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

项目总结

PROJECT SUMMARY Cancer immunotherapy is predicated on overcoming immune tolerance to tumors and facilitating immune- mediated tumor cell killing. Current approaches include the use of therapeutic cancer vaccines, adoptive transfer of immune effectors, and the use of immunostimulatory monoclonal antibodies that block immune checkpoints. Although these therapies have shown promise in treating many types of cancer, they are not effective in all patients. A frequent basis for treatment failure appears to be a tumor microenvironment that does not support the recruitment or infiltration of tumor-reactive T cells. At Kineta, we are developing small- molecule compounds that target RIG-I-like receptor pathways, and other IRF3-inducing pathways, to stimulate innate immunity. Because of the unique immune-stimulating properties of these IRF3 agonists, we have begun to evaluate their potential as cancer immunotherapeutics. Our proof-of-concept compound, KIN1312, induces immunogenic cell death, a 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 tumor. KIN1312 inhibits tumor growth in mice, and mice exhibiting tumor regression in response to KIN1312 are immune to re-challenge with live tumor cells of the same type. In this Phase I application, we will evaluate a panel of structure-activity relationship (SAR)-derived KIN1312 analogs, and a small number of compounds representing alternative chemical scaffolds, with the goal of improving overall potency and drug- like properties. In Aim 1, we will screen compounds for their ability to induce cytokine production in mouse and human cancer cells and to induce apoptotic cell death. In addition, we will measure the ability of compounds to induce translocation of calreticulin to the outer cell membrane, the release of damage-associated molecular patterns, and dendritic cell activation. In parallel, we will rank compounds for desirable drug-like properties including aqueous solubility, metabolic stability, and formulation compatibility. At least four unique chemical series will be chosen for advancement to Aim 2. In Aim 2, we will determine the effects of these compounds on tumor growth in mice. We evaluate the therapeutic effects of the compounds by injection of compound into tumors induced by implantation of CT26 cancer cells. In parallel, we will assess the antitumor effects of systemic (intravenous) administration of KIN1312 that has been formulated in liposomes. We will also use liposome formulated KIN1312 to perform an initial evaluation of in vivo safety. From these studies, we will select a lead and backup chemical series for advancement to Phase II, which 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.