Enhancing Antitumor Immunity: The Role of OX40 Ligand Fusion Proteins and Checkpoint Inhibitors in Preclinical Models

OX40, a receptor predominantly found on activated T cells, including those within tumors, is a target for enhancing antitumor immunity. Agonist OX40 ligands are believed to boost the activity of effector T cells (Teff) and curb the suppressive action of regulatory T cells (Treg). This study presents the characterization and efficacy of a novel agonist OX40 ligand (OX40L) fusion protein, MEDI6383, which is composed of human OX40L receptor binding domains, trimerization domains, and human Fcγ domains.

In vitro assays with MEDI6383 demonstrated activation of the OX40 signaling pathway and enhanced proliferation and cytokine release in primary human Teff cells. The compound also suppressed Treg cell activity in co-cultures. In a human tumor/T cell xenograft mouse model, MEDI6383 showed potent antitumor effects that were contingent on the presence of alloreactive human T cells.

A surrogate mouse OX40L fusion protein (mOX40L FP) was used to evaluate in vivo antitumor activity in multiple syngeneic mouse tumor models. The mOX40L FP exhibited dose-dependent antitumor effects across various tumor models and its activity was linked to the expression of activating Fcγ receptors. Notably, the combination of checkpoint inhibitors with mOX40L FP led to a significantly enhanced antitumor response compared to monotherapy.

The findings indicate that MEDI6383 and similar agonist OX40L fusion proteins have the potential to stimulate T cell proliferation, impede Treg inhibition, and augment antitumor activity, both as standalone treatments and in combination with immune checkpoint inhibitors in preclinical models.