First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors

Abstract

BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.MethodsPhase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.ResultsEighty-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 1–9) 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.ConclusionNo 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 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 numberNCT02923349.

OX40 expressed in endothelial cells facilitates tumor cells to escape from T-cell surveillance through S1P-YAP axis

“…To date, no successful mono-or combination therapy utilising OX40 agonists has been reported. Due to the lack of clinical effectiveness, many pharmaceutical giants have terminated the research and development of OX40 agonists; however, multiplexed immuno uorescence data from tumour biopsies in clinical trials showed actually enhanced activation of CD4+ and CD8+ effector T cells, suppression of CD4+ Treg cells, and increased NK cell activation after OX40 agonist administration 19,21 . Moreover, the treatment outcomes of combining OX40 agonists and PD-1 inhibitors were not superior to continuous use of OX40 agonists 19,39 .…”

“…Analysis of puncture samples from clinical trial patients showed that OX40 agonists enhanced antitumour immunity, including activating CD4+ and CD8+ T cells, natural killer (NK) cells, and inhibiting regulatory T-cell (Treg) functions 19,21 . However, the observed anti-tumour phenotype of the immune microenvironment induced by OX40 activation is not consistent with clinical e cacy.…”

Antibody-based cancer immunotherapy by targeting regulatory T cells

“…The preliminary efficacy showed that among 87 patients with colorectal, ovarian, and non-small-cell lung cancers, one patient with metastatic gallbladder cancer achieved a partial response, and 23 patients achieved stable disease. However, INCAGN01949 did not increase T-cell activation or decrease Tregs in the peripheral circulation, nor did it show any significant effect on T-cell subsets in the tumor biopsies ( 76 ). Therefore, the mechanism of this antibody targeting OX40 needs to be further investigated.…”

Regulatory cells and the effect of cancer immunotherapy

“…Other approaches, such as blockade of TIM-3 [44], V-domain Ig suppressor of T cell activation (VISTA) [45,46], treatment with glucocorticoid-induced TNFR-related (GITR) protein agonistic antibody [47,48], anti-OX40 antibodies [49][50][51], IDO-1 inhibitors [52,53], TGF-β inhibitors [54]VEGF-targeting therapy receptor 2 (VEGFR2) [55,56], PI3K inhibitor and HSP inhibitor (phosphoinositide 3-kinase (PI3K) pathway, or heat shock protein (HSP) [57], have also yielded promising results. Some drugs in combination with immune checkpoint inhibitors are currently the subject of ongoing clinical trials for cancer therapy [58].…”