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Scientists are engineering the immune system to be more aggressive towards cancer cells

An explanation of PD-1 blockade and its applications for cancer immunotherapy

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In 2018, Professors J.P. Allison and T. Honjo were awarded the Nobel Prize in Physiology and Medicine for their breakthrough in cancer immunotherapy, engineering the immune system such that it targets cancer cells more aggressively.

Despite scientists having invested more than a hundred years in researching cancer treatments, it nonetheless remains one of the leading causes of death in the modern age. Difficulties in treating cancer arise particularly out of the numerous different types, as well as vast differences in tumour physiology.

This breakthrough in immunotherapy is on par with the development of chemotherapy, and is positioned to revolutionise the field of cancer treatment.

How can the immune system be use to fight cancer cells?

Cancer is characterised by the uncontrolled growth of abnormal cells. Cancer causes disease by damaging healthy cells and monopolising nutrients. Advancements in immunology, oncology and cell biology have revealed that the immune system plays a role in recognising and defending your body from cancer.

A subtype of white blood cells, known as T-cells, are one of the main fighter cells in the immune system. They are able to identify when a cell has become cancerous and kill the cell by forcing it to undergo apoptosis (cell death).

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The natural brakes on the immune system

However, while the immune system has evolved to defend the body by inflicting considerable damage on invading microbes, it also must know when to reduce the immune response as to not damage healthy cells due to collateral damage.

The body must spare healthy cells through self-tolerance. Specific receptors act as brakes on the immune system, de-escalating the immune response when activated.

For instance, programmed cell death protein 1 (PD-1) is a protein expressed on the surface of T-cells. When PD-1 binds to its complementary molecule, PD-L1, the brakes of the immune system are engaged, resulting in a decrease in T-cell cytolytic activity and preventing the body’s own cells from being attacked.

However, tumour cells are high-specialised and capable of creating specific micro-environments that inhibit immune action against them. Scientists noticed that while T-cells were capable of recognising the tumour cell, they weren’t taking any action against them.

“Tumours can co-opt PD-1 to their own advantage to fly below the radar of the immune system ” — Suzanne Topalian MD

This is because cancer cells trick the PD-1 receptor by also expressing PD-L1 on their surface — initiating the brakes and suppressing T-cell activation. This hijacking of PD-1 has been shown to result in a significant increase tumour invasiveness into neighbouring tissues as their growth is unopposed by the immune system.

A novel breakthrough in cancer immunotherapy

Scientists have designed antibodies that prevent the suppression of the immune system by cancer cells. Much like how antibodies bind to bacteria and viruses, neutralising them during infection, these antibodies bind to PD-L1, preventing it from binding to PD-1 and thus temporarily removing the brakes from the immune system.

“We are essentially super-charging and specifically directing the immune system to target and kill cancer cells.” — Pravin Kaumaya PhD

The removal of the brakes greatly increases the aggression of T-cells as well as removes the ability for PD-L1 on the cancer’s surface to act as a “molecular shield”. An unrestricted and uninhibited immune response is unleashed, with devastating consequences for the cancer.

What cancers can be treated?

This form immunotherapy was first revealed to be possible in a landmark study by Wolchock et al. 2013 published in the prestigious New England Journal of Medicine, showing that this therapy was safe and effective against advanced melanoma. Since then, PD-1 blockade therapy has been shown to be broadly applicable, able to treat cancers such as lung cancer, renal cancer and Hodgkin’s lymphoma. Further clinical trials have been encouraging, with drugs using this blockade therapy resulting in significant reductions in tumour size.

However, this immunotherapy is by no means a silver bullet. As the therapy harnesses your immune system against your tumour, it is possible for your immune cells to turn against your own body, resulting in autoimmune associated problems. Rare but potentially fatal adverse events such as immune-related encephalitis (swelling of the brain) and acute renal failure were found to occur in <1% of patients. Further, follow-up studies on patients post-treatment discovered that some patients (1.8%) developed insulin-dependent diabetes. Fortunately, studies have found that common side effects were typically mild and that the therapy was safer than conventional treatments. For example, a meta-analysis study published in 2017 found that the incidence of adverse effects was 3x less than chemotherapy.

Ultimately, these seminal discoveries are incredibly promising developments and are positioned to revolutionise the way we approach cancer treatment.



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