The body's battle against cancer

Every day, our immune system fights millions of bacteria and viruses, dealing with threats from outside and within. Recognising its potential, scientists are now exploring the possibilities of channelling the immune system to fight cancer. A relatively new addition to these efforts is the research on Immune Checkpoint Blockade Therapy (ICBT).

The idea of harnessing the immune system to fight diseases can be traced back to the mid-1900s, when many researchers pursued immunotherapy as an exciting prospect for cancer treatment. However, what sounded great on paper did not pan out in practice. Towards the later part of the 20th century, cancer immunotherapy began to lose its appeal, and many scientists gave up. Professor James Allison, one of the pioneers of check-point-blockade cancer immunotherapy, held on and with his team, developed Ipilimumab, the first drug ever to improve survival rates among those suffering from advanced cases of skin cancer.

Since this discovery, the field of immunotherapy is gaining wide-spread recognition. As a result, James was awarded the 2014 Breakthrough Prize in life sciences. Today, immunotherapy holds the highest promise in cancer therapy and is touted to be the next big thing in cancer research.

How immunotherapy works

The body’s immune system has its own set of cells and molecules, each with specific functions. They work as a team, discovering and destroying anything that does not belong to our body. In most cases, the immune system can detect and ward off all ominous growths in the body, including cancers. But sometimes, cancerous cells escape the notice of the immune system – either the immune system fails to recognise such cells, or these cells over-produce inhibitory signals that were ideally meant to keep the immune cells in check. Regardless of how the cancer cells escape the action of the immune system, the consequence is that the cancer flourishes.

So, how can the immune system be made effective? One could extricate the immune cells from their constraints or quell the inhibitory signals, thereby letting the immune system act on the cancerous cells. And this is exactly what is achieved by ICBT. Currently, approved ICBT drugs are antibodies that bind to those molecules that prevent the immune cells from killing the cancerous cells, thus ‘freeing’ the immune system, so that it can eliminate cancer.

Antibodies against another receptor on T-cells called programmed death-1 (PD1) are also very effective and recently four novel antibodies got Food and Drug Administration (FDA) approval for various cancer treatments. Ipilimumab, dispensed under the trade name ‘Yervoy’, is one such drug. It activates the immune system by targeting CTLA-4 — a protein receptor that inhibits a class of immune system cells known as Cytotoxic T lymphocytes (CTLs).

Although CTLs can recognise and destroy cancer cells, they are blocked by the presence of CTLA-4. Yervoy is an antibody that binds to CTLA-4, thus relieving the lymphocytes, which can now drift across the body, detecting and destroying cancerous cells.

While there was plentiful research invested in uncovering new molecules that could fight cancer, for many years, some questions remained unanswered. One, for instance, was how Yervoy, which binds to the inhibitory signal molecule CTLA-4, could be successful in silencing the action of CTLA-4, in spite of other molecules that also interact with CTLA-4. How does Yervoy differentiate CTLA-4 from other molecules that resemble CTLA-4 and bind only to CTLA-4? Scientists could not yet answer them.

Crucial insights

A new study by Dr Udupi Ramagopal, associate professor and structural biologist at Poornaprajna Institute of Scientific Research, Bengaluru, with a team of international collaborators from the Albert Einstein college of Medicine, USA and Bristol Myers Squibb, provides crucial insights into the mechanism of action of Yervoy. The researchers have analysed the interaction between Yervoy and CTLA-4 using X-Ray crystallography. The results of this study, published in the Proceedings of the National Academy of Sciences, not only illustrates the molecular interaction between Yervoy and CTLA-4 but also allows the rational design of drugs that can be more effective.

“The thing with most cancer therapies is that even if you treat 99.999% of the disease, one cell is good enough for the cancer to relapse. But with ICBT, you are not working on the cancer cells. You are training the immunological armed forces by eliminating inhibitory signals. And so, in a way you are creating an immunological memory that can fight the cancer,” explains Dr Ramagopal.

And what happens if there is a relapse? “Post recovery, if the cancer does attempt to strike back, even at a different location in the body, the immune system is equipped to fight it. And that is why the ICBT is said to have changed the face of cancer therapy,” he adds.

Although drugs such as Yervoy hold a lot of promise, they also have drawbacks. They don’t always work in all patients who have been administered the drug, and we still don’t know why. Then, there is the issue of side effects. Since Yervoy inactivates CTLA-4 that serve as brakes controlling the lymphocytes, the lymphocytes are now free to attack without checks and balances, resulting in side-effects like stomach pain, bloating, constipation or diarrhoea, fever, breathing or urinating problems. In severe cases, it could lead to neurological complications like paralysis.

Another major drawback with immunotherapy drugs is their production techniques. Antibodies used in such medicines are generated using animal systems, rather than from human systems and goes through a process called humanisation. This might trigger secondary immunological reactions in the body. Also, the high cost associated with the research translates to equally pricey drugs. Today, a course of immunotherapy with Yervoy costs a whopping Rs 77 lakh!

Dr Ramagopal and his team members, Swetha Lankipalli and Shankar Kundapura, are currently engaged in pursuing a simpler, cost-effective alternative with a new class of drugs that can be designed using the basics of protein structural biology. The strategy they follow is simple – they determine the structure of inhibitory molecules and its interaction partners. “By looking at the structures of the inhibitors and its partners, I know which region is responsible for their interaction and which amino acid(s) I need to tweak to design an efficient lead molecule against the inhibitor,” explains Dr Ramagopal.

He also says this new class of drugs might not elicit secondary immune responses, unlike that expected from most animal-developed antibodies. “And the best part is that this approach is way more economical,” he signs off.

(The author is with Gubbi Labs, a Bengaluru-based research collective)