Cancer vaccines have long shown lots of potential but few results. Signs of success now suggest opportunities.
Last April, after years of false starts and frustration, the first-ever therapeutic cancer vaccine gained approval from the US Food and Drug Administration (FDA). Provenge (sipuleucel-T), made by Dendreon in Seattle, Washington, has been demonstrated to extend the survival of patients with late-stage prostate cancer by several months, and its success has shown the way for other cancer vaccines, says James Gulley, a medical oncologist at the National Cancer Institute in Bethesda, Maryland. “We knew there were regulatory challenges that the FDA needed to look at to get this approved,” he says. “So it set the milestones for future paths for our therapeutic vaccines.”
Cancer vaccines have had a boost in the past three years, thanks in part to Provenge's success as well as to a growing number of promising therapies in late-stage clinical trials, says Gulley. Pharmaceutical companies have approached him about developing therapeutic-vaccine commercialization programmes, and small biotechnology firms have shown interest in combining cancer-drug projects with vaccine development.
Hundreds of clinical trials of cancer vaccines are currently under way in the United States, and Hyam Levitsky, an oncologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, sees more promise now than at any time during his 20 years in the field. People thinking about going into cancer-vaccine work can be assured that “there is going to be a future in this”, he says.
Levitsky and his colleagues are optimistic that cancer vaccines will find their way into the standard of care not only because of the success of Provenge but also because of the wealth of trials going on. All this signals research opportunities in the near future. Some of the available jobs, from discovery to manufacturing and testing, are the same as those in the field of conventional vaccines. But cancer vaccines — immunotherapies that trigger or enhance defences against tumours or cancer-causing pathogens — are particularly challenging to develop, and most are still in the experimental stages. They work through a variety of mechanisms, making it difficult for scientists to develop standards to test and approve them. For the best chance of advancing in the field, researchers must have a solid grounding in immunology and the ability to understand how cancers interact with the immune system.
Bench to bedside
Cancer vaccines fall into two major categories: prophylactic vaccines, which are given to healthy people to prevent cancer developing, and therapeutic vaccines, which are intended to treat an existing cancer by strengthening the body's natural defences. Therapeutic vaccines are usually made from cancer cells, or from viruses or molecules present in tumours of some or many types of cancer, whereas preventive vaccines typically target viruses that cause cancer. Most vaccines of both types are developed using a one-size-fits-all approach, such as targeting molecules that are present in the cancers of many patients, but some, including Provenge, are tailored to an individual patient.
Compared with infectious diseases, cancer poses some extra challenges for vaccine-makers — enough to give pause even to optimistic scientists and clinicians. Investigators must ensure that their vaccines target tumour-specific cells without triggering a more general immune response against normal cells. Whereas traditional prophylactic vaccines prevent infections in healthy people, therapeutic cancer vaccines must be given to patients whose immune systems have been weakened by conventional cancer treatments such as chemotherapy. Vaccines can take time to work, so they offer small comfort for those with only a few months to live. And creating personalized therapies entails further scientific and commercial difficulties: it often requires harvesting the patient's own cancer cells or developing companion diagnostics to identify subsets of patients who might benefit from the therapy. “Doing large trials and getting drugs approved and funded when they're individualized is very, very difficult,” says John Sampson, a neuro-oncologist at Duke University Medical Center in Durham, North Carolina.
Anyone wishing to develop cancer vaccines must have a understand tumour immunology, because much of the basic science focuses on understanding the role of the immune system and inflammation in the development and progression of cancer. Only a few institutions offer doctoral programmes specifically in cancer immunology; they include the University of Lausanne in Switzerland and the State University of New York at Buffalo. The majority of cancer immunologists come from either immunology or cancer-biology programmes.
Newcomers to the field should keep in mind that cancer-drug development is risky: it can take a decade or longer for a drug to get from the lab to the clinic. “Your chances of getting something that works are extraordinarily small,” says Sampson. Provenge needed 20 years and three phase III clinical trials to reach FDA approval.
