New gene therapy can be effective against fungal infections in cancer patients -
Sleeping Beauty and fungal infections - not two things one would normally associate together, but for immunocompromised cancer patients they may prove to be a useful combination.
a study conducted at the University of Texas MD Anderson Cancer Center used the Sleeping Beauty gene transfer system for modifying T cells in hopes of fighting against the major life-threatening infections caused by fungi Aspergillus invasive. The results of the study appear in today's issue of the Proceedings of the National Academy of Sciences (PNAS).
This type of gene therapy is already used to recognize tumor-associated antigens. Clinical trials at MD Anderson were the first to use Sleeping Beauty to customize T cells of the immune system to attack specific types of leukemia and lymphoma.
The Aspergillus study, led by Laurence Cooper, MD, Ph.D., pediatric professor in MD Anderson, shows that it can also be effective against fungal infections that can be fatal to immunocompromised patients such as those receiving a transplant of hematopoietic stem cells. Grafts are used to treat cancers of the blood or bone marrow such as leukemia, lymphoma and multiple myeloma.
The study of Cooper, which included collaboration with Dimitrios Kontoyiannis, MD, D.Sc., professor in the Department of Infectious Diseases, used a new method to inhibit the growth of fungi. The Sleeping Beauty system developed at the University of Minnesota, has offered a new approach to genetically modify T cells for human use which is being tested at MD Anderson for immunotherapy.
The team harnessed Sleeping Beauty to develop human T cells express receptors called chimeric antigen receptors (CARs) which forwarded the killing mechanism of T cells T cells displaying targeted RCA sugar molecules in the walls of Aspergillus cells, killing the fungus.
"Mortality associated with invasive Aspergillus still too high, especially in hematopoietic stem cell transplant recipients," said Kontoyiannis. "While antifungal treatments are available, clean weakening the patient's immune system and the emerging resistance to antifungal undermine the effectiveness of drugs. There is an urgent need for effective improvements immune strategies to treat opportunistic fungal infections in patients with severe and persistent immunodeficiency. "
Cooper said that new approaches for invasive Aspergillus are needed urgently. Since the use of CAR has led to an effective treatment of patients with malignant B cells, her team sought to determine whether a car could be developed to redirect T cells specific to fungi.
The gene Sleeping Beauty transfer system earned its name for its ability to "wake up" certain DNA sequences known as the name transposon. researchers find useful transposon as a way to modify the DNA in human cells. Sleeping Beauty transposon used in an approach "cut and paste" the relocation of genetic material.
"We have demonstrated a new approach to Aspergillus based immunotherapy redirecting specific T cells by a CAR recognizes the carbohydrate antigen on the fungal cell wall, "said Cooper. "T cells expressing CAR can be manipulated in an appropriate manner for human application, which allows the immunology translate in immunotherapy."
The approach has implications for genetically modify T cells to target carbohydrates and thus broaden their application in the experimental treatment of pathogens and malignancies.
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