24 JUNE 2015
Fighting cancer with immunotherapy
I have just returned from my annual trip to the United States. Every year, on the first weekend of June, tens of thousands of cancer specialists gather in Chicago, Illinois to listen and share the latest advances in cancer management.
This year, the buzzword resounding in the colossal halls was “immunotherapy”.
Even before the meeting, there was great expectation that there would be a major break-through in this area. Oncologists have already been deploying the use of this new class of immunotherapy agents, rather dramatically 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 does not 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 a cancer cell hid or protected itself from a competent immune system.
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 of the 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 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 per cent reduction in risk for death.
One-year survival rate was 51 per cent for the nivolumab group compared to 39 per cent for the docetaxel group.
These novel agents have also been shown to be effective in treating melanoma, colon cancer and malignant lymphoma.
However, in some patients the tumour may actually increase in size before eventually becoming 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 appears to worsen.
I have two cases which illustrate.
In February 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. I then took him off the PD-1 inhibitors and treated him with combination chemotherapy. After two months, the PET-CT scan showed a marvellous 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.
So far, my success with the use of the PD-1 inhibitors has not been very encouraging. Perhaps it’s because I have deployed them after many lines of chemotherapy.
Attending the annual conference is always exciting. But new discoveries with new promises must however be tempered with caution, as what is seen in clinical trials may not be what we experience in the real world.
Written by Dr Ang Peng Tiam