called chimeric antigen receptors, or CARs, which allow T cells to recognize specific markers on cancer cells. In this case, CAR is a receptor that binds to the CD123 molecule on leukemia stem cells, allowing T cells to seek out and attack cancer cells.
“Leukemia stem cells are a subset of leukemia cells that are resistant to standard chemotherapy drugs and can cause disease relapse,” said the co-senior author. Dr. Monica L. Guzman, Associate Professor of Pharmacology in Medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “CD123 is a marker found on leukemia stem cells, and my lab has been working on designing mouse models to test new CD123-targeted anti-leukemia therapies.”
Although there are effective therapies to treat LAM, the disease eventually returns in most patients, even after achieving complete remission. By engineering T cells to express a CAR that targets CD123, Dr. Guzman and his colleagues hope to rid patients of any remaining leukemic stem cells. CAR T cells are an attractive cancer therapy because they can be grown in large numbers in the laboratory.
“The CAR T cells, called UCART123 cells, used in this study have several very important characteristics,” said Dr. Guzman. “They target a leukemia stem cell marker, they’re derived from healthy donors and manufactured to be ‘off the shelf’ and ready to use for patients when needed, they’re specifically designed to try to minimize toxicity, and they can be eliminated using a drug called rituximab if they overgrow.
When the team tested UCART123 cells in a mouse model of AML, they found that the therapy effectively killed leukemic cells and prolonged survival. The scientists also designed an ultra-sensitive monitoring strategy to detect any residual cancer cells and assess the persistence of UCART123 cells. Finally, they demonstrated that UCART123 cells have specificity against leukemia cells, with minimal toxicity to normal blood cells in mice.
Preclinical results have led to a phase 1 clinical trials UCART123 in patients with relapsed/refractory AML at multiple sites across the United States, including NewYork-Presbyterian/Weill Cornell Medical Center. “These laboratory data strongly support the ongoing clinical trial,” said the trial’s principal investigator and co-lead author. Dr. Gail RobozDirector of the Clinical and Translational Leukemia Program at Weill Cornell Medicine and Oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
“The results of the preclinical study suggest that UCART123 cells are highly selective and specific in targeting AML, and we anticipate that the techniques developed in Dr. Guzman’s lab will help us monitor patients on treatment with UCART123 and optimize their chances of success,” said Dr. Roboz, who is also a professor of medicine in the Division of Hematology and Medical Oncology and a member of the Meyer Cancer Center at Weill Cornell Medicine.
Reference: Sugita M, Galetto R, Zong H, et al. Allogeneic TCRαβ-deficient CAR T cells targeting CD123 in acute myeloid leukemia. Nat Common. 2022;13(1):2227. do I: 10.1038/s41467-022-29668-9
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