RT Journal Article
SR Electronic
T1 VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e003254
DO 10.1136/jitc-2021-003254
VO 9
IS 11
A1 Miriam Bazan-Peregrino
A1 Rocio Garcia-Carbonero
A1 Berta Laquente
A1 Rafael Álvarez
A1 Ana Mato-Berciano
A1 Marta Gimenez-Alejandre
A1 Sara Morgado
A1 Alba Rodríguez-García
A1 Maria V Maliandi
A1 M Carmen Riesco
A1 Rafael Moreno
A1 Mireia M Ginestà
A1 Mercedes Perez-Carreras
A1 Joan B Gornals
A1 Susana Prados
A1 Sofía Perea
A1 Gabriel Capella
A1 Ramon Alemany
A1 Ramon Salazar
A1 Emma Blasi
A1 Carmen Blasco
A1 Manel Cascallo
A1 Manuel Hidalgo
YR 2021
UL http://jitc.bmj.com/content/9/11/e003254.abstract
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 .