Reprogramming myeloid cells by JAK inhibition to enhance checkpoint blockade therapy

Utah State Higher Education System--University Of Utah, Salt Lake City UT

Investigators

Abstract

PROJECT SUMMARY The transformative discovery of immune checkpoint inhibitors (ICIs) has unlocked antitumor immune responses in a wide range of cancer patients. Nonetheless, alternative treatment options are critically needed for the majority of patients who are non-responders to ICIs. Even cancer types known to have the highest response rates such as Hodgkin lymphoma can cause relapsed or refractory disease in a subset of patients. Among the key factors hindering the clinical benefit of ICIs are T cell exhaustion and suppressive myeloid cells. Exhausted T cells can be locked in a dysfunctional state by multiple redundant mechanisms including the suppressive action of myeloid cells. Despite the documented clinical relevance of suppressive myeloid cells, however, targeted therapies remain in clinical development. The Research Plan addresses the hypothesis that JAK inhibitors in conjunction with checkpoint inhibitors convert myeloid cells from a suppressive into an immunostimulatory state, inducing clinical responses in ICI monotherapy-resistant patients. The proposed studies leverage concordant preliminary preclinical and clinical preliminary data from preclinical cancer models and a clinical trial in Hodgkin lymphoma patients with high efficacy. In Aim 1, key mechanistic features of the effects of the JAK inhibitor ruxolitinib will be determined. Aim 2 focuses on the identification of cellular and molecular correlates of response to the combination therapy of ruxolitinib with the ICI nivolumab in Phase 1b and II clinical trials of relapsed or refractory Hodgkin lymphoma, including evaluation of the hypothesis that responders exhibit more baseline circulating suppressive myeloid cells than non-responders. In Aim 3, the cell- intrinsic role of JAK1 and JAK2 in this combination therapy will be established, and the hypothesis that MHC class I-independent responses are preferentially enhanced will be tested. The principal investigator Dr Zak is an immunologist with expertise in chemical biology, computational biology and clinical studies, possessing a comprehensive toolkit to execute this translational project. His long-term goal is to establish an independent research program centered on identifying and targeting immunosuppressive pathways in cancer. Dr Zak has established a clinical collaboration enabling the development of a novel combination therapy. A comprehensive career development plan addresses four key areas of training to enhance the launch of his research program: (1) utilizing relevant models of cancer, (2) design, management and analysis of collaborative clinical studies, (3) grantsmanship and progression towards independent grant submission and (4) establishing a laboratory, hiring, mentoring and management. The career development activities will forge the skills needed to launch and sustain an independent academic research program in cancer immunology.