Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction

Abstract

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Screening and enrollment of study participants. Flowchart depicts the enrollment process for all individuals contacted for study participation. Of the 17 patients evaluated for enrollment at the predose 1 visit, 11 were enrolled (all subjects treated with AdhAQP1) and 6 were deemed ineligible, for the reasons indicated in the figure.

Fig. 2.

Summary of clinical response data. Clinical responses following vector delivery as measured by (A) absolute parotid salivary flow rate from the targeted gland and (B) the proportional increase in peak parotid salivary flow shown as the percent of baseline. Statistical significance was determined using the Wilcoxon matched-pair rank test for the change in absolute values. The Wilcoxon signed rank test was used to test if the peak proportional increase in parotid salivary flow was significantly different from the baseline (100%). Individual changes in parotid salivary flow are shown (C) for absolute salivary flow rates and (D) for proportional changes compared with baseline. Coding for individual subjects is shown as indicated in the Inset in C. All subjects shown in black were considered nonresponders (< 50% increase in salivary flow rate; see text). All subjects shown in colors were considered responders (at least 50% increase in parotid salivary flow rate following AdhAQP1 administration). The days indicated to the right of each peak data point correspond to the days on which that peak parotid flow rate was observed. Visual analog scale (VAS) results from all subjects, at baseline and peak time of parotid salivary flow, are shown for both the amount of saliva perceived (E) (rate how much saliva is in your mouth) and dryness of their mouth (F) (rate the dryness in your mouth). Note that lower VAS results indicate an improvement in symptoms. The colors and symbols used to identify individual subjects are identical to those shown in C. See text for additional details.