Development of a chemically regulated immunotherapy for B-cell malignancies

Project Summary Abstract T cell therapies show incredible promise as treatments for previously intractable relapsed and refractory hematologic cancersUnfortunatelythe incredible efficacy of these therapies has been accompanied by lifethreatening side effects caused by overactivation of the immune systemincluding cytokine release syndrome and neurotoxicityIn some clinical trialsthese side effects have resulted in patient deathsFor T cell therapies to reach their full potential and be applied to a wide range of targets and types of cancerit will be critical to improve their safety profilesOne method to improve safety is to incorporate molecular switches into T cell therapies that would allow for precise control over the timing and magnitude of T cell activityChemically induced dimerizersCIDshave proven to be powerful tools for controlling cellular signaling pathways andin turnbiological activityUnfortunatelyclassical CID systems have some molecular properties that make them undesirable candidates for switches in human T cell therapiesSoteria Biotherapeutics seeks to overcome these limitations using antibody based chemically induced dimerizersAbCIDsa new type of molecular switch that was specifically designed for use in human cell therapiesBy integrating an AbCID based molecular switchthe activity of a T cell therapy will be controllable by a physician through administration of a small molecule drugThis will allow the physician to increase T cell activity when more efficacy is needed and reduce activity when side effects become apparentIn this SBIR Phase I projectwe propose to optimize our chemically regulated AbCID safety switch design and implement it in an improved T cell therapy for B cell malignanciesSpecific aims will focus on optimization of AbCID expression in a mammalian cell expression systemevaluation of chemically regulated T cell activation and cytotoxicity with in vitro primary cell modelsand quantification of the in vivo pharmacokinetic properties of the lead AbCID T cell therapy in miceCompletion of these research aims will directly increase the commercial viability of our lead AbCID based T cell therapy product and will lay the groundwork for in vivo efficacy experiments in mouse models in a Phase II projectThe successful commercial development of an AbCID based T cell therapy will introduce a novel therapeutic option for the treatment of Bcell malignancies and will improve outcomes for patients Project Narrative The promising field of T cell based cancer therapies is hindered by safety concernsincluding patient deaths in clinical trialsThe project described in this proposal involves the development of safer and more efficacious Tcell therapies by using novel small molecule gated biological switches to control T cell activationSuccessful completion of this project will advance the development of new T cell therapies for the treatment of human cancers which will ultimately improve outcomes for patients with B cell malignancies