TY - JOUR

T1 - Ad6-Based GM-CSF Expressing Vector Displays Oncolytic and Immunostimulatory Effects in an Immunocompetent Syrian Hamster Model of Cholangiocarcinoma

AU - Zabelina, Daria S.

AU - Osipov, Ivan D.

AU - Maslov, Denis E.

AU - Kovner, Anna V.

AU - Vasikhovskaia, Valeriia A.

AU - Demina, Diana S.

AU - Romanov, Stanislav E.

AU - Shishkina, Ekaterina V.

AU - Davydova, Julia

AU - Netesov, Sergey V.

AU - Romanenko, Margarita V.

N1 - This research has been supported by the Russian Ministry of Science and Higher Education grants FSUS-2020-0035, FSUS-2022-0021, and FSUS-2025-0012. Additional support was provided by the University of Minnesota Masonic Cancer Center and National Institute of Health R01CA276179.

PY - 2025/1/24

Y1 - 2025/1/24

N2 - Cholangiocarcinoma (CCA), the second most common liver cancer, remains highly resistant to chemotherapy and radiotherapy, leaving patients with unresectable tumors in urgent need of innovative therapeutic approaches. Adenovirus type 6 (Ad6), a species C human adenovirus, offers significant potential for cancer therapy due to its low seroprevalence compared to Adenovirus type 5 (Ad5) and its ability to evade Kupffer cells during systemic delivery. In this study, we developed a novel oncolytic adenovirus vector based on the Ad6 engineered to express human GM-CSF (Ad6-d24-GM) and evaluated its therapeutic efficacy in a novel immunocompetent, replication-permissive Syrian hamster model of CCA. Intratumoral administration of Ad6-d24-GM significantly suppressed tumor growth and prolonged survival without evidence of toxicity, as indicated by stable body weights and normal liver enzyme levels. Both Ad6-d24-GM and wild-type Ad6 induced robust infiltration of CD4+ and CD8+ T cells, as well as CD68+ macrophages within tumors, demonstrating activation of antitumor immunity. Notably, the Ad6-d24-GM group exhibited a statistically significant increase in CD68+ cells compared to wild-type Ad6, highlighting the immunomodulatory effect of GM-CSF transgene. These results demonstrate the oncolytic and immunostimulatory potential of Ad6-based vectors for CCA treatment and validate the Syrian hamster syngeneic CCA-OF model as a valuable platform for studying oncolytic adenovirus therapies.

AB - Cholangiocarcinoma (CCA), the second most common liver cancer, remains highly resistant to chemotherapy and radiotherapy, leaving patients with unresectable tumors in urgent need of innovative therapeutic approaches. Adenovirus type 6 (Ad6), a species C human adenovirus, offers significant potential for cancer therapy due to its low seroprevalence compared to Adenovirus type 5 (Ad5) and its ability to evade Kupffer cells during systemic delivery. In this study, we developed a novel oncolytic adenovirus vector based on the Ad6 engineered to express human GM-CSF (Ad6-d24-GM) and evaluated its therapeutic efficacy in a novel immunocompetent, replication-permissive Syrian hamster model of CCA. Intratumoral administration of Ad6-d24-GM significantly suppressed tumor growth and prolonged survival without evidence of toxicity, as indicated by stable body weights and normal liver enzyme levels. Both Ad6-d24-GM and wild-type Ad6 induced robust infiltration of CD4+ and CD8+ T cells, as well as CD68+ macrophages within tumors, demonstrating activation of antitumor immunity. Notably, the Ad6-d24-GM group exhibited a statistically significant increase in CD68+ cells compared to wild-type Ad6, highlighting the immunomodulatory effect of GM-CSF transgene. These results demonstrate the oncolytic and immunostimulatory potential of Ad6-based vectors for CCA treatment and validate the Syrian hamster syngeneic CCA-OF model as a valuable platform for studying oncolytic adenovirus therapies.

KW - Syrian hamster

KW - adenovirus type 6 (HAdV-C6, Ad6)

KW - cancer

KW - cholangiocarcinoma

KW - immunotherapy

KW - liver cancer

KW - oncolytic virus

UR - https://www.mendeley.com/catalogue/183f7f2c-f74f-3276-915c-94b69433ebca/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85219048184&origin=inward&txGid=2e747d762e14072bb28141262f2efa50

U2 - 10.3390/v17020162

DO - 10.3390/v17020162

M3 - Article

VL - 17

JO - Viruses

JF - Viruses

SN - 1999-4915

IS - 2

M1 - 162

ER -