Intratumoral delivery of a novel oncolytic adenovirus encoding human antibody against PD-1 elicits enhanced antitumor efficacy

Ping Zhou; Xuchen Wang; Man Xing; Xi Yang; Mangteng Wu; Hongyang Shi; Caihong Zhu; Xiang Wang; Yingying Guo; Shubing Tang; Zhong Huang; Dongming Zhou

doi:10.1016/j.omto.2022.04.007

Intratumoral delivery of a novel oncolytic adenovirus encoding human antibody against PD-1 elicits enhanced antitumor efficacy

Mol Ther Oncolytics. 2022 Apr 25:25:236-248. doi: 10.1016/j.omto.2022.04.007. eCollection 2022 Jun 16.

Authors

Ping Zhou^{1

2}, Xuchen Wang^{1

2}, Man Xing^{3

4}, Xi Yang³, Mangteng Wu^{1

2}, Hongyang Shi³, Caihong Zhu³, Xiang Wang³, Yingying Guo⁴, Shubing Tang³, Zhong Huang¹, Dongming Zhou^{3

4

5}

Affiliations

¹ Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
⁴ Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
⁵ The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.

Abstract

To date, diverse combination therapies with immune checkpoint inhibitors (ICIs), particularly oncolytic virotherapy, have demonstrated enhanced therapeutic outcomes in cancer treatment. However, high pre-existing immunity against the widely used adenovirus human serotype 5 (AdHu5) limits its extensive clinical application. In this study, we constructed an innovative oncolytic virus (OV) based on a chimpanzee adenoviral vector with low seropositivity in the human population, named AdC68-spE1A-αPD-1, which endows the parental OV (AdC68-spE1A-ΔE3) with the ability to express full-length anti-human programmed cell death-1 monoclonal antibody (αPD-1). In vitro studies indicated that the AdC68-spE1A-αPD-1 retained parental oncolytic capacity, and αPD-1 was efficiently secreted from the infected tumor cells and bound exclusively to human PD-1 (hPD-1) protein. In vivo, intratumoral treatment with AdC68-spE1A-αPD-1 resulted in significant tumor suppression, prolonged overall survival, and enhanced systemic antitumor memory response in an hPD-1 knockin mouse tumor model. This strategy outperformed the unarmed OV and was comparable with combination therapy with intratumoral injection of AdC68-spE1A-ΔE3 and systemic administration of commercial αPD-1. In summary, AdC68-spE1A-αPD-1 is a cost-effective approach with potential clinical applications. ‬‬‬‬.

Keywords: PD-1; alternative; checkpoint inhibitors; chimpanzee adenovirus; combination cancer therapy; oncolytic virus.