Cancer is the second-leading cause of death in the United States, responsible for one in four fatalities and contributing to $180 billion in direct medical costs. The American Cancer Society estimates that approximately 1.3 million new cases of cancer were diagnosed in the United States during 2001, with seven of the most common cancers accounting for 68% of these cases (Table 1). Today, a diagnosis of cancer is not necessarily a death sentence: there were nearly 9 million cancer “survivors” living in the United States in 1999 (ref. 1), suggesting that current cancer treatments are effective. However, the standard options—surgery, radiotherapy, and chemotherapy—have debilitating and distressing side effects, destroying healthy tissues along with rogue cancer cells.

Table 1 New cases of cancer diagnosed in the United States during 2001
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Will vaccines become an integral part of the treatment of cancer patients in the future? Credit: © Tom & Dee Ann McCarthy, Corbis

Fortunately, biotechnology has opened up avenues for the development of gentler and more selective treatments. For example, the Food and Drug Administration (FDA; Rockville, MD) recently approved two new antibody-based “chemotherapies”: IDEC Pharmaceuticals' (San Diego, CA) Zevalin, a monoclonal antibody attached to the radioisotope Yttrium-90, and Wyeth Pharmaceuticals' (Collegeville, PA) Mylotarg, a monoclonal antibody linked to the anti-tumor agent calicheamicin. Unlike standard chemotherapies, these monoclonal-based agents are designed to deliver their toxic payload specifically to cancer cells, leaving healthy cells unharmed.

Nevertheless, all too frequently, patients face a relapse during treatment or a recurrence of their cancers after treatment is complete. Currently, basic and clinical research is centered on developing so-called therapeutic cancer vaccines for patients who already have cancer. Once the safety and efficacy of the current generation of therapeutic products has been established, next-generation vaccines that could stop cancers growing in the first instance—prophylactic cancer vaccines—will be further investigated. Then, at-risk patients could be inoculated against the cancers that threaten them the most.

To date, research has yielded several cancer vaccines that are now on the market, and over 50 products that are in clinical trials. This retrospective study presents an overview of the clinical development of therapeutic cancer vaccines, highlights the challenges to the development of these products, and finally questions whether these challenges will become obstacles to getting these potentially life-saving products on the market.

Natural born killers

Cancers develop because the body's surveillance system fails. Exactly why the immune system fails to detect and eliminate cancer cells is still poorly understood, but several factors likely contribute. First, cancers arise from the malfunction of healthy cells, so they may not elicit an immune response because they are regarded by the body as “self.” In addition, tumors can actively curb the function of the immune system by secreting immunosuppressive agents and expressing molecules that can induce the death of white blood cells2,3. However, regardless of whether the cancer is invisible to the immune system, or is simply not immunogenic enough, cancer vaccines are designed to boost an anticancer immune response.

In theory, the mode of action of a cancer vaccine is simple: the vaccine prompts the immune system to produce anti-tumor antibodies and cytotoxic T lymphocytes (killer T cells), which target, kill, and clear malignant cells2. In reality, achieving the desired immune response is not so simple: the cancer vaccine must stimulate the immune system in such a manner that healthy cells are spared and only cancerous cells destroyed. To achieve this end, cancer vaccines currently under clinical study incorporate antigens (foreign molecules that stimulate the host's immune system) specific to a particular cancer type. However, cancer antigens alone are weakly immunogenic, and the use of additional immunostimulatory molecules is generally necessary. Furthermore, autoimmunity against native antigens on healthy cells might be induced if the antigen is not sufficiently cancer specific4. Therefore, cancer vaccines must produce a delicate balance between two undesirable states of the immune system—understimulation and overstimulation.

Many means to an end

Cancer vaccines consisting of antigens of varied composition, identity, and source have been studied clinically. Products might consist of antigens that are recombinant proteins, synthetic peptides, carbohydrates, extracted tumor-derived proteins, or monoclonal antibodies. Alternatively, the product might be DNA encoding the antigen of interest. The identity of the antigen used depends on the type of cancer, although some antigens are associated with multiple types5,6. For example, carcinoembryonic antigen (CEA) is the target for several colorectal cancer vaccines, whereas MUC-1 and HER-2 are target antigens for several breast cancer vaccines.

Whole cells displaying cancer-associated antigens can also be used as vaccines. Cells can be derived from two sources: the cancer itself and the immune system. In the first instance, cancer cells are killed (usually by irradiation), then modified either genetically or chemically to increase their immunogenic potential. The identity of the tumor-specific antigens need not be known because the cell itself becomes the vaccine and the immunological key to the destruction of its cancerous relatives. The second method involves producing dendritic cells (DCs) that directly present the tumor antigen to the immune system. DCs are one of a group of so-called antigen-presenting cells, which includes monocytes, macrophages, and antibody-secreting B lymphocytes (B cells), and they can be cultured in large numbers in vitro7. The DCs are loaded with the desired antigen using electroporation and can also be genetically modified to secrete an additional immune-response stimulant such as granulocyte macrophage colony stimulating factor (GM-CSF).

