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 tha triggers asthma is the IgE antibody. Many IgE molecules are bound to the surface of mast cells, which store large amounts of inflammatory mediators. When allergens bind and crosslink IgE, mast cells rapidly release inflammatory mediators and trigger asthma symptoms. Neutralizing IgE should therefore help ameliorate the disease. Omalizumab (Xolair) is the only such medication available today. It improves asthma control and reduces the frequency of attacks. The drug, however, works for only two to four weeks after administration and, thus, requires repeated administration. The drug costs close to $20,000 a year for an average adult patient and its use is recommended only for patients with relatively low levels of IgE. To suppress the level of IgE in a more permanent and cost-effective fashion, we propose to kill cells that produce IgE using T cells, a type of immune cell normally tasked to kill cells infected with viruses. In ths 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 suggest 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. Here, we propose to test an innovative design of receptors specific for allergy-producing cells, a key component for ACT-based therapy for asthma. To this end, we will 1) test the ability of these receptors to redirect T cells to specifically target cell lines producing IgE; 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, our design will pave the way for the development of a novel therapy with the potential to effectively control, or even cure, severe allergic asthma.
Severe allergic asthma is a highly debilitating and sometimes lethal disease that affects a large population, but often cannot be effectively managed by available medications. We have developed a novel approach to treat, and potentially, cure the disease by turning a patient's own immune system against a type of cell that produces a key mediator for the disease. We propose to test the design of a critical component of this approach using cells and animal models.
| Ward, Dana E; Fay, Brittany L; Adejuwon, Adebomi et al. (2018) Chimeric Antigen Receptors Based on Low Affinity Mutants of Fc?RI Re-direct T Cell Specificity to Cells Expressing Membrane IgE. Front Immunol 9:2231 |
