Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

In Vitro and In Vivo Efficacy of a Stroma Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer

Ana Alfano
,
Eduardo G. A Cafferata
ORCID logo ,
Mariela Gangemi
,
Alejandro Nicola Candia
,
Cristian M Malnero
,
Ismael Bermudez
,
Gregorio David Rios
,
Cecilia Rotondaro
,
Nicasio Cuneo
,
David T Curiel
ORCID logo ,
Osvaldo L Podhajcer
* ,
Maria Veronica Lopez
* ORCID logo
Version 1 : Received: 5 May 2023 / Approved: 6 May 2023 / Online: 6 May 2023 (09:25:49 CEST)

A peer-reviewed article of this Preprint also exists.

Alfano, A.; Cafferata, E.G.A.; Gangemi, M.; Nicola Candia, A.; Malnero, C.M.; Bermudez, I.; Lopez, M.V.; Ríos, G.D.; Rotondaro, C.; Cuneo, N.; Curiel, D.T.; Podhajcer, O.L.; Lopez, M.V. In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer. Int. J. Mol. Sci. 2023, 24, 9992. Alfano, A.; Cafferata, E.G.A.; Gangemi, M.; Nicola Candia, A.; Malnero, C.M.; Bermudez, I.; Lopez, M.V.; Ríos, G.D.; Rotondaro, C.; Cuneo, N.; Curiel, D.T.; Podhajcer, O.L.; Lopez, M.V. In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer. Int. J. Mol. Sci. 2023, 24, 9992.

Abstract

More than 1 million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at late stage, either because lack of symptoms such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV) whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer. uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404) a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Keywords

transcriptionally targeted oncolytic adenovirus; gynecologic cancer; human samples; cytokines; ovarian cancer; tumor stroma

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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