PD-L1 And What It Means In Cancer Treatment

by Jane Ashley

We’ve heard of PD-L1 — both in the news and in television ads — but most of us don’t understand what PD-L1 is or why it’s important. Let’s learn more.

T Cell

What is PD-L1?

Our immune system contains T cells that can kill cancer cells. However, our bodies regulate these cells to ensure that they don’t attack our healthy cells (called an autoimmune reaction that could be potentially fatal).

Unfortunately, cancer cells have evolved, over the thousands of years, and learned how to prevent our T cells from killing them. Our T cells have a chemical on their surface called PD-1. Most cancer cells have a protein on their surface called PD-L1, which can deactivate the T cell. 

The PD-L1 protein tricks our T cells into believing that they, the cancer cells, are healthy.

Through the deactivation of our T cells, cancerous tumors develop and grow because our immune system was fooled by the cancer cell’s adaptation. The cancer cell is disguised by the production of PD-L1 so that our cancer-fighting T cells believe that the cancer cells are normal cells in our bodies.

Imagine it like this — we go to war with another country, and our uniforms are red. The other country’s uniforms are green. So we know how to recognize the enemy and kill them. But just imagine if our enemy wears green uniforms that look exactly like ours. How do we know who to kill? This is the way that cancer cells trick our immune system.

The Enemy

Researchers have been wondering for many years how they could get our immune systems to outsmart cancer’s defense mechanisms that protect them from our T cells.

The History of Immunotherapy

What’s old is new — we’ve heard that saying, and this describes the evolution of immunotherapy . The first attempts began in 1891 in New York City when 28-year-old Dr. William Coley treated an 18-year old woman for a lump in her hand following an accident. He thought that the lump was an infection or inflammation following the injury of her hand. But the biopsy revealed that she had aggressive bone cancer called sarcoma. At the time, amputation was the only treatment, and he amputated her arm below the elbow. Unfortunately, her cancer spread throughout her body. She died in January 1891 at the tender age of 18.

Dr William Coley

Dr. Coley was deeply affected by the loss of his young patient and began studying 15 years of hospital records. One case caught his eye. A patient with sarcoma “spontaneously regressed” after an infection of erysipelas (a kind of strep). As he researched, he found a few other cases of regression after cancer patients experienced an infection.

In a leap of faith, he injected erysipelas into a cancerous neck tumor of a terminally-ill patient. The patient’s cancer completely regressed, and he lived for eight more years.

Dr. Coley continued to experiment with using both live and heat-killed bacteria to treat cancer. He had mixed results. During that period, radiation therapy was developed and produced more reliable results, so Dr. Coley’s work was largely forgotten.

Dr. Coley’s son, Bradley, succeeded him at Memorial Sloan Kettering as head of the bone tumor service. Dr. Coley’s daughter, Helen (who was not a physician), garnered the attention of Dr. Lloyd Old with her father’s old case files. He founded the Cancer Research Institute. He did studies on bladder cancer treated with BGG (a weakened version of the bacterium that causes tuberculosis) — which is now FDA-approved treatment for bladder cancer.

Although scientists did not have the extensive knowledge of our immune system , they suspected that injecting a disease-causing bacteria into a tumor could “jump-start” the immune system to kill the cancer cells in the tumor. They were on the right track.

How has immunotherapy evolved?

Scientists have long suspected that blocking a cancer cell’s PD-L1 mechanism could potentially allow our T cells as part of our immune system to target cancer cells.

Merck developed Keytruda (pembrolizumab) — a new type of drug that blocks the PD-1 pathway to help prevent cancer cells from hiding so that our body’s immune system can attack them. It was first approved in 2014 for the treatment of melanoma patients who had the BRAF mutation. The rest is history. Keytruda is approved to treat 13 types of cancer and tumors that display microsatellite instability-high (MSI-H) status, including colorectal and pancreatic cancers.

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The workings of our immune system are complex. Once scientists made a significant breakthrough about PD-L1, they have been busy studying other kinds of cancer and other genetic mutations to learn how to harness our immune systems to tackle other kinds of cancer.

Fast forward to 2020, and there are a substantial number of immunotherapy drugs called immune checkpoint inhibitors that work in similar manners to Keytruda (pembrolizumab). Newer drugs target CTLA-4 pathways, often found in breast, ovarian, and prostate cancers.

Clinical trials now abound exploring potential treatments for other kinds of cancer. These trials are mostly on-hold due to the COVID-19 pandemic, but clinical trials will resume to explore other mechanisms that cancer cells utilize and also vaccines to prevent the development of cancer.

So WhatNext?

Immunotherapy appears to be the future of cancer treatment. Yet some cancers, like colorectal cancer, have proven difficult. It’s important for every cancer patient who is diagnosed with advanced Stage IV cancer to ask for genomic testing to see if they have the markers that would benefit from immunotherapy. We must be pro-active for ourselves.

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