Abstract 3739: Different combination regimens for OX40 agonists and PD-1 inhibitors exert different antitumor effects in OX40 humanized mice
Authors: Li Yi , Zhang Yanlei , Qiu Xiaolei , Feng Dongxiao , Sun Ruilin , He Daniel X. 
Published: March 2024

Abstract
OX40, also known as CD134 or TNFRSF4, is a member of the tumor necrosis factor receptor (TNFR) superfamily which mainly expressed on the surface of activated T cells including Treg cells. Engagement of OX40 with its ligand, TNFSF4, leads to effector T cell expansion and cytokine release, inhibits activation-induced cell death (AICD) and promotes the survival of antigen-specific memory T cells. In contrast to the massive hit of immune checkpoint inhibitors like PD-1 and PD-L1, the benefit of agonistic antibodies in clinical trials has not been completely demonstrated to date. On one hand, higher doses could leads to T cell exhaustion or AICD, paradoxically, with no efficacy improvement. Another hand, the limited understanding of the biology of immune checkpoints underlying “accelerator and brake” should account for the slow clinical progress of OX40-targeted biologics. It seems that the dosing sequence or timing of anti-OX40 and anti-PD-1 is an important consideration in combination therapies. Given this, we firstly evaluated the antitumor effects of two different anti-human OX40 agonists in syngeneic MC38 and Pan02 tumor models, respectively, in hOX40 knockin mice. We observed tumor regressions upon treatment of OX40 agonistic Ab1 in a dose-dependence way in the homozygous hOX40 knockin mice engrafted with MC38 tumors. The anti-hOX40 Ab1 at high-dose (10 mg/kg) led to ~60% TGI, but no response at very low dose (0.1 mg/kg). Furthermore, the homozygous hOX40 knockin mice inoculated with Pan02 pancreatic tumors were treated with a novel strong anti-hOX40 agonist (Ab2) and surrogate anti-mPD-1. Notably, Anit-hOX40 (Ab2) alone at low dose (1 mg/kg, Q3D*9 doses) exerted strong anti-tumor potency (TGI=59.3%, p&lt; 0.005) and no statistical significant antitumor difference was observed between high-dose group (at 5mg/kg) and low-dose group (at 1 mpk) as monotherapy, though anti-hOX40 (Ab2) at 5mg/kg showed the best therapeutic response (TGI=72%, p=0.0002) among all treatment groups. In contrast, the second therapeutic response was observed in the combo group treated with first dosing of 5mg/kg anti-hOX40 (Ab2) combining delayed dosing of 10mg/kg anti-mPD-1 (TGI=64%, p&lt; 0.005) and the concurrent dosing group of Ab2 (5 mg/kg, Q3D × 9 doses) plus anti-mPD-1 (2 mg/kg, Q3D × 9 doses) (TGI=62.3%, p= 0.001). In conclusion, different human-specific OX40 agonists displayed different anti-tumor activity as monotherapy, and different dose led to different antitumor potency for the same agonist. In terms of different combination regimens, although no advanced benefit was observed for the combination of anti-mPD-1/anti-OX40 (Ab2) in comparison to strong anti-OX40 agonist (Ab2) alone, it demonstrated that the dosing timing and sequence of either anti-PD-1 or anti-hOX40 did has impact on the therapeutic outcome.
Citation Format: Yi Li, Yanlei Zhang, Xiaolei Qiu, Dongxiao Feng, Ruilin Sun, Daniel X. He. Different combination regimens for OX40 agonists and PD-1 inhibitors exert different antitumor effects in OX40 humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3739.