Whether made up of isolated antigens or whole cells, cancer vaccines can be derived from either the patient's own cells (autologous products) or from those of human donors (allogenic products). The specificity of autologous preparations might increase the effectiveness of the treatment, but the manufacture of such vaccines is labor intensive and time consuming, and products would not be available immediately. On the other hand, allogenic products may be easier to produce, being made from commonly expressed antigens (such as CEA), and would be available “off the shelf”; allogenic products are not, however, patient specific and therefore could be less effective.

Cancer vaccines in the clinic

The pharmaceutical and biotechnology industry's interest in cancer vaccines is revealed here in an analysis of the number of companies that initiated studies of these products during the past decade (Fig. 1, and see “Analysis criteria”). From 1993 to 2001, 28 companies that had not previously developed cancer vaccines initiated clinical studies of at least one product, and at least three products have entered clinical study each year since 1993 (Fig. 1). However, few companies have expanded their development programs for cancer vaccines during this period. The majority (61%) of companies sponsored clinical studies of just one product, and only five (15%) sponsored clinical studies of more than three cancer vaccines. Development of cancer vaccines might be more aggressively pursued when more products are approved and confidence and experience in developing this type of product has increased.

Figure 1: Clinical trials of cancer vaccines initiated annually between 1985 and 2001.
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© Amy Center

Year of first clinical study of cancer vaccine was unknown for one product and one company.

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On the other hand, companies seem to have maintained their commitment to the products that they moved into clinical trials. To date, only 18 of the 70 products that entered clinical study have been discontinued (Table 2). In total, 14 products are in phase 1, 24 products are in phase 2, and 14 products are in phase 3. The products that entered clinical study the earliest have advanced in development the furthest. Of the products that entered clinical study during 1985 to 1989, four (67%) are in phase 3. Nearly half of the products that entered clinical study during 1990 to 1994 are in either phase 3 (26%) or phase 2 (16%). Of products that entered clinical study during 1995 to 1999, only four (11%) are in phase 3, whereas none of the cancer vaccines that entered clinical study during 2000 to 2001 are beyond phase 2.

Table 2 Current status of cancer vaccines in the United States designated by year of first entry into clinical trials
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So far, the pace of clinical development for cancer vaccines is similar to that of monoclonal antibody (mAb) anticancer therapeutics. Approximately half of the 77 mAbs currently in development or under review by the FDA are being studied as treatments for cancer8. The anticancer mAbs currently in phase 2 were in phase 1 for 17 months, whereas those currently in phase 3 were studied for an average of 19 months in phase 1 and 41 months in phase 2. By comparison, cancer vaccines currently in phase 2 were studied an average of 20 months in phase 1, whereas those currently in phase 3 were studied an average of 25 months in phase 1 and 38.5 months in phase 2 (Table 3). Phase 3 length, typically the longest, cannot be calculated for the cancer vaccines because none of the products in the analysis cohort have completed phase 3.

Table 3 Mean and median phase lengths for cancer vaccines and anticancer mAbs
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The duration of clinical trials (combining phases 1–3) for anticancer mAbs and new chemical entities (NCEs) approved in the United States might provide a benchmark for the likely duration of clinical development of cancer vaccines. Currently, five anticancer mAbs are approved in the United States. These mAbs were in clinical development prior to first approval for an average of 83 months. The 11 anticancer NCEs approved in the United States from 1996 to 1998 were in clinical development for an average of 81 months9. In comparison, cancer vaccines in phase 3 have already been in clinical development for a minimum average of 64 months (Table 3), and phase 3 will probably take longer than phase 2 (38.5 months). These data suggest that the clinical development of the cancer vaccines likely to be considered for approval earliest will take a minimum average of 102 months—an even more protracted timeline than that for the clinical development of anticancer mAbs and NCEs.

Previous studies have already shown that clinical development of biopharmaceuticals in general is taking longer10. There are many possible reasons why clinical development is being slowed: studies have become increasingly complex because more procedures are required for each study participant (for example, if a specific side effect is identified, companies feel obliged to check that parameter in all future studies, resulting in an add-on effect for screens) and study costs are rising. In addition, mergers and acquisitions and the in-licensing of products may delay clinical development programs.

The vaccine landscape

Fourteen cancer vaccines are currently in phase 3 of clinical development in the United States (Table 4), and these products are being studied as treatments for five of the most prevalent cancers in the United States. Four are potential treatments for melanoma, and four are being studied as treatments for cancers of the digestive system (colon, rectum, stomach, and pancreas). Two products are being studied for prostate cancer, and two for non-Hodgkin's lymphoma. One cancer vaccine is in clinical studies as a treatment for small-cell lung cancer.

Table 4 Therapeutic cancer vaccines in phase 3 and beyond in the United States
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As the identities of potential antigens are established, competing companies might develop vaccines based on the same target but composed of different molecules (such as peptides, proteins, or DNA) and involving the use of different immunostimulatory adjuvants. For example, at least five melanoma vaccines incorporating the gp100 antigen have entered clinical studies sponsored by four different companies.

