Replication Competent Adenoviruses in Cancer Patients

A. Clinical Trial Results with Wild-Type Adenovirus

Over the past century a diverse array of viruses were injected into cancer patients by various routes, including adenovirus, Bunyamwara, Coxsackie, dengue, feline panleukemia, Ilheus, mumps, Newcastle disease virus, vaccinia, and West Nile [1, 45-47], These studies illustrated both the promise and the hurdles to overcome with oncolytic viral therapy. Unfortunately, these previous clinical studies were not performed to current clinical research standards, and therefore none give interpretable and definitive results. At best, these studies are useful in generating hypotheses that can be tested in future trials.

Although suffering from many of the trial design flaws listed below, a trial with wild-type adenovirus is one of the most useful for hypothesis generation but also for illustrating how clinical trial design flaws severely curtail the utility of the study results. The knowledge that adenoviruses could eradicate a variety of tumor cells in vitro led to a clinical trial in the 1950s with wild-type adenovirus. Ten different serotypes were used to treat 30 cervical cancer patients [47]. Forty total treatments were administered by either direct intratumoral injection (n = 23), injection into the artery perfusing the tumor (n = 10), treatment by both routes (n — 6), or intravenous administration (n = 1). Characterization of the material injected into patients was minimal. The volume of viral supernatant injected is reported, but actual viral titers/doses are not; injection volumes (and by extension doses) varied greatly. When possible, the patients were treated with a serotype to which they had no neutralizing antibodies present. Corticosteroids were administered as nonspecific immunosuppressive agents in roughly half of the cases. Therefore, no two patients were treated in identical fashion.

Nevertheless, the results are intriguing. No significant local or systemic toxicity was reported. This relative safety is notable given the lack of preexisting immunity to the serotype used and concomitant corticosteroid use in many patients. Some patients reported a relatively mild viral syndrome lasting 2-7 days (severity not defined); this viral syndrome resolved spontaneously. Infectious adenovirus was recovered from the tumor in two-thirds of the patients for up to 17 days postinoculation.

Two-thirds of the patients had a "marked to moderate local tumor response" with necrosis and ulceration of the tumor (definition of "response" not reported). None of the seven control patients treated with either virus-free tissue culture fluid or heat-inactivated virus had a local tumor response (statistical significance not reported). Therefore, clinically evident tumor necrosis was only reported with viable virus. Neutralizing antibodies increased within 7 days after administration. Although the clinical benefit to these patients is unclear, and all patients eventually had tumor progression and died, this study did demonstrate that wild-type adenoviruses can be safely administered to patients and that these viruses can replicate and cause necrosis in solid tumors despite a humoral immune response. The maximally tolerated dose, dose-limiting toxicity, objective response rate, and time to tumor progression, however, remain unknown for any of these serotypes by any route of administration.

B. A Novel Staged Approach to Clinical Research with Replication-Selective Viruses: The Example of d/1520 (Onyx-Ol 5)

For the first time since viruses were first conceived as agents to treat cancer over a century ago, we now have definitive data from numerous phase I and II clinical trials with a well-characterized and well-quantitated virus. dl1520 (Onyx-O15, a.k.a., CI-1042, Pfizer, Inc.) is a novel agent with a novel mechanism of action. This virus was to become the first virus to be used in humans that had been genetically engineered for replication selectivity. We predicted that both toxicity and efficacy would be dependent on multiple

Staged Development approach: Replication-selective agents for cancer

Intra tumoral ► ► (+) chemotherapy antitumoral combination data activity

Intra peritoneal

/n/ra-arterial/hepatic artery

Intra venous

Staged Development approach: Replication-selective agents for cancer

Figure 4 Staged clinical research and development approach used in research and development with dl1520 (Onyx-Ol 5). Once safety and biological activity was demonstrated by the intratumoral route, clinical trials were initiated sequentially to study intracavitary instillation (initially intraperitoneal), intraarterial infusion (hepatic artery) and eventually intravenous administration. Only patients with advanced and incurable cancers were enrolled on trials initially. Once safety was demonstrated in these patients, trials were initiated in patients with premalignant lesions. Finally, clinical trials of combinations with chemotherapy were initiated only after the safety of dl1520 as a single agent had been documented by the relevant route of administration. Reprinted with permission from Gene Therapy.

Figure 4 Staged clinical research and development approach used in research and development with dl1520 (Onyx-Ol 5). Once safety and biological activity was demonstrated by the intratumoral route, clinical trials were initiated sequentially to study intracavitary instillation (initially intraperitoneal), intraarterial infusion (hepatic artery) and eventually intravenous administration. Only patients with advanced and incurable cancers were enrolled on trials initially. Once safety was demonstrated in these patients, trials were initiated in patients with premalignant lesions. Finally, clinical trials of combinations with chemotherapy were initiated only after the safety of dl1520 as a single agent had been documented by the relevant route of administration. Reprinted with permission from Gene Therapy.

factors including (1) the inherent ability of a given tumor to replicate and shed the virus, (2) the location of the tumor to be treated (e.g., intracranial vs peripheral), and (3) the route of administration of the virus. In addition, we felt it would be critical to obtain biological data on viral replication, antiviral immune responses and their relationship to antitumoral efficacy in the earliest phases of clinical research.

We therefore designed and implemented a novel staged clinical research and development approach with this virus (Fig. 4). The goal of this approach was to sequentially increase systemic exposure to the virus only after safety with more localized delivery had been demonstrated. Following demonstration of safety and biological activity by the intratumoral route, trials were sequentially initiated to study intracavitary instillation (initially intraperitoneal), intraarterial infusion (initially hepatic artery), and eventually intravenous administration. In addition, only patients with advanced and incurable cancers were initially enrolled on trials. Only after safety had been demonstrated in terminal cancer patients were trials initiated for patients with premalignant conditions. Finally, clinical trials of combinations with chemotherapy were initiated only after the safety of dl1520 as a single agent had been documented by the relevant route of administration.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment