Inducible immune resistance to protect lungs earns prestigious support

Immunology research to investigate the mechanisms of a new aerosol treatment, which induces an innate immune response to protect against pathogens that cause pneumonia, asthma, and other lung diseases, has earned major funding from the National Heart, Lung, and Blood Institute.

“This research will help protect patients who are most vulnerable to pneumonia, especially patients with cancer,” said Scott Evans, M.D., the principal investigator for this research program and an associate professor of Pulmonary Medicine at The University of Texas MD Anderson Cancer Center. Pneumonia is a major cause of death in patients with leukemia, and 10% of admissions at MD Anderson are associated with pneumonia as the main diagnosis or as a complication.

Also known as the Emerging Investigator Award, the R35 grant awarded to Evans supports a research program rather than a specific research project. The award is only available to principal investigators who have already received two R01 grants or the equivalent from the National Institutes of Health and recognizes the quality and importance of the proposed work.

This award, $6.2 million over 7 years, will support Evans’ immunology research program based on his previous studies in harnessing the immune system to control asthma, pneumonia and chronic lung disease.

Immunology research to stifle bacteria, viruses

With every breath, microbes enter the lungs, and the body deploys nonspecific innate immune system responses via epithelial cells lining the airways. Evans and his team designed a synthetic aerosol, a combination of two synthetic ligands that bind Toll-like receptors, to stimulate these mucosal responses to protect against respiratory pathogens, such as bacteria, viruses, or fungi, before they are well-established in the lungs. He calls this process inducible resistance.

This synthetic aerosol has demonstrated protection against numerous pneumonia-causing pathogens in mouse models and in other animals. Even in immunocompromised mice with leukemia, the aerosol protects against pneumonia. In the asthma studies, the aerosol not only protects against acute virus-induced injury, but also has long-term immunomodulatory effects that prevent allergic asthma.

The aerosol is currently being developed by Pulmotect, a company founded by Evans and other MD Anderson physicians, and is in a phase 2 clinical trial. The trial complies with MD Anderson conflict-of-interest policies.  

The R35 grant will support four research areas. “We do not fully understand the underlying mechanisms of inducible resistance; in fact, some aspects of this treatment are counterintuitive,” Evans explains.

The first objective is to better understand the signaling events initiated by the aerosol treatment. The aerosol is composed of two ligands that individually are not protective and would not seem to work together; however, these molecules synergistically induce protection. As part of this effort, the research team also will investigate novel signaling pathways and receptors to identify better or more efficient treatment options.

Identifying the pathogen-killers

The second objective is to investigate the mechanisms by which the aerosol induces production of reactive oxygen species. Reactive oxygen species usually are associated with tissue injury, but the reactive oxygen species induced by the aerosol have protective antimicrobial effects. Evans and his team were the first to report that the aerosol-induced reactive oxygen species are produced from two different sources in epithelial cells: dual oxidases and mitochondria.  

The third objective is to better understanding which aerosol-induced molecules actually kill pathogens. The broad protection induced by the aerosol is associated with generation of numerous potentially antimicrobial molecules, but perhaps only a small set of the induced molecules may be sufficient for the same effects.

“In this endeavor, we also hope to extend the application of the aerosol to preventing or treating tuberculosis,” he said.

In the fourth objective, the research team will investigate the mechanisms underlying the surprising finding that inducible resistance to viral asthma confers long-term immunomodulatory effects against allergic asthma.

“My goal is to translate this technology into the clinic to protect patients from pneumonia and other lung diseases during peak vulnerability, such as when patients with cancer receive chemotherapy treatments,” he said.