All analyses of pharmacodynamic activity were validated and shown to be suitable in detecting changes

All analyses of pharmacodynamic activity were validated and shown to be suitable in detecting changes. Open in a separate window Figure 3 T-cell activity in blood samples of patients treated with INCAGN01949. tumors. Patients received INCAGN01949 monotherapy (7C1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. Results Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1C9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of 200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. Conclusion No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood KB130015 and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. Trial registration number NCT02923349. Keywords: Clinical Trials as Topic, Immunomodulation, Lymphocytes, Tumor-Infiltrating, T-Lymphocytes, Tumor Microenvironment WHAT IS ALREADY KNOWN ON THIS TOPIC OX40 agonist antibodies have been shown to reduce tumor growth in preclinical models, but the benefit of these agents in clinical studies has not been demonstrated KB130015 to date. WHAT THIS STUDY ADDS This phase I/II, first-in-human study demonstrates that monotherapy with the OX40 agonist antibody INCAGN01949 was generally well tolerated, with one patient achieving a partial response and 23 achieving stable disease (SD) among 87 enrolled patients with advanced solid tumors. This study adds to published literature reporting patients achieving SD with other OX40 agonist antibodies; however, objective responses Mouse monoclonal to CD54.CT12 reacts withCD54, the 90 kDa intercellular adhesion molecule-1 (ICAM-1). CD54 is expressed at high levels on activated endothelial cells and at moderate levels on activated T lymphocytes, activated B lymphocytes and monocytes. ATL, and some solid tumor cells, also express CD54 rather strongly. CD54 is inducible on epithelial, fibroblastic and endothelial cells and is enhanced by cytokines such as TNF, IL-1 and IFN-g. CD54 acts as a receptor for Rhinovirus or RBCs infected with malarial parasite. CD11a/CD18 or CD11b/CD18 bind to CD54, resulting in an immune reaction and subsequent inflammation are rarely observed in the advanced cancer setting. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Optimizing the therapeutic potential of OX40 agonists may require novel combinations and/or sequential dosing strategies, or evaluation in patients with immunologically responsive tumors. Introduction Immune cell receptors modulate key cellular functions that typically require activation or inhibition of signaling pathways to regulate immune responses.1C4 Immune checkpoint receptors have been shown to negatively regulate antitumor immune responses in the tumor microenvironment, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, expressed on activated cytotoxic T cells and regulatory T cells (Tregs)), programmed death-ligand 1 (PD-L1; expressed on activated dendritic cells, macrophages, and tumors), and KB130015 programmed cell death protein 1 (PD-1; expressed on activated T and B cells, natural killer cells, and antigen-presenting cells).5 The identification of inhibitory and stimulatory immune receptor targets has led to the development of immune receptor-specific monoclonal antibodies as potential targeted immunotherapies for the treatment of cancer.4 6 7 Antitumoral immunity may also be achieved by agonist antibody activation of T-cell costimulatory receptors, which mostly belong to the tumor necrosis factor receptor superfamily (TNFRSF).5 8 OX40 (also known as CD134 or TNFRSF4) has been shown to positively regulate lymphocyte activation, proliferation, and apoptosis, depending on the tumor microenvironment.9 10 Expression of OX40 has been detected on activated T cells, including CD4+ and CD8+, and is constitutively expressed on Tregs.11 OX40+ T cells have been found in tumor samples from patients with melanoma, cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma, and breast, colon, gastric, and ovarian.