Immunotherapies, including biologics and cell-based therapies, are emerging as highly promising and effectivestrategies for the treatment of cancer. Accompanying the great potential of these approaches are continuingchallenges, including 1) untargeted global immune modulation associated with biologics, resulting in seriousside effects; 2) challenges in scalability of cell-based therapies (e.g., Adoptive/CAR-T therapies) andbispecifics, 3) lack of differentiation, as most efforts are focused on relatively few therapeutic targets andmechanisms; and 4) the lack of flexible platforms to rapidly and efficiently target new indications andmechanisms. To address these challenges, we describe a novel class of soluble precision biologics for thetreatment of cancer. Our approach manipulates antigen-specific (i.e., clonal) lymphocyte populations bycovalently linking single chain peptide-MHC (sc-pMHC) and costimulatory molecules in a manner thatrecapitulates the proximity, orientation and overall organization experienced at the immunological synapse.The sc-pMHC unit serves to selectively target distinct T cell clones for the delivery of a modulatory domain thatcan represent any potential costimulatory function. These constructs are generated as Fc-fusion proteins (i.e.,IgG) for enhanced avidity and stability. This combined targeting:modulation construct is referred to as synTac(artificial immunological Synapse for T-cell Activation). Using this strategy we have already demonstratedclonal-specific T cell proliferation and activation in vitro, and clonal T cell expansion in vivo. The extremespecificity associated with these reagents eliminates the extensive side effects associated with currently usedimmunotherapeutics and the highly modular design supports a wide range of indications and therapeuticmechanisms via substitution of the disease relevant peptide epitope and comodulatory modules, respectively.The proposed work focuses on the continued development of the synTac platform for the selective in vivoexpansion of CTLs that specifically target malignancies.
Our Specific Aims are:
AIM 1 : Continued development of the synTac fusion protein platform, including the exploration of newpresentation platforms with altered stoichiometries and new comodualory domains.
AIM 2 : Assessment of affinity and overall molecular organization on synTac efficacy to realize newinsights into cell surface receptor signaling and new strategies for controlling synTac therapeutic activity.
AIM 3 : Application of synTacs to specific disease regression models to investigate synTac function inmelanoma and pancreatic cancer, using disease and tumor regression models, including HLA-A2 transgenics.The continued success of this program promises to deliver a unique and highly flexible platform for the rapiddevelopment, evaluation and implementation of a novel family of biologics to treat a range of indications via anumber of distinct mechanisms, and position us to initiate clinical trials for pancreatic ductal adenocarcinoma.
Existing immunotherapies offer remarkable opportunities for the treatment of cancers; autoimmune diseaseand infectious diseases; however; these untargeted therapies elicit ?global? and indiscriminant modulation (i.e.;global stimulation or inhibition) of immune function; predisposing patients to a host of serious and potentiallylife threatening side effects. We are developing a novel highly specific set of therapeutics to treat a wide rangeof malignancies without undesirable side effects.
