Abstract
The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study. We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade. Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4+ and CD8+ T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy > 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing. Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.
Highlights
Therapeutic blockade of T-cell inhibitory receptors, such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death 1 protein (PD-1), has provided meaningful clinical benefit for patients with a broad range of malignancies [1]
One class of molecules being developed to directly enhance antitumor T-cell responses is agonists of T-cell costimulatory receptors expressed on the surface of activated, tumor-infiltrating T cells belonging to the CD28 or TNF receptor superfamily
The ability of BMS-986178 to stimulate T-cell responses in vitro was dependent on Fc–Fc g receptor (FcgR) interactions; addition of the antibody in the absence of FcgR (CD32a) expression on antigen-presenting cells (APC) in the assay did not lead to enhancement of anti-CD3– mediated induction of IFNg over the isotype control (Supplementary Fig. S3C)
Summary
Therapeutic blockade of T-cell inhibitory receptors, such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death 1 protein (PD-1), has provided meaningful clinical benefit for patients with a broad range of malignancies [1]. This success has led to a significant increase in the efforts toward the preclinical and clinical development of an array of immunomodulatory molecules for the treatment of cancer. One class of molecules being developed to directly enhance antitumor T-cell responses is agonists of T-cell costimulatory receptors expressed on the surface of activated, tumor-infiltrating T cells belonging to the CD28 or TNF receptor superfamily A large body of preclinical data has demonstrated www.aacrjournals.org
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