Turning the immune system on cancer

Photo: A*STAR

A new era in the fight against cancer is on the horizon and it got some 30,000 cancer doctors and researchers excited at the latest American Society Of Clinical Oncology meeting held in the United States earlier this month.

Among the attendees was local oncologist Ang Peng Tiam, who said that the buzzword resounding in the colossal halls of the event was "immunotherapy".

To put it simply, this strategy makes use of a patient's own immune cells to attack cancer.

Even before the meeting, there was great expectation that there would be a major breakthrough in this area, said Dr Ang, who is in private practice.

Among the highlights was the presentation of results from a phase-three trial that compared an immunotherapy drug, called nivolumab, with a conventional chemotherapy drug, docetaxel, in patients with non-small cell lung cancer, said Dr Elaine Lim, a senior consultant at the department of medical oncology at the National Cancer Centre, Singapore (NCCS).

These patients had failed to respond to standard first-line chemotherapy.

Each trial showed that those who received the immunotherapy drug lived an average of three months longer than those who received chemotherapy, said Dr Lim.

Oncologists here have already been deploying the use of this new class of immunotherapy agents, mostly on "named patient basis" or in clinical trials.

The former means that if a doctor thinks that a patient could benefit from a drug which has not yet been approved by the authorities for general use, he can ask the drug manufacturer to provide a supply for that patient.

This is timely news as it was reported earlier this week that new cancer cases here have jumped by about 17 per cent since 2010.


The idea behind immunotherapy is not new. Doctors have long thought that the immune system could be used to fight certain cancers, said Dr Toh Han Chong, deputy director of NCCS and a senior consultant at its division of medical oncology.

More than 100 years ago, before the immune system was well understood, American surgeon William Coley found that some post-surgery cancer patients fared better after getting an infection.

Dr Coley then started treating cancer patients in the late 1800s by infecting them with certain kinds of bacteria. These have come to be known as Coley's toxins.

While he was somewhat successful, he was overtaken by other forms of cancer treatment, such as radiation therapy. For many years, immunotherapy sat on the back burner.

Things have changed as the knowledge of how the immune system works has expanded exponentially, said Dr Toh.

In the past few years, the United States Food and Drug Administration has, for the first time, approved the use of immunotherapy drugs for skin and lung cancers.

These decisions were backed by recent studies, such as an international one on skin melanoma. Researchers found that a combination of two immunotherapy drugs - ipilimumab and nivolumab -- stopped the disease from growing for nearly a year in 58 per cent of cases.

But the study authors also noted that 36 per cent of the patients given the two-drug combination had to stop the therapy due to side effects.


Doctors say immunotherapy could offer hope to people with cancer that is difficult to treat, such as melanoma and advanced lung cancer that has spread throughout the body.

It is no miracle cure, but it is certainly a game changer, said Dr Toh.

The body's immune system often does not recognise cancer as "foreign" because the disease cleverly "disguises" itself from immune detection, he said.

Immunotherapy drugs work in various ways, such as by switching the immune system back on.

In the last 10 years or so, NCCS has completed many different types of immunotherapy trials and continues to evaluate more, said Dr Toh.

There is also the promise of longer-term control of the disease, said Adjunct Associate Professor Goh Boon Cher, head and senior consultant at the department of haematology-oncology at National University Cancer Institute, Singapore (NCIS).

For instance, some of the modified T-cells (immune cells) used in immunotherapy can remain in the body for years. This can lead to long periods of cancer remission, added Associate Professor Chng Wee Joo, a director and senior consultant at NCIS.

NCIS is currently running several phase-one trials for several types of immunotherapy, including that for breast cancer and haematologic malignancies (blood and bone marrow cancer), he added.

There are three major ways that immunotherapy can be used to fight cancer - by using drugs that operate as signal breakers, through T-cell therapy and cancer vaccines. We highlight two of them.


These drugs work by breaking a "don't kill me" signal that cancer cells send to immune cells.

When a T-cell recognises abnormal cells and foreign pathogens, such as viruses and bacteria, it gets activated and eliminates these potential threats.

The body also has a number of natural "brakes" on the immune system to prevent it from killing the body's own healthy cells.

