Small-molecule agonists of the RIG-I-like receptor pathway as cancer immunotherapeutics

PROJECT SUMMARY Cancer immunotherapy is predicated on overcoming immune tolerance to tumors and facilitating immunemediated tumor cell killingCurrent approaches include the use of therapeutic cancer vaccinesadoptive transfer of immune effectorsand the use of immunostimulatory monoclonal antibodies that block immune checkpointsAlthough these therapies have shown promise in treating many types of cancerthey are not effective in all patientsA frequent basis for treatment failure appears to be a tumor microenvironment that does not support the recruitment or infiltration of tumor reactive T cellsAt Kinetawe are developing smallmolecule compounds that target RIG I like receptor pathwaysand other IRFinducing pathwaysto stimulate innate immunityBecause of the unique immune stimulating properties of these IRFagonistswe have begun to evaluate their potential as cancer immunotherapeuticsOur proof of concept compoundKINinduces immunogenic cell deatha cell death pathway that elicits an innate immune activation cascade within the tumor microenvironment that primes a T cell response against tumor neoantigens and that recruits activated T cells into the tumorKINinhibits tumor growth in miceand mice exhibiting tumor regression in response to KINare immune to re challenge with live tumor cells of the same typeIn this Phase I applicationwe will evaluate a panel of structure activity relationshipSARderived KINanalogsand a small number of compounds representing alternative chemical scaffoldswith the goal of improving overall potency and druglike propertiesIn Aimwe will screen compounds for their ability to induce cytokine production in mouse and human cancer cells and to induce apoptotic cell deathIn additionwe will measure the ability of compounds to induce translocation of calreticulin to the outer cell membranethe release of damage associated molecular patternsand dendritic cell activationIn parallelwe will rank compounds for desirable drug like properties including aqueous solubilitymetabolic stabilityand formulation compatibilityAt least four unique chemical series will be chosen for advancement to AimIn Aimwe will determine the effects of these compounds on tumor growth in miceWe evaluate the therapeutic effects of the compounds by injection of compound into tumors induced by implantation of CTcancer cellsIn parallelwe will assess the antitumor effects of systemicintravenousadministration of KINthat has been formulated in liposomesWe will also use liposome formulated KINto perform an initial evaluation of in vivo safetyFrom these studieswe will select a lead and backup chemical series for advancement to Phase IIwhich will include second stage medicinal chemistry optimization and preclinical development as a novel immunotherapy aimed at modifying the tumor microenvironment to facilitate immune mediated tumor cell killing PROJECT NARRATIVE The goal of cancer immunotherapy is to stimulate the immune system to specifically target and eliminate tumor cellsWe are developing a new type of immunotherapy drug that induces cancer cell death in such a way that the dying cancer cells stimulate a tumor specific immune response to eliminate tumor growth and prevent tumor reoccurrenceBecause of this mechanism of actionour drug may be used to improve the efficacy of other immunotherapiessuch as immune checkpoint blockers