Most big pharmaceutical companies are still watching from the sidelines, choosing not to fund or hire for early-stage development, says Karl-Josef Kallen, chief scientific officer of CureVac, a biotechnology firm based in Tübingen, Germany. Vincent Tuohy, an immunologist at the Cleveland Clinic Lerner Research Institute in Ohio, has struggled to raise funds for a phase I clinical trial of a prophylactic vaccine aimed at women with a high risk of developing breast cancer. “I'm having a rough time trying to convince the pharmaceutical industry, whose business model is based predominantly on treatment and diagnostics, to enter the preventive space for these cancers,” says Tuohy, who has also been turned away by government funding agencies and non-profit organizations.
One exception is GlaxoSmithKline (GSK), whose immunotherapeutics division is looking for clinical development managers for early- and late-stage cancer-vaccine development, medical affairs and project management at its biologics research hub in Rixensart, Belgium. The ideal candidates have experience in immunotherapeutics or general oncology, or specialize in specific types of cancer, says Roya Paganini, senior manager in charge of talent acquisition at GSK Biologicals in Rixensart.
Smaller, discovery-focused biotechnology companies may have more opportunities. CureVac, for example, is looking for PhD-level research scientists to design vaccines and plan experiments to test them. They also need to be able to tweak the therapy's dose and dosing schedule in combination with existing and new therapies, to demonstrate its efficacy.
Most training in designing and running clinical trials for cancer-drug development is simply not that helpful for vaccine development. Unlike traditional cancer therapies, for example, vaccines do not have a 'maximum tolerated dose'. In fact, the appropriate dosing, scheduling of treatment and end points for vaccines all differ vastly from those for traditional drugs.
That makes immunology training, whether formal or on-the-job, essential for success. Principal investigators who are involved in patient care usually have medical doctorates, board certification in internal medicine or paediatrics, and experience in an oncology fellowship lasting several years. Immunology is not a distinct subspeciality of oncology, so researchers should decide early on whether clinical research centred on cancer immunology is a path they wish to pursue. During an oncology fellowship, scientists with an interest in cancer vaccines should seek a mentor with experience as a faculty investigator, says Levitsky, adding that fellows might expect to design and help to analyse the results of one or two trials. By the time Gulley had finished his fellowship at the National Institutes of Health in Bethesda, he had nearly completed one clinical trial and had ideas for several more. Fellows training with Levitsky also sit in on first-year medical-school immunology courses and attend specialized seminars and journal clubs to stay up-to-date in the field.
Trials need skilled clinical-research coordinators, who often work with or under the principal investigator to speed recruitment or reduce costs in clinical trials. “I think we need to find people who are much better at figuring out ways to do clinical trials well but efficiently,” says Sampson, who has graduated from a 'master of health sciences in clinical research' programme at Duke. The university also offers a non-degree option for clinicians, nurses and scientists.
In principle, making cancer vaccines is not that different from making monoclonal antibodies or other biologics, so one need not have a cancer-research background to get into manufacturing, quality control or quality assurance, says George Mitra, director of the Biopharmaceutical Development Program at the National Cancer Institute's facility in Frederick, Maryland. However, individualized vaccines can be more like a specialized research project, in which clinicians collect cells from a patient with cancer and use them to make a vaccine for that patient. Making such vaccines requires more skilled labour and experience than making generalized vaccines, says Mitra. Creating Provenge, for example, involves a process called leukapheresis, in which antigen-presenting cells are harvested from a patient's blood and purified. The cells are then sent to a Dendreon facility, where researchers cultivate them with a proprietary manufactured protein commonly found on prostate-cancer cells. The resulting vaccine is returned to the patient's physician. It must be administered in three different treatments, each of which requires the same manufacturing process.
Although the odds are long, if an individualized vaccine becomes commercially feasible, industrial manufacture would require PhD- and master's-level scientists with a background in cellular processing, who are trained in blood apheresis, bone-marrow transplantation or graft engineering, as opposed to more traditional drug manufacturing areas, says Levitsky.
If the field continues to grow, interested scientists will have options. But the field's biggest draw may be the potential to help desperate patients. “To me, it's immensely rewarding to see that we can make a difference in patients' outcomes and survival, without causing significant side effects,” says Gulley. “That's what's going to keep me working in this field and make me try for bigger improvement in outcomes for these patients.”
See Outlook p.450
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Chi, K. Cancer research: Promise of protection. Nature 471, 537–538 (2011). https://doi.org/10.1038/nj7339-537a