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Cancer doctors embrace drugs that boost immune system to beat disease

At the age of 15, Andrew Howard was diagnosed with metastatic melanoma after a biopsy of a lump removed from his neck revealed a cancerous tumour. In addition to chemotherapy, the doctor advised Howard’s parents to seek palliative care for their son, who only had months to live.

Miraculously, Howard defeated the death sentence, passing the milestone five-year survival mark, which indicated a less than 0.01 per cent chance of the cancer returning.

But at age 25, the melanoma resurfaced. This time, the cancer had spread to his brain, lungs, stomach and legs. The civil servant from Melbourne, once again, was told he only had a few months to live.

Unlike his encounter with his oncologist a decade ago, however, Howard’s cancer doctor offered hope instead of suggesting the family prepare for his death. Professor Jonathan Cebon, medical director of the Olivia Newton-John Cancer Research Institute in Australia, prescribed surgery, radiation and chemotherapy – and introduced immunotherapy, a new class of cancer treatment that harnesses the body’s immune system to combat tumours.

Receiving immunotherapy through a six-month clinical trial, the tumours all over his body shrank at a “great rate”, deeming the trial a “success”, Howard says, though one last tumour had to be removed via surgery. Nearly three years later, Howard remains cancer-free.

“It may sound a bit rough, but this is a really good time to have cancer,” says Howard, 29, who has a six-month-old son. “I’m really lucky to have got cancer at this time when these treatments are available.”

Howard is just one of an increasing number of patients with so-called incurable cancers who have beaten the odds with immunotherapy. Since the first immunotherapy drug – ipilimumab, for metastatic melanoma – was approved by the US Food and Drug Administration in 2011, a clutch of others have been approved to treat cancers including melanoma, lung renal cell carcinoma, Hodgkin’s lymphoma, bladder, head and neck cancers.

Successes in clinical trials have swayed once-sceptical doctors, many of whom now see immunotherapy as the greatest hope for the battle against cancer.

“We’re very close to a cure for some cancers,” said James Allison, the chairman of immunology at the University of Texas MD Anderson Cancer Centre in Houston, during the opening presentation of the recent International Congress of Immunology in Melbourne.

Allison’s pioneering cancer immunotherapy work over the decades resulted in the development of ipilimumab. To date, more than 50,000 patients have been treated by the drug. One of the longest surviving patients who took the drug has had no relapse in the past 15 years, Allison says. She took just a single injection of ipilimumab in May 2001 after not responding to other treatments. Her wish was to see her children graduate from high school – today, she has grandchildren.

“The field [of immunotherapy] is moving at a geometric pace,” Allison says, “it’s not just experimental any more.”

Scientists in Hong Kong and the region, such as Professor Tony Mok Shu-kam, a clinical oncologist at Chinese University and lung cancer expert, are also involved in research in this field. Immuno-oncology will be the theme of the 21st Annual Scientific Symposium of the Hong Kong Cancer Institute in November, which is expected to attract more than 400 leading experts to the city.

Hong Kong professor takes lead on cancer immunotherapy trial

Cancer immunotherapy was built out of “very basic research” that goes back more than 40 years, says Professor Peter Doherty of the University of Melbourne, who delivered a lecture at the congress in Melbourne. In 1974, he and Swiss colleague Rolf Zinkernagel discovered how our immune system clears virally infected cells from the body through white blood cells known as “killer” T cells, a finding that won the pair a shared Nobel Prize in Physiology or Medicine in 1996.

Cancer cells sends signals to put the brakes on T cells. Immunotherapy works by turning those T cells back on, helping them recognise and attack cancer cells.

There are four major types of cancer immunotherapy, but really only two have shown major breakthroughs, according to Jay Berzofsky, vaccine branch chief of the Centre for Cancer Research at the US National Cancer Institute.

One is immune checkpoint inhibitors, which are largely antibodies that target molecules that suppress or inhibit the immune response. “By blocking these molecules, one allows the immune response that’s trying to reject the cancer to succeed,” Berzofsky explains.

“The other approach is adoptive cell therapy, where instead of allowing the patient’s immune system to try to fight the cancer, one generates artificially altered cells from the patient that are better able to do that, expands them into larger numbers and gives them back to the patient.”

But what if the immune system just doesn’t see the cancer? That is where Berzofsky’s latest research comes in: his team is trying to develop therapeutic vaccines that can alert the immune system to the presence of the molecules on a cancer tumour that couldn’t be recognised by the immune system.

Berzokfsky and colleagues have developed a vaccine that targets prostate cancer and has shown “very promising results”. In a study published last month in the journal Oncoimmunity, almost three quarters of 40 early-stage prostate cancer patients who received the vaccine experienced slowing of tumour growth. Based on this unexpectedly strong effect, a randomised placebo-controlled phase II trial is planned.

For Professor Laurie Glimcher, dean of medicine at Cornell University and the next CEO of the renowned Dana-Farber Cancer Institute in the US, the focus is on studying tumour micro-environments.

“If you take out a chunk of tumour, you’ll see the majority of that tumour is not made up of tumour cells but a variety of immune cells that are highly immunosuppressive. Certain tumours are particularly affected by this very immunosuppressive micro-environment – ovarian cancer is one of them,” says Glimcher.

Studying ovarian cancer further, Glimcher’s team have discovered a gene called XBP1 that allows ovarian cancer cells to evade the immune system. In preclinical studies, the team have shown turning off the gene restores the immune system against ovarian tumours.

“The high death rate in ovarian cancer has remained the same over the last 40 years because there have been no new therapeutic strategies,” Glimcher says. “This study offers us a new approach – a bright beacon of hope.”

For all the hope and hype that immunotherapy provides, however, the fact remains that not everyone benefits from the treatments.

“Some do, many don’t,” admits Cebon. “There’s a real task to try to identify the patients who are going to benefit from treatment, and to understand why others don’t.”

Howard, Cebon’s melanoma patient, calls himself one of the “lucky” ones. Berzofsky suggests there are two issues involved: the types of cancer and the patient’s immune system.

“Among different types of cancer, it has been discovered that some cancers have a lot of genetic mutations that create differences from the normal tissues that the immune system can recognise, and are more likely to have benefit from checkpoint inhibitors because there are more targets for the immune system to attack,” explains Berzofsky. “For example, cancers like melanoma, lung and bladder have a lot of mutations, whereas prostate cancer tends not to have many.

“Then, you also have the problem that even within a particular type of cancer like melanoma or lung, maybe only 20-25 per cent of patients are responding. It seems to relate a lot to whether the patient’s immune system is already trying to make an immune response that can be helped by these agents.”

Ultimately, Glimcher says no single treatment will provide a solution.

“It’s going to be a combination therapy that’s going to be required so that no patient with cancer has to die of their disease,” she says. “We’re talking about combinations of immunotherapies along with therapies that target the tumour itself.”