SPOTLIGHT ON CANCER RESEARCH

Cutting-edge therapy builds on an age-old discovery

The growing field of immunotherapy is looking for new ways to employ the body's immune system in the fight against cancer

The field has evolved to the point where you're on the horizon of making a large impact. Robert Abraham, chief scientific officer, Pfizer Oncology Research Unit

A HUNDRED and fifty years ago a New York doctor, William Coley, read about a patient whose bone cancer vanished after a high fever. Coley wondered whether there was a link between the fever and the cancer remission, and began intentionally injecting bacteria into the tumors of his patients to give them severe infections. His unorthodox methods worked, and Coley successfully treated hundreds of cancer patients, despite never quite understanding why.

Now scientists have figured out why Coley's technique had such significant effects, and are developing his idea to come up with revolutionary advances in cancer therapy. The germ of Coley's success came from a concept now termed cancer immunotherapy – coaxing the body's own immune system into fighting the disease. Scientists have known for decades that cancer cells are exceptionally effective at evading the body's natural immune response, which is why most treatments employ other ways to destroy or remove cancerous cells, such as radiation therapy, surgery and chemotherapy.

But by increasing the production of immune cells and molecules, engineering immune cells to recognize tumors as foreign, or preventing tumors from blocking the immune system, researchers initially shrunk or eliminated tumors in mice. Over the past five years, those advances have been applied to human patients, with large clinical trials on immunotherapy agents showing positive against blood, skin, breast, lung, and other cancers. The approach not only offers hope of curing cancer, but of causing fewer systemic side effects than conventional chemotherapies, meaning a new set of opportunities for cancer researchers looking to impact on patients' lives.

Immunotherapies comprise antibodies, which directly attack cancer cells; vaccines, which spur the body to make its own antibodies; and drugs that promote general activity of the immune system. Today, immunotherapy-based approaches are used in about three percent of cancer patients, but a recent report by Citigroup concluded that in the next decade, immunotherapy will become the cornerstone of treatment in up to 60% of cancer cases and the industry will reap up to US$35 billion per year.

Located in Tampa, Florida, Moffitt Cancer Center has over 4,200 employees and contributes nearly US$2bn annually to the economy of the state. Credit: MOFFITT CANCER CENTER

For basic biologists, immunologists, oncologists, and pharmaceutical chemists, the field of immunotherapy is rich in research and development opportunities. “Immuno-oncology is a really up and coming field, especially in light of some of the successes we have already seen this decade,” says Helen Sabzevari, senior vice-president of Immuno- Oncology at the pharmaceutical company EMD Serono.

However, there are important unanswered questions about how to optimize immunotherapy techniques, says Richard Vile, an immunologist at the Mayo Clinic in Rochester, Minnesota, whose team specializes in experimental cancer therapies based on the immune system. These questions represent new challenges for those entering the field. “The more we understand the details of the immune system and its interactions with tumors, the more we find out we don't yet know.”

Immunological mimicry

From William Coley's day firmly into the twentieth century, attempts at immunotherapy hinged on the general principle that any increase in the immune system's activity helped the body fight cancers. But as the basic science of immunology has matured, the approach has become more detailed. “Immunotherapy is evolving from a very broad brush to actually targeting very specific pathways,” says Vile. “The individual molecules involved are better understood than ever before, and the challenge for the next few years is understanding how all those pathways truly interact and how to apply that knowledge to the clinic.”

One development has been to make antibodies in the lab which mimic the desired action of the immune system. For instance, tumor cells can avoid the immune system by mounting a protein called PDL1 on their outer surface, which shields them against T-cells – the primary immune response to a tumor. PDL1 sticks to a protein on the surface of T-cells called PD1, an interaction which ‘shuts down’ the T-cell and protects the tumor.

