PT  - JOURNAL ARTICLE
AU  - Miriam Bazan-Peregrino
AU  - Rocio Garcia-Carbonero
AU  - Berta Laquente
AU  - Rafael Álvarez
AU  - Ana Mato-Berciano
AU  - Marta Gimenez-Alejandre
AU  - Sara Morgado
AU  - Alba Rodríguez-García
AU  - Maria V Maliandi
AU  - M Carmen Riesco
AU  - Rafael Moreno
AU  - Mireia M Ginestà
AU  - Mercedes Perez-Carreras
AU  - Joan B Gornals
AU  - Susana Prados
AU  - Sofía Perea
AU  - Gabriel Capella
AU  - Ramon Alemany
AU  - Ramon Salazar
AU  - Emma Blasi
AU  - Carmen Blasco
AU  - Manel Cascallo
AU  - Manuel Hidalgo
TI  - VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects
AID  - 10.1136/jitc-2021-003254
DP  - 2021 Nov 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e003254
VI  - 9
IP  - 11
4099  - http://jitc.bmj.com/content/9/11/e003254.short
4100  - http://jitc.bmj.com/content/9/11/e003254.full
SO  - J Immunother Cancer2021 Nov 01; 9
AB  - Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer.Methods VCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography.Results VCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption.Conclusions VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma.Trial registration number EudraCT number: 2012-005556-42 and NCT02045589.All data relevant to the study are included in the article or uploaded as online supplemental information. Acknowledgments The study team thanks patients and families for their willingness to participate in the clinical trial of VCN-01 by intratumor administration. Thanks to Marti Farrera and Silvia Torres-Manjon for technical assistance and processing biological samples. Graphical Abstract was created with BioRender.com .