Cancer Vaccines: A Shot in the Dark?

London Thursday April 14, 2005- The idea of developing cancer vaccines is far from a novel concept. In fact initial attempts using tumor immunotherapy to combat cancer were made in the late 19th century by American Dr William Coley. Dr Coley administered bacterial extracts known as Coley's toxins to patients with advanced cancer in the hope of inducing a non-specific systemic immune response and immune-mediated anti-tumor effects. Unfortunately, despite Coley's early efforts and those of numerous investigators in the intervening years, over a century later there is still no effective therapeutic cancer vaccine on the market, according to a new report from independent market analyst Datamonitor*.

Grand plans

The concept of cancer vaccines is a promising idea, but putting the theory into practice has proved extremely difficult. To date, very few large-scale clinical trials have demonstrated a survival benefit associated with a cancer vaccine and studies have experienced a high rate of clinical failure, says Datamonitor oncology analyst Fleur Pijpers. "Overcoming immune tolerance appears to be the key to success, however translating the basic knowledge into clinical practice has proved difficult," she says.

Cancer vaccines are currently being developed to confer active, specific immunotherapy directed against tumor-associated antigens, while inducing minimal systemic toxicity. This approach offers advantages over the relatively crude nature of conventional cancer treatments such as chemotherapy, which attacks all dividing cells (including healthy ones) in order to kill the tumor and may be associated with unpleasant side effects such as nausea, vomiting and alopecia, Pijpers says. "However cancer vaccines are unlikely be regarded as a replacement for current therapies. At best they will serve to complement current therapies, with the potential to eliminate the need for multiple lines of treatment."

The lack of any commercial success in the cancer vaccines market to date reflects the fact that ongoing development has brought to light an entirely new set of clinical, regulatory and strategic challenges. A lack of precedent is reflected by the fact that regulatory procedures pertaining to cancer vaccines are not well developed and standardized response assessment criteria need to be established to facilitate the approval of cancer vaccines.

Fragmented market

The cancer vaccine market is highly fragmented with at least 64 companies involved in clinical development, 80% of which are small biotechnology firms, Pijpers says. "Companies with multiple cancer vaccine candidates in development have relatively immature portfolios, therefore opportunity for commercial success cannot be based on pipeline volume alone. As a result, it is difficult to identify a key player within this market."

"However, several companies are supported by strong strategic partnerships with major oncology players which are likely to facilitate the path to commercialization by providing human capital and financial resources to aid negotiation of clinical, strategic and regulatory challenges," she says.

While most 'generalized' vaccine approaches are capable of mass manufacture and confer minimal safety and sterility concerns, others, specifically autologous formulations, are associated with cost-effectiveness issues, Pijpers says. "Autologous vaccines are made from the cells of a patient's surgically removed tumour. The need for patient-specific cells incorporates extra costs into the manufacturing process, affecting the ability to achieve economies of scale, and there are also transport and logistics issues."

"Consequently, three quarters of cancer vaccines currently in the development pipeline are generalized vaccines, a trend that reflects the ease of manufacture and economies of scale achieved via this formulation."

Antigen-specific cancer vaccines dominate all phases of development, constituting 60% of the current pipeline. This is due to their relatively high specificity, ease of manufacture, opportunity for repeated administration and low level of safety concerns in comparison to autologous or cell-based vaccines. Cell-based therapies constitute 36% of the development pipeline, Pijpers says. "Although their manufacture and formulation confers significant complexity, as well as post-production sterility and distribution concerns, it is this vaccine strategy that has provided the most compelling clinical evidence to date," she says.

In terms of indication, potential commercial rewards tend to dictate tumor focus. The 'big four' tumor types- breast, prostate, colorectal and non-small cell lung cancer - will always remain commercially attractive targets purely due to the sheer size of these patient populations.

Melanoma and renal cell carcinoma are also favorable targets, because they are the tumor types that have been most extensively studied in terms of oncology immunology and there is an established evidence base demonstrating that both tumor types may respond to immunotherapeutic treatment, Pijpers says. "Pancreatic cancer is characterized by an aggressive nature, high levels of resistance to conventional therapy and an exceedingly poor patient prognosis. By approaching its treatment from a different angle and employing a novel immunotherapeutic approach such as a cancer vaccine, it is hoped that some of these challenges can be mitigated."

Opportunities rife for promising vaccine candidates

The cancer vaccine market remains wide open, although two late-phase pipeline candidates have shown potential for commercialization:

CancerVax/Serono's Canvaxin and Dendreon's Provenge. Canvaxin constitutes an allogeneic formulation: indicating that cultured tumor cell lines are used to formulate the vaccine, rather than patient-specific cells. This should help expedite Canvaxin's path to commercialization despite the fact that a recent Phase III trial evaluating the vaccine in stage IV (metastatic) melanoma did not show any benefit over placebo, Pijpers says. "Another phase III study is still ongoing, this time in stage III disease. We still think that this has a good chance of demonstrating the vaccines clinical benefit because it is evaluating Canvaxin in the same context as an earlier phase II study which demonstrated improved 5-year and median overall survival compared to patients who received no further treatment."

"It is also notoriously difficult to demonstrate efficacy benefit in metastatic melanoma. Given the immunologic mechanism of cancer vaccines Datamonitor believes it's unlikely that any cancer vaccine, used alone, would be able to show significant clinical benefit in this context. It's much better to use cancer vaccines in the context of minimal residual disease, post surgery, when the immunologic response that the vaccine generates will be most effective in preventing relapse and prolonging disease stabilization," she says.

Provenge is forging the way within the technologically appealing dendritic cell cancer vaccine class, Pijpers says. "Despite not meeting its primary endpoint of time to progression, Provenge is the first cancer vaccine to demonstrate an overall survival benefit in large-scale, randomized Phase III clinical trials."

Sales forecasts to 2014 for the late-phase cancer vaccines are not particularly high in comparison to traditional oncology products. "Certainly no therapeutic vaccine is set to achieve blockbuster status, as it is likely to take some time before the concept is fully integrated into established clinical practice," Pijpers says. "That said, Provenge is forecast to achieve the highest level of sales: Datamonitor is forecasting $194 million by 2014."

"Ultimately, despite Dr William Coley's best intentions more than a century ago, it seems more time is going to pass by before we see cancer vaccines playing a significant role in cancer treatment."

* Pipeline Insight: Cancer Vaccines and Cell Therapies - Technical Know How Needs Translation Into Clinical and Commercial Rewards

Datamonitor analysts are available for comment

Footnotes

1)         Wiemann & Starnes, 1994

Datamonitor

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(18/4/05)