COBRE Investigator Zhengyu (Mark) Ma Awarded NIH R21 Grant for Innovative Asthma Study.
On June 15, 2015 Mark Ma was awarded a new 2-year grant (R21AI119841) for a project entitled “Redirect T Cell Specificity to IgE-Expressing B Cells for Severe Allergic Asthma.”
Severe allergic asthma is a highly debilitating and sometimes lethal disease that affects more than one million people in the U.S. The disease is triggered by allergic immune reactions to normally harmless substances in the environment, such as pollens and dust mites. The reactions cause inflammation of the airways that increases the contractility of the surrounding smooth muscles. This leads to narrowing of the airway and the characteristic symptoms of breathlessness, wheezing and cough, together with episodes of marked worsening of symptoms known as asthma attacks. The disease often cannot be effectively controlled with available medications. Patients require large doses of corticosteroids in combination with other potentially toxic medications and still may suffer from serious symptoms and frequent life-threatening asthma attacks. More effective therapeutic approaches are urgently needed to improve patients’ quality of life.
A key player in the allergic reaction that triggers asthma is the IgE antibody. When allergens bind and crosslink IgE, mast cells rapidly release inflammatory mediators and trigger asthma symptoms. A new drug, omalizumab (Xolair), neutralizes the IgE and improves asthma control and reduces the frequency of attacks. However the drug is only effective if levels of IgE are low, it requires repeated administration, and is expensive. To suppress the level of IgE in a more permanent and cost-effective fashion, Dr. Ma proposes to kill cells that produce IgE using T cells, a type of immune cell normally tasked to kill cells infected with viruses. In this approach, called “adoptive T cell therapy” or ACT, T cells isolated from a patient are genetically modified to express engineered receptors that recognize the harmful cells. The T cells are then infused back into the same patient to kill the target cells. Exciting breakthroughs have been made using ACT against cancer. A number of leukemia patients treated in clinical trials with ACT have achieved complete remission. Past research and recent developments using this approach suggests that ACT should be safe and effective for long-term control of severe allergic asthma, mainly thanks to the ability of modified T cells to persist over a long period of time, in some cases for more than a decade. Dr. Ma will test an innovative design of receptors specific for allergy-producing cells, a key component for ACT-based therapy for asthma. To this end, he will 1) test the ability of these receptors to redirect T cells to specifically target cell lines producing IgE; and 2) test the potency and specificity of these receptor using freshly isolated primary human T cells and IgE producing cells, and using animal models. If proven effective, this design will pave the way for the development of a novel therapy with the potential to effectively control, or even cure, severe allergic asthma.