by Dr. Ang Peng Tiam
Every year, on the first weekend of June, tens of thousands of cancer specialists will gather in Chicago, Illinois to listen and share the latest advances in cancer management. In year 2015, the buzzword that kept resounding in the colossal halls was “immunotherapy”.
Even before the meeting, there was great expectation that there would be a major breakthrough in this area. Oncologists have already been deploying the use of these new class of immunotherapy agents called programmed cell death protein-1 inhibitors (PD-1 inhibitors).
Back in mid-90s, two colleagues and I were involved in cancer research into the immune system in cancer patients. We started by asking the question whether cancer occurred in patients because their immune system was impaired. When we studied the cells responsible for immunity (T-cells and B-cells) in patients diagnosed with cancer, we found that there was no difference between those with cancer and healthy individuals.
That being the case, how did the cancer cells escape detection by our body’s immune system?
Our theory was that cancer cells had the ability to “camouflage” themselves. Somehow, they must have been able to hide such that our body’s immune system is not able to detect these “rogue cells” and destroy them. To prove our point, we took consent from patients with cancers that were superficial and easily accessible. We injected foreign genetic material directly into these tumours. This was to enable the tumours to present themselves as foreign (meaning not of one’s self) to the immune system. Much to our delight, we saw some of these tumours shrink in size and even disappear. This helped us to deduce that the problem did not lie with deficiency in our immune system but rather with the way cancer cells hid or protected itself from a competent immunity. For our efforts, we were presented Singapore’s National Science Award for outstanding medical research in 1997.
Fast forward to the present decade, researchers have found that the T-cells in our immune system have a surface receptor called programmed cell death protein-1 (PD-1). The cancer cells can produce a protein (called a ligand) which can block this receptor and prevent the T-cell from attacking and killing the cancer.
Two pharmaceutical companies have now come up with antibodies that prevent this blockade, thereby freeing the activated T-cells to do their job of killing the cancer cells. The two immunotherapy drugs currently available are pembrolizumab (Keytruda®) and nivolumab (Opdivo®). The results of some studies using immunotherapy were nothing short of amazing.
In one study that was code-named CheckMate-057, advanced lung cancer patients, who have been previously treated with first-line chemotherapy, were randomized between receiving standard chemotherapy docetaxel (control arm) versus treatment with nivolumab (the experimental arm). The results of the study showed that patients who received nivolumab lived longer than those on the control arm. Patients receiving nivolumab had a 27% reduction in risk for death. One-year OS was 51% for the nivolumab group compared to 39% for the docetaxel group. These novel agents have also been shown to be effective in treating melanoma, colon cancer and malignant lymphoma.
One of the interesting features that was seen in some patients was that the tumour may actually increase in size before it became smaller. This unusual phenomenon poses a dilemma for clinicians as we have to make judgement calls on whether to stop the treatment when the cancer is seen to be worse.
In Feb 2015, Patrick, a 60-year old patient with heavily pre-treated stage four lung cancer were started on PD-1 inhibitors. After two months, the PET-CT scan showed that the cancer was getting worse. He was then treated with combination chemotherapy and after two months, the PET-CT scan showed a marvelous response.
In April 2015, another heavily pre-treated stage four lung cancer patients was started on PD-1 inhibitors. After a month, the PET-CT scan showed that some of the tumours were getting better but others were getting worse. We have decided to push on with the therapy, hoping that the sites that progressed despite treatment would eventually respond favorably. Indeed, our persistence paid off as her latest scan in November showed a marvelous overall response. The cancer nodules seen in both her lungs either disappeared or became smaller
So far, my success with the use of the PD-1 inhibitors has been mixed, perhaps it is because I have deployed them after many lines of chemotherapy. Patient selection is critical if we hope to see higher success rates. Random deployment of these expensive agents is not the answer to our quest for cancer cure.
The excitement over the use of immunotherapy has not waned. Rather, with the recent announcement of President Carter achieving cancer remission after treatment with pembrolizumab has heightened interest.
