Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers

Abstract

We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15-30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.

Figure 1

Acute pharmacokinetics after virus treatment. The virus genomic DNA in the sera was quantified by qPCR at 15 minutes, 30 minutes, and 4 hours post-virus infusion. Shown are data from patients who received the virus doses at 3.0e8, 1.0e9, and 3.0e9 pfu. For the virus dose at 3.0e9 pfu, the quantities of the virus genome in the blood are statistically higher than those at two lower doses at 15 and 30 minutes post-treatment (**P < 0.01).

Figure 2

The antibodies against vaccinia virus in the sera of patients right before treatment and 22 days PT. The anti-VV antibodies as measured by enzyme-linked immunosorbent assays (ELISA). (a) The data were collected on sera from patients who received the virus dose at 1.0E9 PFU (n = 3). The “vaccinated control” indicated a healthy volunteer from our laboratory who was vaccinated with smallpox vaccine 5 years ago and served as a control to patients who had been vaccinated 54–76 years ago. (b) The data were collected on sera from patients who received the virus dose at 3.0E9 PFU (n = 3). (c) Shown are another presentation on the mean values when the sera were diluted at 1: 5,120. Data on D0 (day 0) provided the baseline and the data on D22 (day 22) post-treatment showed increased titers of antisera as determined by ELISA assays. The data are mean ± SD from six patients treated at two higher doses of the virus.

Figure 3

Detection of the virus at non-tumor sites in two patients. (a) Patient #3 developed an exuative ulcer on the forearm on day 4 post-treatment. This lesion was biopsied on day 4 and the exudate was subjected to analysis of the infectious virus. (b). Patient #9 had oral thrush at the time of virus administration. Lip swab was performed on day 3 to detect infectious virus.

Figure 4

Cytokine levels in plasma. Cytokine concentrations in the plasma collected before and 4 hours after vvDD treatment were determined via Luminex assays. (a) The whole panel of cytokines assayed. All cytokines were analyzed on a logarithmic scale except those denoted by * were analyzed using the Box-Cox transformation method. * indicated adjusted P values based on log-transformed values. (b) Key inflammatory cytokines (IL-6 and IL-8). (c) Th1 (IL-2, IFN-γ, and TNF-α) and Th1-related (IL-7 and GM-CSF) cytokines. (d) Th2 cytokines (IL-4, IL-5, and IL-13). Pre-T: pretreat; Post-T: 4 hours post-treatment. The P values in the graphs are indicated, *P < 0.05; **P < 0.01; ns: no significant.

Figure 5

Clinical activity of vvDD in cancer patients after systemic delivery. (a). One patient with cutaneous lesions (patient #4, with melanoma) was photographed before and 23 days after treatment. The clinical regression of lesions is shown by necrosis of an in-transit metastasis at 23 days post-treatment. (b). The patient #2 with metastatic colorectal cancer in the liver demonstrated a mixed response 6 weeks after treatment on PET-CT with resolution of some of the liver metastases.