847 Optimal dose selection of ADG126 (a masked anti-CTLA-4 SAFEbody®) with significantly widened therapeutic index compared to ipilimumab in combination with anti-PD-1 antibodies informed by QSP modeling

BackgroundActivation of anticancer T cell immunity by checkpoint inhibition has become a key tool in the clinical management of cancer, but efficacy is limited in part by the suppressive activity of myeloid cells. Reprogramming myeloid cells from a suppressive into an immune-enhancing state is a goal of significant translational interest. Using preclinical and clinical studies, we investigated the potential of JAK inhibitors to enhance the efficacy of checkpoint inhibitors in a myeloid-dependent manner.MethodsThe combination therapy of systemic treatment with the JAK inhibitor ruxolitinib with anti-PD1 + anti-CTLA4 was evaluated for efficacy and biomarkers compared to checkpoint inhibitors (ICI) alone in four murine immunocompetent models of cancer. Tumor-infiltrating, blood and lymphoid organ immune cells were phenotyped using single-cell transcriptomics, functional assays and flow cytometry. The combination therapy was clinically tested in an investigator-initiated Phase I/II clinical trial of ruxolitinib with nivolumab in relapsed or refractory Hodgkin lymphoma (NCT03681561). Patients who previously failed to respond to ICI received ruxolitinib for 1 week then nivolumab every 4 weeks concurrent with ruxolitinib. Hematologic, transcriptomic and flow cytometric analyses were performed on peripheral blood collected at baseline and after ruxolitinib treatment.ResultsThe ruxolitinib + ICI combination was superior to ICI in 3/4 of the tumor models examined in controlling tumor growth. Compared to ICI alone, tumor sizes were reduced by >50% in the MC38 (mean volume 123.1 vs 283.2 mm3, n=9 per group, p=0.0094), LLC1 and A20 models (survival hazard ratio 0.47, n=30 per group, p=0.025). Remarkably, we observed a broad shift of tumor monocytes and granulocytes from a suppressive into an immunostimulatory state characterized by the expression of MHC-II and the ability to stimulate T cell proliferation. Depleting monocytic or granulocytic cells abrogated the beneficial effect of ruxolitinib. Hodgkin lymphoma patients in the ruxolitinib with nivolumab trial exhibited a disease control rate of 63% (12/19) including 5 complete responses. Ruxolitinib treatment in these patients did not impair T cell numbers or cytokine production but significantly reduced the neutrophil-to-lymphocyte ratio (NLR, mean difference -0.82, n=14, p=0.0023) and the percentage of LOX1+ granulocytic suppressor cells in peripheral blood (mean 0.27 of baseline, p=0.0009). The reduction in NLR was significantly greater in complete responders than in progressive disease patients (mean -2.6 vs -0.58, respectively, p=0.023).ConclusionsThe combination of ruxolitinib with ICI was effective in preclinical models and in a Phase I/II Hodgkin lymphoma clinical trial, identifying JAK inhibition with ICI as a promising myeloid-modulating immunotherapy.Trial RegistrationThe clinical trial identifier number is NCT03681561.Ethics ApprovalThis work was approved by the Institutional Review Boards of the University of Minnesota (STUDY00001341) and The Scripps Research Institute (IRB-19–7408, IRB-21–7803).