Autoimmune diseases like rheumatoid arthritis, psoriasis, and inflammatory bowel disease can be debilitating. They occur when the immune system mistakenly targets healthy cells and organs in the body.
Roughly 4 – 8% of Americans suffer from such conditions.
The reason these diseases are not more prevalent is because of a series of safeguards within our immune system.
Called immune checkpoints, they act as controls that reduce the activity of killer T-cells and NK cells, the main attack dogs of the immune system.
One prominent immune checkpoint is called Programmed Cell Death Protein 1, or PD-1. While it performs a significant role in preventing autoimmune diseases, PD-1 also puts the body at a serious disadvantage when fighting certain cancers.
PD-1 and PD-L1 checkpoint inhibitors are advanced immunotherapy drugs that show a lot of promise in helping us fight cancer using the body’s defense mechanisms.
As of 2023, these drugs have been approved for the treatment of at least nine different cancers, and more are under development.
A Brief Introduction to PD-1 and PD-L1 Checkpoint
PD-1 is a protein found on the surface of T-cells in the body. PD-L1 is a related protein, found in many healthy cells and some cancer cells. PD-L1 binds to the PD-1 protein, creating an immune checkpoint that prevents T-cells from destroying the cells carrying PD-L1.
When cancer cells gain the ability to express PD-L1, it significantly reduces the immune system’s ability to destroy those cells. Further, PD-1 also promotes the programmed death of T-cells, to prevent them from harming healthy cells.
In 1992, a team of researchers at the Kyoto University led by Tasuku Honjo identified PD-1 and discovered its role in controlling and preventing autoimmune diseases.
A series of experiments over the next decade revealed that blocking PD-1 could help in treating certain cancers.
Meanwhile, another research team led by Dr. Lieping Chen at the Mayo Clinic discovered the PD-L1 molecule on tumors and its role in helping cancer evade detection.
Both teams proved that by using antibodies that target these proteins, it is possible to stimulate T-cell activity and kill cancer cells.
For his seminal contributions to the discovery of PD-1 immune checkpoint inhibitors, Tasuku Honjo was awarded the Nobel Prize for Medicine in 2018.
He shared the prize with James P. Allison, another pioneer in the CTLA-4 immune checkpoint.
PD-1/PD-L1 Inhibitors Approved by the FDA for Cancer Treatment
Nivolumab was the first PD-1 inhibitor to undergo clinical trials in 2006. It received FDA approval in 2014. Since then, seven other PD-1/PD-L1 inhibitors have received the green signal for the treatment of various late-stage cancers.
Here is a quick overview of them all:
- Nivolumab (Opdivo) – melanoma, lung, head, neck, liver, esophageal, colorectal, and gastric cancers
- Pembrolizumab (Keytruda) – melanoma, lung, bladder, head, neck, and esophageal cancers, classic Hodgkins Lymphoma
- Atezolizumab (Tecentriq) – bladder, lung, liver, and breast cancers
- Avelumab (Bavencio) – Merkel cell carcinoma, bladder and kidney cancers
- Durvalumab (Imfinzi) – bladder, lung, and biliary tract cancers
- Cemiplimab (Libtayo) – squamous cell skin cancer
- Dostarlimab (Jemperli) – endometrial cancer
- Retifanlimab (Zynyz) – Merkel cell carcinoma
While these drugs have shown remarkable success, PD-1/PD-L1 checkpoint is not the only factor that determines tumor growth.
Numerous studies have shown that optimal results can be obtained when PD-1/PD-L1 inhibitors are used in combination with other therapies.
“There is indeed a synergistic effect of immune checkpoint inhibitors alongside other cancer treatment modalities,” accepts Dr. J. Wes Ulm, MD, Ph.D., an expert in therapeutic drug development.
“Longstanding approaches such as radiotherapy, chemotherapy, and of course surgery help to debulk and reduce the overall tumor burden, while more specialized treatments home in on cancer cells in a more pinpoint manner.”
For example, CTLA-4 inhibitor Ipililumab is widely used in conjunction with PD-1 inhibitor Nivolumab to treat several late-stage cancers including melanoma.
This is because studies have shown better outcomes when these drugs are used together.
Side Effects and Other Major Concerns
According to Dr. Bryan Oronsky, MD, Ph.D., Chief Development Officer at EpicentRX, most cancer patients, up to 60% do not respond positively to inhibitor antibodies that target PD-1/PD-L1 or CTLA-4.
This is not taking into account cancers that are not very susceptible to these drugs.
“Breast, prostate, pancreatic, ovarian, biliary, and microsatellite stable colorectal cancers are associated with low immunotherapy response rates—these are also referred to as “cold” tumors, unlike melanoma, and NSCLC, which tend to be immunotherapy-responsive or “hot”,” explains Dr. Oronsky.
Certain patients are also ill-suited for PD-1/PD-L1 inhibitor treatments. Oncologist Dr. Danielle Leonardo had this to say:
“Patients with autoimmune diseases may not be optimal candidates for this treatment because immunotherapy activates a patient’s immune system which may worsen the autoimmune disease.”
Leonardo added that patients on high-dose steroids “may not be optimal candidates as steroids may negate the immune response.”
Dr. Jonathan Stegall, MD, an integrative oncologist in Atlanta, GA, flags the myriad side effects patients often have to endure while taking Immune Checkpoint Inhibitors.
“Side effects from immune checkpoint inhibitors can vary. Gastrointestinal side effects such as nausea, vomiting, decreased appetite, constipation, and diarrhea can occur, as can more general symptoms such as weakness,” he said.
However, despite the dangers associated with autoimmune toxicities and other side effects, experts remain bullish about the future impact of PD-1/PD-L1 and CTLA-4 inhibitors.
According to Dr. Oronsky, the future is in combination.
“The hunt is on for a combination ‘dream team’ that will make ICIs work better particularly in ‘immunologically cold’ tumors such as pancreatic adenocarcinoma, prostate cancer, biliary tract cancer, microsatellite stable colorectal cancer etc.”
