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Immune Checkpoint Blockade Therapy – Unleashing the immune system in a war against cancer

Photo: Siddharth Kankaria / Research Matters

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The defence system of the human body is incredible. Given the kind of challenges it faces, from microbes such as bacteria and viruses, on a daily basis, the fact that we are all still alive is nothing short of a miracle. The immune system, that deals with threats from the outside world, can also combat threats from within equally well. This is why scientists are now exploring the possibilities of channelling the immune system to fight cancer. However, the idea that one can harness the immune system to do so is not new.

In the mid-1900s, although not everyone was convinced, immunotherapy was being pursued by quite a number of researchers as an exciting prospect for cancer treatment. But what sounded great on paper simply didn’t work as well in practice. The results of studies on treating cancer with immunotherapy were pretty bleak. Towards the later part of the 20th century, the concept of cancer immunotherapy began to lose its appeal, and many scientists gave up. However, few held on, and one among them was Prof. James Allison, the pioneer of the so-called “check-point-blockade” cancer immunotherapy as it stands today. What began in the late 1980s, as a quest to understand the responses of certain immune cells, turned out to be the research that would redefine the face of cancer therapies. By 2011, Ipilimumab, the immunotherapy-based-drug designed by him and his team, was shown to become the first drug ever to improve survival rates among those suffering from advanced cases of skin cancer (melanoma).

Since this discovery, the field of immunotherapy is gaining wide-spread recognition. In fact, in 2016, two of the three groups of scientists predicted by Thomson Reuters as potential Nobel Prize winners, worked in the field of cancer immunotherapy. Recognising the importance of immunotherapy, Prof. James Allison was awarded the 2014 Breakthrough Prize, considered by many as the Russian Nobel, in life sciences. Today, immunotherapy is the approach that holds the highest promise in cancer therapy. It is also touted to be the next big thing in cancer research.

Immunotherapy: How does it work?

The immune system of our body is often likened to the defence sector of a nation for good reasons. It has its own set of cells and molecules, each conferred with specific responsibilities towards protecting the body. They work as a team, discovering and destroying anything that does not belong to our body.

Imagine that you learn of the presence of a group of criminals responsible for heinous criminal acts throughout your city. What would you do? Either you could devise various strategies to take them down yourself, or you could call the security forces, acknowledging their expertise, and assist them in whatever ways to set things straight. Immunotherapy is when you choose the second option.

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 for various reasons. Either the immune system fails to recognise the cancer due to their constraints, or it may be that the cancer cells over-produce inhibitory signals – signals that were ideally meant to keep the immune cells in check. This ensures that the homicidal immune cells stay away. Regardless of how the cancer cells escape the action of the immune system, the consequence is that the immune system ceases to be effective, and the cancer flourishes.

How does one make the immune system effective in such cases? 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 the latter is exactly what is achieved by ‘Immune Checkpoint Blockade Therapy’(ICBT). Currently approved ICBT drugs are antibodies that bind to those molecules, which prevent the immune cells from killing the cancerous cells. They work by ‘freeing’ the immune system so that it can eliminate cancer.
Yervoy – the breakthrough drug

The story of ICBT begins with the success of Ipilimumab, which was dispensed under the trade name ‘Yervoy’. The drug 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 drift across the body, detecting and destroying cancerous cells.

The success of Yervoy raised hopes that immunotherapy can work against cancer and sent out a widespread frenzy in the medical and pharmaceutical industry with a new drug out for trial, every couple of months. Although some worked, others did not. While there was plentiful research invested in uncovering new molecules that could fight cancer, 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.
Research in India finds answers

Dr Udupi Ramagopal, Associate Professor and structural biologist at Poornaprajna Institute of Scientific Research, Bangalore, has been working on the structural aspects of immune modulators for almost a decade now.  In a recent study, Prof. Ramagopal together with a team of scientists from Albert Einstein College of Medicine (USA) and Bristol-Myers Squibb have analysed the interaction between Yervoy and CTLA-4 using X-Ray crystallography, providing crucial insights into the mechanism of action of Yervoy. The results of this study, published in the Proceedings of the National Academy of Sciences (PNAS), 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 Immune Checkpoint Blockade Therapy, you are not working on the cancer cells. You are training the immunological armed forces by eliminating inhibitory signals. And so, you are creating an immunological memory that can fight the cancer”, explains Prof. 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, there are a number of disadvantages. Firstly, it doesn’t always work in all the patients that it has been administered to, 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 a number of side effects including 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 its production techniques. Antibodies used in medicines like Yervoy are generated using animal systems, rather than from human systems. This might trigger secondary immunological reactions in the body. There is also the high cost associated with the research that translates to equally pricey drugs. Today, a course of immunotherapy with Yervoy costs a whopping ₹77 lakhs!

Prof. Ramagopal and his team members Ms. Swetha Lankipalli and Mr. 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. Protein molecules – including inhibitors and their interaction partners are huge conglomerations of amino acids, just like a huge bunch of grapes with hundreds of grapes (amino acids) on it. When an inhibitor molecule interacts with any another molecule, not all the amino acids are involved in the interaction. 

The strategy followed by Prof. Ramagopal and his team is simple – they determine the structure of inhibitory molecules and its interaction partners. Once they know which amino acids resides where and figure out which amino acids are involved in the interaction, they can effectively design molecules that can bind to the inhibitor. “This way, looking at the structures of the inhibitors and its partners, I know which region is responsible for their interaction. So, I know which amino acid(s) I need to tweak to design an efficient lead molecule against the inhibitor”, More importantly, it is derived from our own molecule, so it may not elicit immune response, unlike that expected from most animal-developed antibodies, explains Prof. Ramagopal.  “And the best part is that this approach is way more economical”, concludes Prof. Ramagopal enthusiastically, raising hopes for those battered by cancer.