Abstract DDT01-02: Unleashing anti-tumor immunity through anti-OX40 monotherapy and in combination with anti-PD-L1
Authors: Kim Jeong M. 
Published: August 2015

Abstract
Cancer immunotherapy has the potential to induce durable responses through the generation of tumor-specific T cell memory. In addition to cognate antigen recognition, T cells require costimulation via stimulatory receptors for optimal memory T cell development and the establishment of anti-tumor immunity. OX40 is a costimulatory molecule that is expressed on activated effector and regulatory T cells. Agonistic antibodies against OX40 are predicted to counteract the immunosuppressive tumor microenvironment and promote T cell-dependent, anti-tumor immunity via two mechanisms: (1) binding to OX40 on antigen-experienced effector T cells increases their proliferation and cytokine production and (2) binding to OX40 on activated regulatory T cell inhibits their suppressive function, which in turn enhances the T cell based immune response.
MOXR0916 is a humanized monoclonal antibody that binds to the human OX40 costimulatory receptor in an agonistic fashion. Binding of MOXR0916 to OX40 on activated human T cells in vitro resulted in the costimulation of effector T cell proliferation and IFN-g production, whereas binding to regulatory T cells inhibited their suppressive function. Due to sequence divergence between human and mouse OX40, a murine agonist antibody was employed to assess anti-tumor efficacy and T cell dynamics in murine syngeneic tumor models. In preclinical tumor models, anti-mouse OX40 administration induced a spectrum of anti-tumor activity, including durable responses. Animals with a complete response to anti-OX40 treatment were resistant to tumor rechallenge, indicating generation of tumor-specific memory. Tumor regression in anti-OX40 sensitive tumor models was associated with increased intratumoral expression of IFN-g, granzymes, and perforin at baseline, suggesting that anti-OX40 treatment augments latent immune responses to the tumor. Administration of anti-OX40 in several tumor models results in an increase in intratumoral CD8+ T cells and a decrease in regulatory T cells. Both anti-tumor efficacy and pharmacodynamic modulation of effector and regulatory T cells required antibody crosslinking. Similarly, anti-human OX40 MOXR0916 required antibody crosslinking to costimulate effector T cells.
Treatment of agonistic anti-OX40 antibodies was capable of enhancing tumor immunity despite the activity of multiple inhibitory pathways including the PD-1- PD-L1 axis. In preclinical tumor models, the combination of anti-OX40 and a blocking antibody to the inhibitory receptor PD-L1 led to increased tumor growth inhibition and increased number of complete responses compared to either agent alone. This combination activity was associated with an increase in the expression of IFN-g associated genes and activated CD8+ T cells in the tumor. Together, these studies demonstrate that anti-OX40, both as a single agent and in combination with anti-PD-L1 can induce robust immune responses in animal tumor models.
Citation Format: Jeong M. Kim. Unleashing anti-tumor immunity through anti-OX40 monotherapy and in combination with anti-PD-L1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT01-02. doi:10.1158/1538-7445.AM2015-DDT01-02