Indeed, the wide variety in the type of cancer vaccines in phase 3 studies might reflect the lack of consensus on the best way to produce an immune response to cancerous cells. No single antigen type makes up a majority of the products—six are either peptide or protein antigens, four are whole cells (tumor cells or dendritic cells), two are monoclonal antibodies, one is antigen-encoding DNA, and one is a ganglioside antigen (Table 4).

Marketed products

Three cancer vaccines developed by US-based companies are currently marketed outside the United States (Table 4): OncoVax is marketed in The Netherlands by Intracel (Frederick, MD) as a treatment for colon cancer; Avax Technologies' (Overland Park, KS) M-Vax is licensed for the treatment of melanoma in Australia; and Corixa (Seattle, WA) markets Melacine in Canada for patients with stage IV melanoma.

Both OncoVax and M-Vax are modified autologous tumor cells, and because the cells come from different patients, they have variable composition and inherent batch-to-batch variation. The products are therefore not regulated as therapeutics in The Netherlands or Australia but are custom made in processing facilities that are licensed by the health authorities in the two countries. Melacine is an allogenic cancer vaccine consisting of lysed cells from two human melanoma cell lines combined with a proprietary adjuvant. The product contains at least eleven melanoma-associated antigens (HMW-MAA, Melan-A/MART-1, gp100, TRP-1, S-100, GD2, GD3, MAGE-1, MAGE-2, MAGE-3, and tyrosinase).

All three marketed products are currently in clinical trials in the United States. However, the FDA's recent requests for information about the composition and characterization of two other cancer vaccines—Dendreon's (Seattle, WA) Provenge and CancerVax's (Carlsbad, CA) Canvaxin—suggest that the FDA has yet to clarify the regulation of these cell-based products.

The only cancer vaccines marketed in the United States are three bacillus Calmette–Guérin (BCG) products, which are treatments for carcinoma in situ of the bladder. The BCG therapeutics are different substrains of attenuated Mycobacterium bovis, which first entered clinical studies in 1921 as a vaccine against tuberculosis11. The first marketed therapeutic cancer vaccine was, therefore, derived from a traditional prophylactic vaccine. The BCG cancer vaccines are injected directly into the bladder, and locally stimulate the immune system to kill the cancerous cells. Unlike the antigen-based vaccines currently in development, the exact mode of action of the BCG products is unknown. Therefore, the BCG products are of limited use as models for the cancer vaccines currently in clinical development.

Potential obstacles ahead?

Cancer might become more common in the United States, the European Union, and Japan because the average age of their populations is increasing. In the United States, the number of cancer patients over the age of 85 is expected to increase fourfold between 2000 and 2050 (ref. 1). Progress in medicine already extends the lives of many cancer patients, and so the number of people experiencing relapse or developing metastases may well increase in the future. The therapeutic cancer vaccines currently in clinical development have the potential to help this population of cancer patients.

However, there are several obstacles that could prevent new products from reaching the market. First is the enormous number of tumor antigens, adjuvants, and strategies that could be used to create therapeutic cancer vaccines: it will not be possible to study every permutation in patients to find the optimal product, so effective methods for weeding out preclinical candidate vaccines are needed. Second is the inexperience of the sponsoring companies, the majority of which are biotechnology companies, each with fewer than three cancer vaccines in clinical development and no marketed therapeutics. The pharmaceutical industry can offer little guidance: the few multinational pharmaceutical companies that specialize in vaccines develop prophylactic rather than therapeutic vaccines, and these generally protect against infectious diseases. Third is the novelty of the products: the cancer vaccines are disparate enough that the experiences of one company might not be useful to another.

The most pressing issue is whether these obstacles will result in delays in approvals for the products. Certainly, the novelty of the products could be a drawback during the approval process because of the relative lack of experience and scientific expertise at the FDA in reviewing cancer vaccines. Potentially, there could also be a higher level of scrutiny for therapeutic cancer vaccines, which act by less well-studied mechanisms than those of anticancer mAbs and NCEs. Similar factors might also hinder approvals in the European Union and Japan.

In the United States, companies can speed the process of clinical development by using the FDA's Fast Track program (legislated as part of the FDA Modernization Act of 1997), designed for therapeutics that have the potential to address unmet medical needs and can treat serious and life-threatening diseases. The program provides sponsors with additional avenues for communication with the FDA during the clinical development of a product with a Fast Track designation. Currently, only 2 of the 52 cancer vaccines in development have this designation. In addition, these products might be eligible for priority review, reducing the time until the FDA's first action (the first formal response to the application submitted) on the licensing application to six months or less.

Therapeutic cancer vaccines have the potential to change the standard of care for cancer patients. However, the companies developing these products face a number of obstacles, in part because of the diversity and novelty of the products. The challenge for the future will be to rationally design products based on optimized strategies, target only the most promising candidates emerging from preclinical models, and carefully design clinical studies in relevant patient populations to ensure that cancer vaccines reach the patients that so desperately need them.