• 8/26/2005
  • Hampshire, England
  • Fleur Pijpers, Richard Faint & Nish Saini
  • Nature Reviews Drug Discovery 4, 623-624 (2005);

Unmet needs across the oncology market remain high, with most traditional therapies representing a trade-off between levels of specificity, efficacy and toxicity. The development of therapeutic cancer vaccines, designed to confer active, specific immunotherapy directed against tumour-associated antigens (TAAs), could be the ideal solution for the successful eradication of some cancers. Cancer vaccines offer the prospect of high specificity, low toxicity and prolonged activity. However, although there is a solid technical and scientific rationale behind the development of vaccines, this theory has yet to be consistently translated into clinical practice and, to date, most cancer vaccines have been associated with high rates of clinical failure. Beyond scientific hurdles, the relative immaturity and lack of precedence in the cancer vaccine market has also brought to light an entirely new spectrum of clinical, regulatory and strategic challenges.

Challenges in an unprecedented market

From a clinical perspective, cancer vaccines are most likely to complement current oncology therapies rather than serve as replacements. However, some cytotoxics have known immunosuppressive properties, and therefore the optimal scheduling of chemotherapy administration needs to be defined in order to avoid compromising the activity of therapeutic cancer vaccines.

The design of clinical trials for cancer vaccines and the regulatory assessment of vaccine technologies raise additional issues: as a result of their mode of action and hypothetical prolonged antitumour activity, the optimal assessment of cancer vaccines might require a shift away from the established endpoint designations that have been used to evaluate traditional oncology therapies. For example, prolonged disease stabilization might be a more relevant endpoint to the design of cancer vaccine trials than any measurement of tumour regression. For this reason, and given our understanding of tumour growth kinetics, cancer vaccines are more likely to demonstrate clinical benefit in the setting of minimal residual disease rather than in metastatic disease. Developers, however, seem reluctant to re-focus their efforts on the former, because demonstrating clinical benefit will require a longer and subsequently more costly patient follow-up than is required in the setting of more advanced disease.

Coordinated efforts between the major global regulatory bodies and cancer vaccine researchers will facilitate the development of relevant assessment criteria of patient response that can be reproducibly applied to the design and evaluation of technologies in ongoing clinical development. It has been widely suggested that immune monitoring might constitute a viable response criterion for the assessment of cancer vaccines, although optimal methods for measuring this have yet to be developed.

Current pipeline

The current cancer vaccine market is characterized by a dearth of approved products, although a dynamic and dense pipeline is set to change this. With at least 78 agents in clinical development and the involvement of at least 64 companies, the market is wide open. Although regulatory procedures for cancer vaccines need adapting, the first product to reach the market will smooth the way forward for all those behind it and overcome the associated challenges.

Classification of vaccine technologies

Three-quarters of the current cancer vaccine pipeline comprises ‘generalized’ or ‘off-the-shelf’ vaccines that are based on specific carbohydrates, proteins or other easily replicated structures that are capable of being mass produced. The remainder consist of ‘personalized’ or autologous vaccines; these are based on antigens harvested from individual patient’s tumour cells. This trend reflects the ease of manufacture and economies of scale achievable with generalized vaccines.

The ‘generalized’ and ‘personalized’ vaccine classifications can each be further subdivided into one of three types: polyvalent, antigen-specific and dendritic-cell-based approaches; and within the first two categories further sub-classifications of vaccine type can be defined. Antigen-specific cancer vaccines dominate all phases of clinical development, constituting 63% of the R&D pipeline. Their dominance is secondary to their perceived higher specificity, ease of production, lower cost of manufacture and reduced levels of concern related to product contamination.

Despite this trend, it is unclear what class of vaccine is likely to dominate the future vaccine market, if any. ‘Generalized’ vaccines, in part a result of their limited range of ‘relevant’ antigen expression, have been associated with a higher rate of clinical failure than ‘personalized’ approaches.

To date, despite concerns related to the complexity of manufacture and formulation, as well as post-production sterility and distribution concerns, it is has been a ‘personalized’ dendritic cell-based vaccine strategy that has provided the most compelling clinical evidence. Dendreon’s Provenge constitutes patient-specific dendritic cells loaded with a TAA (prostatic acid phosphatase), and is the only vaccine to date to demonstrate a survival benefit in a large-scale randomized trial for prostate cancer, despite not meeting its primary endpoint of time to progression.

Commercial rewards dictate focus

The ‘big four’ tumour types of breast, prostate, colorectal and lung cancer remain commercially attractive indications for developers because of their high patient potential and commercial value. Furthermore, melanoma and renal-cell carcinoma are also the focus for developers, given their tractability to immunotherapy. However, it is the haematological tumours such as leukaemia, lymphoma and myeloma that are perhaps the ideal target indication owing to their anatomical location, which facilitates the access of vaccine-generated immune-effector cells.

Future focus

There are many aspects of commercializing cancer vaccines that will require developers, regulators and clinicians to collaborate on an unprecedented level to expedite the delivery of these new therapies to patients. One of the single biggest challenges will be to bring together the keepers of disparate intellectual property — for example, vaccine-delivery technologies, immune adjuvants and formulation techniques — and combining these pools of expertise to produce effective cancer vaccines with broad clinical application. On the basis of forecast peak sales and the assumption that the most promising Phase III pipeline candidates are granted marketing approval, Datamonitor estimates that the potential worth of the therapeutic cancer vaccine market will be US$633 million by 2014.

Market indicators

The current cancer vaccine market is highly fragmented, and comprises at least 78 clinical development agents. At present, 18% of these pipeline candidates are in Phase III clinical trials or pre-registration, whereas 33% and 49% are in Phase II and Phase I clinical trials, respectively. The pipeline is dominated by antigen specific cancer vaccines.

At least 64 companies are involved in clinical R&D, 80% of which are small biotechnology firms. Strategic collaborations with established oncology players will expedite the path to market by providing the marketing and development expertise, as well as financial resources, necessary to negotiate the unique clinical, strategic and regulatory challenges that the commercialization of cancer vaccines presents. However ‘big pharma’ still needs convincing that vaccines are a risk worth backing. The success of one or two cancer vaccines will stimulate the formation of developmental partnerships.

Using epidemiology-based forecast peak sales and the assumption that the most promising pipeline candidates in Phase III clinical trials are granted marketing approval, we estimate that the market could be worth US$633 million by 2014.

Authors’ affiliations:
Fleur Pijpers, M.Eng., is an Oncology Analyst, Richard Faint, M.B.A., Ph.D., is Lead Oncology Analyst and Nish Saini, Pharm.D., is a Senior Oncology Analyst at Datamonitor Healthcare, Charles House, 108–110 Finchl