However, many cancer tumours trick the immune cells into applying these "brakes". The devious tumour cells actually "hypnotise" the T-cells into not killing them, said Dr Toh.

The tumour cells do this by expressing a protein, PD-L1. This connects with the PD1 protein on the attacking T-cells and activates the "don't kill me" signal, leaving the cancer cells to multiply and spread.

Drugs that target either PD-L1 or PD1 can break this signal, said Dr Toh.

Ipilimumab and nivolumab are examples of these signal breakers.

This type of treatment has been shown to work quite dramatically when there are many immune cells surrounding the tumour cells, such as in melanoma and Hodgkin's lymphoma (a type of cancer of the white blood cells), said Prof Chng.

Such signal breakers have also been found to be helpful in treating certain types of colon cancer, aggressive breast cancer, as well as cancer of the bladder, head and neck, and kidneys.

But the therapy does not come cheap. Nivolumab, which has been approved for Hodgkin's lymphoma, will cost about $14,000 for one month of treatment, said Prof Chng.

For patients who are on clinical trials, their treatments are free.


This "promising form" of immunotherapy uses one's own body's modified T-cells to attack the cancer cells, said Dr Toh.

At NCCS, doctors and researchers are studying this treatment method on nose cancer (nasopharyngeal cancer or NPC).

This is done by targeting the Epstein-Barr virus (EBV) proteins found on the surface of NPC cells that triggers this type of cancer to develop, said Dr Toh.

In this method, T-cells are taken from the blood of patients with advanced nose cancer.

The T-cells are infected with the EBV proteins and "trained" to recognise only NPC cells. The T-cells continue to learn and grow for several weeks in the laboratory until they reach a "strike force" of more than one billion, all trained to recognise, home in and attack the EBV proteins on NPC cells, said Dr Toh.

This strike force is then infused back into the patient, with minimal side effects, he added.

In a phase-two study at NCCS published last year, patients under T-cell therapy, following four cycles of chemotherapy, achieved a median survival of 29 months, compared with 14 to 22 months reported in other studies.

In addition, 62 per cent of the study's patients were alive at the two-year mark, compared with none to 44 per cent in other studies.

At NCIS, T-cell therapy is being used to target B-cell leukaemia and lymphoma, said Prof Chng. The institute is also creating T-cell therapies that target other forms of cancer.

Early results show that the treatment is safe. So far, patients have tolerated the treatment very well, said Prof Chng.

There are two other ways to kill cancer with T-cell therapy - with chimeric antigen receptor T-cell therapy and tumour-infiltrating lymphocytes.

The former method extracts a patient's T-cells and then attaches an antibody fragment that enables them to recognise and target specific proteins on cancer cells.

Meanwhile, tumour-infiltrating lymphocytes are a type of white blood cells found in tumours. They are removed from the tumour environment which is telling them not to kill the cancer. They are then expanded to large numbers in the laboratory before being infused back into the patient.

Studies are ongoing, with previous studies showing promising results.


An unusual phenomenon in immunotherapy is that the tumour may grow before eventually shrinking, sometimes for a few months after treatment, said Dr Toh.

This pattern was observed in nine out of 35 patients with advanced NPC in the NCCS clinical trial. They were treated with chemotherapy first, followed by infusions of T-cells.

One of them was a 62-year-old Chinese man, who had incurable NPC which had spread to his liver.

He completed his chemotherapy followed by six infusions of T-cells by November 2009.

His disease was well-controlled until June 2010, when the cancer masses grew larger.

However, in August 2010, the cancerous growths in his liver shrank and he remained well with no further symptoms.

In March 2011, his tumours grew bigger again. His condition then stabilised for about four months.

He lived life normally all this while, and remained symptom-free although his cancer eventually spread further.

He died five years after his T-cell treatment began, a considerable length of time given that a patient with late-stage NPC has an average survival span of about 12 to 18 months, said Dr Toh.

Still, this is positive news for many cancer sufferers.

"This means that patients have another therapeutic option that can be very effective for certain types of cancer," said Prof Chng.

Immunotherapy may also work well with existing treatments.

"We are truly excited that harnessing the body's immune cells is finally making real and broad impact in the war on cancer. This is only the dawn of a new beginning," said Dr Toh.

This article was first published on June 25, 2015.
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