A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer☆
Introduction
Nearly 22,000 ovarian cancer patients are diagnosed in the U.S. annually [1]. With no effective screening, symptoms are often nonspecific and the majority of affected patients present with advanced disease. Though advances in surgical cytoreduction and cytotoxic chemotherapy have improved median survival, most patients develop chemotherapy resistance and ultimately succumb to their disease [2], [3], [4], [5]. Thus, there is a need for novel therapeutic approaches for this disease.
To address this need, several gene therapy strategies have been evaluated for ovarian cancer treatment [6], [7]. Virotherapy utilizing serotype-5 conditionally-replicative adenoviruses (CRAds) has been the basis for one such approach. This strategy takes advantage of the propensity of serotype-5 CRAds to infect cancer cells, replicate selectively within these cells, and induce cell death via oncolysis. The prototype CRAd, ONYX-015, was a serotype-5 adenovirus modified to conditionally replicate in cells with p53 deficiencies. ONYX-015 has been evaluated in early phase trials, demonstrating feasibility and safety when administered intraperitoneally (IP) to patients with recurrent ovarian cancer [8], [9]. However, the clinical utility of serotype-5 CRAds, such as ONYX-015, in ovarian cancer may be hampered by their inability to effectively infect ovarian cancer cells due to the paucity of the primary serotype-5 adenoviral cell surface receptor, the coxsackie-adenovirus receptor (CAR), on their surface [10], [11].
We have developed several novel approaches designed to enhance the infectivity of serotype-5 adenoviruses utilizing various CAR-independent pathways. In one of these approaches, we have modified a serotype-5 adenovirus by replacing its knob with a serotype-3 knob onto its fiber (Supplemental Fig. 1). This alters the tropism of these 5/3 serotype-chimeric adenoviruses towards serotype-3 adenoviral receptors, which are more abundantly expressed by ovarian cancer cells [12]. Our preclinical studies have demonstrated a reporter-gene-expressing Ad5/3 chimeric adenoviral vector to display higher transgene expression compared to unmodified reporter-gene-expressing adenoviral vectors in established and primary ovarian cancer cells [13].
This 5/3 serotype-chimeric fiber knob modification has been incorporated into the CRAd, Ad5/3-Δ24 [14] (Supplemental Fig. 1). Ad5/3-Δ24 contains a 24-base-pair deletion in the E1A constant region 2 (CR2) allowing for selective replication within Rb-p16-deficient tumor cells, a deficiency observed in most ovarian cancer cells [15], [16]. The replicative and oncolytic potency of Ad5/3-Δ24 has been confirmed in vitro in various established and primary ovarian cancer cell lines [14]. Additional preclinical studies have established the antitumor activity of Ad5/3-Δ24 in in vivo ovarian cancer models [14]. Biodistribution and safety studies conducted in Syrian hamsters demonstrated that IP-administered Ad5/3-Δ24 remained predominantly confined to the abdominal cavity and was well-tolerated [17]. Thus, Ad5/3-Δ24 seemed suited to be evaluated in early phase clinical trials in the context of gynecologic cancers.
The primary purpose of this study was to determine the maximum tolerated dose (MTD) and toxicities associated with IP administration of Ad5/3-Δ24 in patients with selected recurrent ovarian and other select gynecologic cancers. The antitumor activity and biologic effects were also assessed.
Section snippets
General design
This was a standard 3 + 3 dose-escalating phase I trial evaluating IP Ad5/3-Δ24 in cohorts of eligible patients. The study was approved by both the Institutional Review Board (IRB) and the Institutional Biosafety Committee (IBC) of the University of Alabama at Birmingham (UAB). The study was also approved by the NIH Recombinant DNA Advisory Committee and the U.S. Food and Drug Administration (FDA).
Eligibility
Eligible patients included women 19 years or older with recurrent epithelial ovarian, primary
Patient demographics and treatment
From June 2010–December 2011, 10 patients met eligibility criteria and were enrolled in the study. One patient experienced a complication related to IP catheter placement, and did not receive treatment. Table 1 summarizes patient demographics. All other nine patients completed Ad5/3-Δ24 treatment according to protocol without dose interruptions.
Toxicity associated with intraperitoneal administration of Ad5/3-Δ24
As noted, one patient had a complication related to the placement of her IP catheter and was not treated per protocol. Briefly, she developed sepsis the
Discussion
Various tropism alterations to enhance the cellular infectivity of adenoviral based gene therapeutics have been accomplished. This study reports on the safety and potential efficacy of the novel infectivity-enhanced, serotype-chimeric adenovirus Ad5/3-Δ24 in patients with recurrent ovarian and other select gynecologic cancers. Incorporation of the serotype-3 knob onto the serotype-5 fiber in this CRAd enhances infectivity and improves oncolysis in ovarian cancer models [12], [13], [14]. In this
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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Financial support: This project has been funded in whole or in part with funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was also supported by the UAB Comprehensive Cancer Center's Clinical Protocol and Data Management Shared Facility (P30 CA013148).