Real-life Sleeping Beauty is being used for the first time to combat fungal infections and improve leukemia and lymphoma treatment in the laboratory of Laurence Cooper, MD, PhD, at The University of Texas MD Anderson Cancer Center. Dr. Cooper’s study, authored by a number of researchers at MD Anderson and The University of Texas Graduate School of Biomedical Sciences, was published online ahead of print in Proceedings of the National Academy of Sciences.
“While antifungal therapies are available, the patient’s own weakened immune system and emerging resistance to antifungals compromise the drugs’ effectiveness,” explained Dimitrios Kontoyiannis, MD, ScD, a collaborator in the Department of Infectious Diseases, in a news release. “There is a dire need for effective immune enhancements strategies for the treatment of opportunistic fungal infections in patients with profound and persistent immune defects.”
To address this need, the team engineered T-cells to recognize sugar molecules in Aspergillus, a type of fungus that can cause life-threatening infections, cell walls to kill the fungus. This was accomplished using the Sleeping Beauty gene transfer system developed at University of Minnesota and used previously by MD Anderson for gene therapy with blood cancer. Sleeping Beauty awakens transposon DNA sequences and relocates genetic material.
Specifically, Dr. Cooper’s team redirected the killing machinery of T-cells by inducing expression of chimeric antigen receptors (CARs), which recognize Aspergillus. “We demonstrated a new approach for Aspergillus immunotherapy based on redirecting T-cell specificity through a CAR that recognizes carbohydrate antigen on the fungal cell wall,” said Dr. Cooper. “The T-cells expressing the CAR can be manipulated in a manner suitable for human application, enabling this immunology to be translated into immunotherapy.”
This technique may have great utility for patients with blood and bone marrow cancers–such as leukemia, lymphoma, and multiple myeloma–who are receiving hematopoietic stem cell transplants. “Mortality associated with invasive Aspergillus remains unacceptably high, especially in hematopoietic stem cell transplant recipients,” said Dr. Kontoyiannis. Already, clinical trials at MD Anderson evaluated Sleeping Beauty-engineered immune system T-cells in attacking leukemia and lymphoma.
The approach used by the present study is similar to one previously approved by the Food and Drug Administration for manufacturing CD19-specifc CAR-expressing T-cells, suggesting that CAR T-cells may be “a clinically appealing strategy to enhance immunity for opportunistic fungal infections,” according to the study abstract.