At Fred Hutchinson Cancer Research Center in Seattle, Washington, oncologist Mac Cheever leads the Cancer Immunotherapy Trials Network (CITN). Cheever has been involved in immunotherapy since the 1970s, when clinicians observed that cancer patients who developed an immune response following a bone marrow transplant recovered from leukemia better than those whose immune system did not respond. The National Cancer Institute-funded network of researchers from 29 institutions is collaborating to move selected immunotherapies from the lab to clinical trials. One such therapy uses a monoclonal antibody called anti-PD1, which itself binds to PD1, blocking the cancer cell from doing so and therefore lifting the brakes on T-cell proliferation.

Trials have so far shown anti-PD1 to have an impact on 30 percent of melanomas, and around 20 percent of lung cancers. The lung cancer results are particularly exciting, Cheever says, as “lung cancer was not felt to be an immune responsive tumor”. “I would predict going forward just three or four years, almost every patient will be evaluated to see if they'll respond to anti-PD1 drugs,” he adds.

Work in Moffitt's basic science laboratories includes immunotherapy research. Credit: MOFFITT CANCER CENTER

Despite the progress, establishing how to evoke a response in the other 80 percent of patients, using other immunotherapies or combinations of drugs, remains one of the big challenges in the field.

Researchers at Pfizer's oncology research unit around the US are trying to work out why some patients naturally develop T-cells that recognize a cancer, and others don't, and why immunotherapy drugs work better in some people than others.

In spite of stigma due to early failures, another avenue that offers much potential is cancer vaccines, says Sabzevari. “I think this field is just getting started and we will see a lot of successes in the coming years,” she says.

Researchers at EMD Serono are working on cancer vaccines using immunotherapy. Credit: EMD SERONO

Answering these questions means straddling the intersection between basic science and patient data. The immune system is complex, says Robert Abraham, chief scientific officer at Pfizer's Oncology Research Unit in New York, “and when you intertwine that with tumor biology, the complexity becomes quite daunting.” Abraham says these challenges are what make it such an invigorating field of research for young scientists to pursue.

Diversity pays

The future success of the field relies on co-operation between scientists in academia and industry, says Sabzevari. “When I was at graduate school there was always this concept of academia versus pharma and I think the time has come to completely break down these barriers,” she adds.

The best advances will also come from a mix of backgrounds, says Vile. “The beauty of immunology is that it really touches so many other fields—molecular biology and biochemistry can easily be applied to what we're studying. When you have people coming in from different fields they build up their own views and look at the problems from a new angle.”

Sabzevari's research background is in oncology and immunology, and she says this is an exciting time for scientists with that breadth of expertise. “Individuals with a good understanding of cancer biology and a solid training in immunology can see the biggest picture, and apply it,” she says.

Abraham says the greatest demand is for scientists with specific training in immunology, immunobiology, and T-cell biology.

According to tumor immunologist Jeffrey Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa, Florida, resilience is also vital. “To succeed in this field you need to accept the fact that you're going to fail most of the time and not get discouraged by that. You need to be incredibly stubborn.”

Weber encourages young scientists interested in immunotherapy to pursue a joint MD/PhD course of study, which can prepare them for the balance of clinical skills and basic research know-how that the career requires. “I'd encourage people at the get-go to start working in a lab. A few will survive and those are the people who have the potential to be great scientists.”

The key is a genuine interest in immunology, says cellular immunologist Hans-Reimer Rodewald, who warns against entering the field for the wrong reasons: “I don't think it's a good idea to jump into the field just because it's hot.”

Rodewald received his PhD from the Max-Planck Institute of Immuno-biology in 1988 and now works at the German Cancer Research Center (DKFZ) in Heidelberg. There he is trying to understand how to better model the interaction between the immune system and tumors in mice. As a basic scientist, the clinical implications may seem far removed from his work, but for Rodewald the excitement is in answering scientific questions. Immunotherapy, he adds, is “a great field and a young field.”

For others, such as Abraham, it's the clinical applications that are the most rewarding, and which seemed outside the realm of possibility when he was working as a bench scientist in immunology. “Back then, clinical applications in oncology seemed so far away. As you were working in the lab, you didn't have any sense that what you were studying could be helping patients,” he says. “Now the field has evolved to the point where you're on the horizon of making a large impact.” Or as Weber puts it: “It's a good time to be in the field, and the best is yet to come.”

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