Immunotherapy today - revolution in treatment of solid tumours

Understanding Cancer and Beyond 2018 - the new paradigm in cancer management

Dr Richard Quek is a Senior Consultant specializing in Medical Oncology at Parkway Cancer Centre.
Dr Richard Quek is a Senior Consultant specializing in Medical Oncology at Parkway Cancer Centre. PHOTO: PARKWAY CANCER CENTRE

In the 1890s, bone surgeon William Coley observed that post-surgical infections had helped cancer patients to recover better from their cancer. He believed that their infections had stimulated their immune system to fight the cancer; and it was upon this theory that Coley and other cancer researchers around the world begun looking into the development of biological agents to provoke an immune response and treat the cancer.

Since the early 2000s, significant progress has been made in this form of cancer treatment, called immunotherapy. Oncologists often use immunotherapy alongside or after standard cancer treatments, such as surgery, radiotherapy and chemotherapy, but are increasingly harnessing it as a first-line treatment as well.

Traditional treatment: Chemotherapy and targeted therapy  

Normal cells are biologically conditioned to respond to signals to grow or stop growing, repair themselves and regenerate. Cancer cells do not respond to such signals due to inherent genetic mutations. As a result, they multiply uncontrollably resulting in a mass of tissue called tumour.

Chemotherapy, a traditional form of cancer treatment, works by stopping tumour cells from growing, dividing and spreading by breaking the DNA of dividing cell. However, as it is cytotoxic (toxic to cells) and does not discriminate between healthy cells and cancer cells. 

Targeted therapy, on the other hand, first involves molecular profiling of cancer, looking for mutations present in cancer cells. These mutations allow cancer cells to grow unchecked. Drugs are then administered to target and switch off these mutations, thereby killing the cancer. As these targeted agents are specific for the mutations in the cancer cells, they avoid collateral damage to healthy cells, and are therefore better tolerated by patients.

What Is Immunotherapy?

Immunotherapy is a new form of cancer treatment that uses patient’s own immune system to fight off the cancer. To understand how immunotherapy works, we must first understand how our immune system defends the body against infections and diseases.

Immune cells or T cells, which are part of the immune system, constantly “patrol” the body to detect signs of infection or disease. When they encounter another cell, they probe certain proteins on its surface to tell whether that cell is healthy or infected/cancerous. Healthy cells are left alone; but if the proteins indicate that the cell is infected or cancerous, the T cell will mobilize in numbers to attack it.

In a well-functioning immune system this process is tightly regulated with checks and balances in place to prevent excessive T-cell immune activity which may inadvertently result in collateral damage to normal tissue from an overly enthusiastic immune response. These checks and balances occur at “immune checkpoints”, which control, enhance or reduce a person’s immune activity according to the situation required.

However, in a state of cancer, these immune checkpoints are “hijacked” by cancer cells to evade the immune system allowing it to grow unchecked. They do so by escaping detection or secreting chemicals that inactivate the immune cells that come to the scene, thus preventing the immune system from recognising and attacking them.

How Immunotherapy Works

Immunotherapy works either by making it easier for the immune system to find and destroy cancer cells directly, or by boosting the capability of the immune system in fighting cancer.

Collectively, the main types of immunotherapy now being used to treat cancer are called checkpoint inhibitors. They are monoclonal antibodies, man-made versions of immune system proteins, that unleashes the immune system onto the cancer. These drugs basically take the “brakes" off the immune system, helping it to better recognise and attack cancer cells.

The initial discovery checkpoint inhibitor in cancer treatment started with a protein called CTLA-4 which revolutionised the treatment of metastatic melanoma (skin cancer), one of the most stubborn cancers to treat. The first checkpoint inhibitor, Ipilimumab, was approved by the FDA in 2011 for the treatment of melanoma. Ipilimumab boosts the immune system by promoting the function and growth of T cells. These T cells in turn go on to destroy the melanoma cells. Melanoma patients treated with Ipilimumab have improved disease control and longer survival that those treated with standard treatment.

At around the same time, huge discoveries were made in another important immune checkpoint pathway involving PD1 and PD-L1. PD-1 is a checkpoint protein that resides on T cells. While cancer cells have large amounts of PD-L1, which help them evade immune attack. When the PD-L1 of cancer cells attaches itself to PD-1 on the T cells, it basically tells the T cell to leave it alone. Pembrolizumab, Nivolumab, Atezolizumab and Durvalumab are just some of the checkpoint inhibitors used to target these proteins, blocking the binding between PD-1 and PD-L1, and thus provoking the immune system to attack the tumour without reprieve.

Cancer researchers are constantly developing more effective ways of treating advanced cancers. One strategy is through the combination of two immunotherapy drugs, targeting both the CTLA-4 and PD1/PD-L1 pathways through the combined use of Ipilimumab and Nivolumab. This has shown to be effective in advanced melanoma and a whole host of other cancers. 

The Impacts Of Immunotherapy

The landscape in the treatment of solid tumours has changed dramatically in recent years, thanks to the impressive successes scored by immunotherapy and its superior outcomes in many types of cancers. It is currently approved for use in the treatment of cancers like melanoma, kidney, lung, bladder, head and neck, stomach, liver, cervix and Hodgkin lymphoma etc.

The future of immunotherapy is exciting, as scientists continue to devote a great deal of research to the development of newer agents, and test out new immunotherapy-drug combinations, which could potentially improve cure rates and enhance long-term control of cancers.