Attending the annual conference always gets me all excited. New discoveries with new promises must however be tempered with caution, as all that we see in clinical trials, may not be what we experience in the real world.
Dr. Ang Peng Tiam
Medical Director and Senior Consultant,
Dr. Ang Peng Tiam graduated from the National University of Singapore (NUS) with Bachelor in Medicine and Surgery in 1982. He did his residency in Internal Medicine and was conferred the Master of Medicine (Internal Medicine) in 1986. He completed his Fellowship in Medical Oncology at MD Anderson Cancer Centre, Houston, Texas and Stanford University Medical Centre in 1989.
Dr. Ang was awarded Singapore President’s scholarshop in 1977. He was awarded the Prof Sir Gordon Arthur Ransome Gold medal for being the top candidate in the Master of Medicine Clinical Examincations in 1986, and Singapore’s National Science Award in 1996 for his outstanding contributions in Medical Research. In recognition of his public service, the Sultan of Kedah conferred upon him a datukship in 2003. Dr Ang was founding Head of the Department of Medical Oncology at Singapore General Hospital from 1991 to 1997. He held the concurrent post of Director of the Oncology Centre and Clinical Associate Professor at the Faculty of Medicine, NUS. He remains a Visiting Consultant at National Cancer Centre and is the Vice Chairman of Singapore Cancer Society.
He was past President of Singapore Society of Oncology. He maintains a keen interest in research and has published and presented more than 100 papers and abstracts.
What Patients should know about Immunotherapy?
Immunotherapy is a relatively new form of anti-cancer treatment that has yielded promising results in recent years. A form of treatment using individual’s immune system to fight cancerous cells, immunotherapy is the latest cancer treatment modality that has been approved by FDA. Although promising, this new treatment modality does not signify the end of humanity’s struggle against cancer
“Through immunotherapy, the immune system can be enhanced to detect the cancerous cells more effectively. This treatment can aid in stopping or slowing the growth of cancer cells, prevent cancer from spreading to other parts of the body, and helping the immune system work better at destroying cancer cells. It is also important for patients to know, that similar to all medical treatments, there are certain limitations to what immunotherapy can achieve,” warns Dr Ang. “It is our duty and responsibility to share and clear the misconceptions surrounding immunotherapy.”
Misconception 1: Immunotherapy suits all cancer types
Immunotherapy as a new treatment modality has shown promising prognosis especially for lung cancer and melanoma patients. Those diagnosed with early stages of cancer or those who are responding well to other treatments should continue and not switch to immunotherapy.
Immunotherapy has also been shown to be effective in treating Hodgkin’s disease (a form of lymphatic cancer), and some efficacy in treatment of triple-negative breast cancer, colon cancer, gastric cancer and head & neck cancers.
Misconception 2: Immunotherapy suits all cancer patients
Researchers and clinicians are still just beginning to learn how best to deploy immunotherapy in treatment of cancer. At this time, there is no place for use of these agents in early stage cancer.
In those with advanced or metastatic cancer, especially those who have failed conventional therapies, immunotherapy offers new hope.
Misconception 3: Immunotherapy has no side-effects or downtime
Treatment with chemotherapy and radiotherapy can sometimes cause serious short-term and long-term side-effects. By and large, the toxicity profile of immunotherapy is significantly less and considerably safer. As the primary action of immunotherapy lies in “taking the brakes off” the immune system, the side-effects of such treatment arises from injury to normal tissue caused by the one’s own immune system. These include pneumonitis causing shortness of breath, skin rashes, transient fall in blood pressure and flu-like symptoms.
As opposed to standard chemotherapy and targeted agents, the positive responses through immunotherapy are sometimes evident even after discontinuing the treatment.
Dr. Ang comments, “Although clinical trials and studies on immunotherapy are still under way, this form of treatment will hopefully provide patients with an alternative that has higher effectiveness with lower side effects. We look forward to potentially delivering more effective therapy for cancer patients while reducing the injury to the human body. Opportunities in combination therapies will be worth looking into as well.”