VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects

Abstract

BackgroundPancreatic 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.MethodsVCN-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.ResultsVCN-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.ConclusionsVCN-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 numberEudraCT number: 2012-005556-42 and NCT02045589.

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

“… 21 VCN-01 has shown oncolytic activity and synergistic effects when combined with nab-paclitaxel plus gemcitabine in preclinical models of pancreatic ductal adenocarcinoma. 20 Also, a phase I clinical trial of intratumoral administration of VCN-01 in patients with pancreatic ductal adenocarcinoma demonstrated local tumor control and the modification of tumor matrix stiffness when administering VCN-01. 20 …”

“… 20 Also, a phase I clinical trial of intratumoral administration of VCN-01 in patients with pancreatic ductal adenocarcinoma demonstrated local tumor control and the modification of tumor matrix stiffness when administering VCN-01. 20 …”

“…We are currently monitoring the anti-Ad5 NAbs titers over longer periods of time to identify when such levels are low enough to allow a second intravenous administration. In a separate clinical trial, VCN-01 was repeatedly administered directly into PDAC tumors (IT) because the impact of NAbs with this type of delivery is minimal 20 although, through this type of administration viral biodistribution is restricted to the injection site and metastatic sites are not infected. Repeated intravenous administration, if feasible, will offer better biodistribution of the virus within each tumor mass and has the potential to reach all metastatic tumor sites.…”

“… 30 31 Preclinically, VCN-01 has also demonstrated enhanced delivery of chemotherapy and therapeutic antibodies into the tumor. 20 A putative advantage provided by the virally-expressed hyaluronidase would be the combined local expression of PH20 for approximately 28 days with an intrinsic oncolysis resulting in tumor debulking and induction of intratumor inflammation. VCN-01 has also recently demonstrated to reduce tumor stiffness in patients with PDAC treated via intratumoral administration which suggests that VCN-01 replicates within the tumor mass and induces stromal disruption.…”

“…VCN-01 has also recently demonstrated to reduce tumor stiffness in patients with PDAC treated via intratumoral administration which suggests that VCN-01 replicates within the tumor mass and induces stromal disruption. 20 Of note, higher levels of hyaluronidase detected in patients’ serum may be associated with a more pronounced tumor response in patients. In this line, stromal disruption may be only the initial mechanism that enables the induction of additional long-lasting mechanisms.…”