Antitumor-specific T-cell responses induced by oncolytic adenovirus ONCOS-102 (AdV5/3-D24-GM-CSF) in peritoneal mesothelioma mouse model.

Lukasz Kuryk,Anne‐Sophie W Møller,Sari Pesonen,Mariangela Garofalo,Magnus Jaderberg,Ramon Alemany,Vincenzo Cerullo

doi:10.1002/jmv.25229

Abstract

Oncolytic adenoviral immunotherapy activates the innate immune system with subsequent induction of adaptive tumor‐specific immune responses to fight cancer. Hence, oncolytic viruses do not only eradicate cancer cells by direct lysis, but also generate antitumor immune response, allowing for long‐lasting cancer control and tumor reduction. Their therapeutic effect can be further enhanced by arming the oncolytic adenovirus with costimulatory transgenes and/or coadministration with other antitumor therapies. ONCOS‐102 has already been found to be well tolerated and efficacious against some types of treatment‐refractory tumors, including mesothelin‐positive ovarian cancer (NCT01598129). It induced local and systemic CD8+ T‐cell immunity and upregulated programmed death ligand 1. These results strongly advocate the use of ONCOS‐102 in combination with other therapeutic strategies in advanced and refractory tumors, especially those expressing the mesothelin antigen. The in vivo work presented herein describes the ability of the oncolytic adenovirus ONCOS‐102 to induce mesothelin‐specific T‐cells after the administration of the virus in bagg albino (BALB/c) mice with mesothelin‐positive tumors. We also demonstrate the effectiveness of the interferon‐γ the enzyme‐linked immunospot (ELISPOT) assay to detect the induction of T‐cells recognizing mesothelin, hexon, and E1A antigens in ONCOS‐102‐treated mesothelioma‐bearing BALB/c mice. Thus, the ELISPOT assay could be useful to monitor the progress of therapy with ONCOS‐102.

Highlights

Malignant mesothelioma is a fatal form of cancer, which is difficult to diagnose and cure.[1,2] Its primary cause is exposure to asbestos, and it has a long latency period, sometimes as long as 20 years
We show the induction of T‐cells specific for mesothelin, hexon, and E1A antigens after the treatment of mesothelioma‐bearing BALB/c mice with ONCOS‐102 and the effectiveness of the interferon (IFN)‐γ enzyme-linked immunospot (ELISPOT) in detecting this response
ONCOS‐102 causes immunogenic cancer cell death[19] and the subsequent release of tumor antigens to be processed by antigen‐presenting cells, resulting in the ONCOS‐102 and (D) PBS, respectively, stimulated with hexon pool, E1A pool, mesothelin pool, phorbol 12-myristate 13-acetate (PMA), and Ionomycin, respectively

Summary

| INTRODUCTION

Malignant mesothelioma is a fatal form of cancer, which is difficult to diagnose and cure.[1,2] Its primary cause is exposure to asbestos, and it has a long latency period, sometimes as long as 20 years. Ranki et al[16,17] reported the results of a Phase I study (NCT01598129) in which ONCOS‐102 (Ad5/3‐Δ24‐GM‐CSF) was well tolerated and induced local and systemic CD8+ T‐cell immunity in patients with treatment‐refractory and immune‐cell poor solid tumors. They observed an upregulation of programmed death ligand 1 (PD‐L1) after treatment with ONCOS‐102, suggesting that combination of ONCOS‐102 with checkpoint inhibitors, including PD‐1/PD‐L1 inhibitors, could be beneficial against such refractory tumors. The spots were counted using the ELISpot Reader (AID, Strasberg, Germany)

| MATERIALS AND METHODS

| RESULTS AND DISCUSSION

CONFLICTS OF INTEREST