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.
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.
Scientists hypothesized that VCN-01 could sensitize tumor cells to chemotherapy. Thus, they evaluated the efficacy of VCN-01 in combination with gemcitabine or nab-paclitaxel plus gemcitabine in immunodeficient and immunocompetent preclinical models of PDAC.
First, they evaluated the efficacy of the combination of VCN-01 plus gemcitabine in the immunocompetent Syrian hamster with HP-1 subcutaneous pancreatic tumors. We administered VCN-01 IT alone or in combination with IP gemcitabine. Neither gemcitabine nor VCN-01 alone induced antitumoral effect in this hamster tumor model. Limitation posed by the semipermissiveness of human adenovirus in the hamster model is likely to have a strong impact on the efficacy of VCN-01 alone. However, the combination of IP gemcitabine and IT VCN-01 resulted in a synergistic antitumoral effect which was significantly superior to control and either treatment alone. These results indicate that VCN-01 induces powerful chemosensitization to gemcitabine treatment in the semipermissive.
They also compared a single dose of intravenous VCN-01 plus four doses of IP gemcitabine to either treatment alone in the HA rich human pancreatic NP-9 tumor model grown subcutaneously in athymic mice. VCN-01 antitumor activity was superior to gemcitabine alone, and the combination of both treatments was significantly better than either single treatment alone for controlling tumor growth up to day 79. VCN-01 treated tumors were positive for the key viral replication gene, E1A, and showed decreased HA content at the study end confirming that the transgene hyaluronidase PH20 was functionally expressed.
They next tested intravenous VCN-01 in combination with nab-paclitaxel plus gemcitabine in a subcutaneous human pancreatic tumor model (NP-18). VCN-01 alone significantly decreased tumor growth compared with untreated tumors in the NP-18 model. Nab-paclitaxel plus gemcitabine reduced tumor volume in all treated tumors, leading to complete regression in 25% of (3/12) tumors. However, all regressed tumors relapsed after stopping chemotherapy administration. The combination of VCN-01 plus nab-paclitaxel plus gemcitabine reduced tumor growth to a greater extent than both treatments administered separately, leading to complete regression in 80% (8/10) of tumors. In addition, 50% (4/10) of these tumors continued with complete regression until the end of treatment (day 90).
They next selected the TP-11 model because of its high HA content and architectural resemblance to human PDAC when implanted orthotopically. In this model, all treated groups demonstrated reduced tumor volume compared with nontreated animals on day 28. There was a minor non-significant reduction in tumor volume due to VCN-01 (27%), whereas a significant reduction was observed with nab-paclitaxel plus gemcitabine (37%) and a further significant decrease was achieved with the combined treatment (VCN-01 and nab-paclitaxel plus gemcitabine) (48%). In a separate experiment, using a slightly longer evaluation timepoint (day 36), VCN-01 showed a significant tumor reduction (29%) in the TP-11 tumor model.
Treatment with VCN-01 alone and in combination with chemotherapy was well tolerated
Their study proves that VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma. This study has been published in Journal for ImmunoTherapy of Cancer recently.
Sherry
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