Elsevier

Gynecologic Oncology

Volume 130, Issue 3, September 2013, Pages 518-524
Gynecologic Oncology

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

https://doi.org/10.1016/j.ygyno.2013.06.003Get rights and content

Highlights

  • Ad5/3-Δ24 is a serotype chimeric, infectivity enhanced CRAd.

  • Ad5/3-Δ24 has shown oncolysis and antitumor activity in preclinical ovarian cancer models.

  • Recurrent ovarian & other select gynecologic cancer patients were treated with IP Ad5/3-Δ24.

  • At the doses evaluated, Ad5/3-Δ24 is a safe potential therapeutic option in these patients.

Abstract

Objective

The conditionally replicative adenovirus Ad5/3-Δ24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Δ24 achieves significant oncolysis and anti-tumor activity in ovarian cancer models. The purpose of this study was to evaluate in a phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Δ24 in recurrent ovarian cancer patients.

Methods

Eligible patients were treated with IP Ad5/3-Δ24 for 3 consecutive days in one of three dose cohorts ranging 1 × 1010–1 × 1012 vp. Toxicity was assessed utilizing CTC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response.

Results

Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grades 1–2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased CA-125 from pretreatment levels one month after treatment. Ancillary biologic studies indicated Ad5/3-Δ24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody effect.

Conclusions

This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Δ24, as a potential therapeutic option for recurrent ovarian cancer patients.

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).

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