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 Bazan-Peregrino, Miriam
A1 Garcia-Carbonero, Rocio
A1 Laquente, Berta
A1 Álvarez, Rafael
A1 Mato-Berciano, Ana
A1 Gimenez-Alejandre, Marta
A1 Morgado, Sara
A1 Rodríguez-García, Alba
A1 Maliandi, Maria V
A1 Riesco, M Carmen
A1 Moreno, Rafael
A1 Ginestà, Mireia M
A1 Perez-Carreras, Mercedes
A1 Gornals, Joan B
A1 Prados, Susana
A1 Perea, Sofía
A1 Capella, Gabriel
A1 Alemany, Ramon
A1 Salazar, Ramon
A1 Blasi, Emma
A1 Blasco, Carmen
A1 Cascallo, Manel
A1 Hidalgo, Manuel
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 .