Chimeric antigen receptor (CAR) T cell therapy for severe allergic diseases.

PROJECT SUMMARY/ABSTRACT Severe allergic diseases afflict an increasingly large population and significantly impact the patients' quality of life. Approximately 25 million Americans suffer from asthma; 5-10% from severe or uncontrolled asthma. Around 32 million Americans have food allergies; 8%, or 5.6 million, are children. An estimated 0.5% to 5% of adults and 1.8% of children live with chronic urticaria. There are currently no cures for severe allergic diseases. High-dose corticosteroids are traditionally used to manage symptoms but are associated with significant side effects. While antibodies targeting mediators of allergic responses have recently emerged as alternatives, life- long administration is required. Progress has been made in oral immunotherapy for peanut allergy but treatment is not without significant adverse events, and it does not negate continued food avoidance after a five- to nine-month dose escalation course of treatment. Therefore, novel approaches that can achieve long- term suppression of symptoms with a single treatment are urgently needed. Recent decades have seen the successful development of T cells engrafted with chimeric antigen receptors (CAR T cells) for treating hematologic malignancies, where the CAR directs T cells to recognize and kill cancer cells. Importantly, a single infusion has been shown to result in the persistence of functional CAR T cells for more than 10 years. Thanks to intensive research efforts from academia and the pharmaceutical industry, the safety profile of CAR T cells is continuously improving, and the cost of manufacturing is expected to drop significantly. As the result, CAR T cell therapy is being actively developed for non-cancer diseases such as autoimmune diseases. We have developed two innovative CAR T cell designs that are capable of efficiently and specifically killing B cells producing IgE, the key mediator of allergic immune responses. The results, however, were all obtained from in vitro experiments using cultured cells. In this Phase I project, we propose to determine the potency of CAR T cells in immunocompromised mouse models that are relatively straightforward to establish. Specifically, we will determine the ability of CAR T cells to eliminate IgE-producing human U266 myeloma cells in NSG mice (Aim 1), and to eliminate IgE-producing primary human B cells in PBMC-NSG mouse models. Data from this project will pave the way for a phase II study that tests the potency as well as the toxicity of our CAR T cells in more physiological settings, including immunocompetent or humanized mouse models. Our long-term goal is to develop a safe and cost-effective CAR T cell therapy that can achieve long-term (years to decades) suppression of allergic symptoms, or even a cure for severe allergic diseases, with a single treatment.