Verapamil results in increased blood levels of oncolytic adenovirus in treatment of patients with advanced cancer - PubMed (original) (raw)

Verapamil results in increased blood levels of oncolytic adenovirus in treatment of patients with advanced cancer

Anniina Koski et al. Mol Ther. 2012 Jan.

Abstract

Calcium channel blockers including verapamil have been proposed to enhance release and antitumor efficacy of oncolytic adenoviruses in preclinical studies but this has not been studied in humans before. Here, we studied if verapamil leads to increased replication of oncolytic adenovirus in cancer patients, as measured by release of virions from tumor cells into the systemic circulation. The study was conducted as a matched case-control study of advanced cancer patients treated with oncolytic adenoviruses with or without verapamil. We observed that verapamil increased mean virus titers present in blood after treatment (P < 0.05). The frequency or severity of adverse events was not increased, nor were cytokine responses or neutralizing antibody levels different between groups. Signs of possible treatment-related clinical benefits were observed in both groups, but there was no significant difference in responses or survival. Thus, our data suggests that the combination of verapamil with oncolytic adenoviruses is safe and well tolerated. Moreover, verapamil treatment seems to result in higher virus titers in blood, indicating enhanced overall replication in tumors. A randomized trial is needed to confirm these findings and to study if enhanced replication results in benefits to patients.

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Figures

Figure 1

Figure 1

Higher virus titers seen in serum of patients treated with verapamil. (a) Percentage of serum samples positive for oncolytic virus DNA as detected by quantitative PCR. (b) Maximum titers in serum samples within the indicated time interval after treatment. (c) Floating bars plot showing mean virus titers (horizontal line) in positive serum samples after treatment, with ranges (box). (d) Virus titers in serum during first cycles of oncolytic adenovirus treatments with (n = 6) and without (n = 6) verapamil. Horizontal line indicates mean. (e) Virus titers in serum after treatments (n = 30+30) of patients who had received prior adenovirus treatments. (f) Mean virus titers of all samples at each time point plotted at respective time points (median of sample days) for illustration of area under the curve analysis.

Figure 2

Figure 2

Verapamil does not affect cytokine responses. Serum samples were analyzed at several time points for levels of inflammatory cytokines (a) interleukin (IL)-6, (b) IL-8, (c) IL-10, (d) tumor necrosis factor (TNF)-α, and (e) GM-CSF, shown as dot plots with horizontal line at mean cytokine concentration. *P < 0.05 and **P < 0.01 between the two time points indicated by the capped line. There were no significant differences between verapamil patients and controls at any time point.

Figure 3

Figure 3

Verapamil does not impact neutralizing antibody responses. Neutralizing antibody titer against the virus used in each treatment was determined by serial dilutions of serum samples. Illustrated as median neutralizing antibody titer for each time point for (a) treatment cycles (n = 6+6) of patients with no previous adenovirus treatments and (b) treatment cycles (n = 30+30) of patients who had received prior adenovirus treatments. *P < 0.05 against neutralizing antibody titer at baseline. There was no significant difference between verapamil patients and controls.

Figure 4

Figure 4

Response rates and survival in verapamil patients and controls. Responses were analyzed (a) radiologically, (b) with tumor markers measured from blood, (c) symptom alterations, and (d) overall signs of efficacy (radiology, markers, symptoms). DC, disease control; PD, progressive disease, i.e., stable disease or better response. (e) Kaplan–Meier analysis of overall survival of patients. Patients who were still alive at the time of submission of the manuscript were censored (tick marks). No significant differences were seen (P = 0.457). P values and n indicated in figures.

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