In 1984, US Navy officer Linda Taylor was diagnosed with metastatic melanoma, a highly aggressive form of skin cancer with a survival rate of less than 10%. Taylor’s official navy file status was “death imminent” when she came to Dr. Steve Rosenberg, a pioneer of immunotherapy at the National Cancer Institute in Bethesda, Maryland.
Dr. Rosenberg was trialing an experimental immunotherapy drug for late stage cancers called Interleukin-2. Trials in 66 other patients had ended in failure. Taylor’s odds were slim to nonexistent. But miraculously, the therapy worked and she survived.
Interleukin-2 works by boosting the production of the immune cells that fight cancer in the body (T-cells). In Taylor’s case, the replenished T-cells successfully fought cancer from within, causing her tumors to vanish within months.
This is the central premise behind using immunotherapy in cancer treatment – killing cancer using the body’s defense mechanisms. From preventive vaccines to life-saving treatments for advanced-stage cancers, we have witnessed numerous breakthroughs in immunology in the last four decades.
Perhaps the most monumental of these are in the area of immune checkpoint inhibitors (ICIs). For their immense contributions to the field of ICIs, specifically in the research of the proteins CTLA-4 and PD-1, James P. Allison and Tansuku Honjo received the 2018 Nobel Prize for Physiology/Medicine.
What are Immune Checkpoint Inhibitors?
The immune system uses aggressive T-cells and NK cells to attack and kill detected cancer cells. These cells carry deadly proteins like perforin and granzyme capable of annihilating even healthy cells. Uncontrolled T-cells can cause autoimmune diseases and even lead to organ failure and death.
This is why the immune system relies on a system called immune checkpoints. According to Dr. Jonathan Stegall, MD, an integrative oncologist in Atlanta, GA, we can think of them as the “brakes” of the immune system, preventing the immune system from attacking things it shouldn’t.
T-cells have receptor proteins on their surface. Healthy cells have ligand molecules that can bind with these proteins. When a T-cell comes in contact with a healthy cell, the protein and ligand bind to create an immune checkpoint.
This process sends an “off” signal to the T-cell, preventing it from destroying the healthy cell. Trouble arises when cancer cells acquire the ability to produce these ligand proteins.
“This “hijacking” of immune checkpoints allows cancer to hide from the immune system and T-cells/NK cells and continue growing and spreading. Immune checkpoint inhibitors are medications designed to target cancer-specific immune checkpoints, thereby allowing the body’s immune system to see cancer cells and attack them,” explains Dr. Stegall.
The inhibitors are lab-synthesized monoclonal antibodies (MAB). These drugs usually have the suffix “mab” at the end of their names. Many of the inhibitors target two major immune checkpoint pathways – CTLA-4 and PD-1/PD-L1.
The Significance of Immune Checkpoint Inhibitors in Cancer Treatment
“Immune checkpoint inhibitors have been around for a little over a decade now. The first to be FDA-approved was ipilimumab (Yervoy), for the treatment of melanoma. Nivolumab (Opdivo) was FDA approved in 2014, also to treat melanoma,” says Dr. Stegall.
According to the National Library of Medicine, 24 different monoclonal antibodies were approved for the treatment of various cancers in 2016. By 2023, the number had risen to around 40, according to an updated list published by The Antibody Society, a non-profit organization.
Most of the treatments are targeted towards late-stage metastatic cancers, where traditional treatments like chemotherapy and radiation therapy have extremely low chances of success.
In the 1990s, James P. Allison discovered that by inhibiting CTLA-4 pathways in mice, even advanced cancers like melanoma can be treated effectively to a degree that was not possible with conventional therapies.
For instance, treatment combining CTLA-4 and PD-1 inhibitors have resulted in complete remission of late-stage melanoma in 20% of patients, with very low risk of subsequent relapse. This is simply unprecedented in the context of conventional therapies.
Advances in the field in the last few decades have radically altered our approach towards cancer treatment itself. This is why there is so much interest in ICI drug research these days.
Treatment Efficacy, Potential Side Effects, and Other Complications
Unfortunately, ICI drugs have an uneven record when it comes to treatment efficacy, as pointed out in the Journal of ImmunoTherapy of Cancer.
Dr. Stegall concurs – “Although immune checkpoint inhibitors can work very well in some cases, the grim reality is that a majority of patients do not have an effective anticancer immune response as a result of receiving these drugs.”
The success rates can swing wildly depending on the type of cancer and the condition of the patient. In the United States, success rates were shown to be as low as 15%.
According to Dr. Bryan Oronsky, MD, Ph.D., and Chief Development Officer at EpicentRX, ICI therapies targeting CTLA-4 and PD-1 checkpoints work best against melanomas, head and neck cancers, bladder cancers, and renal cell cancers.
“Breast, prostate, pancreatic, ovarian, biliary, and microsatellite stable colorectal cancers are associated with low immunotherapy response rates,” says Dr. Oronsky. But in his opinion, only 40% of patients show a positive response to ICIs even when they suffer from a responsive tumor.
Potentially severe side effects are also a major concern. Minor side effects include gastrointestinal issues like nausea, vomiting, decreased appetite, constipation, and diarrhea. Weakness, fatigue, and skin rashes can also occur.
Autoimmune conditions, though less frequent, are not uncommon, says Dr. Stegall. “This is due to the immune system being less restricted, and thus being able to act more aggressively – including targeting the body’s normal, healthy components.”
This risk increases when immunotherapy is combined with other treatment modalities like surgery or chemotherapy. Patients who suffer from autoimmune disorders are not considered for inhibitor therapy due to significant risk of adverse events.
“Turbocharging the body’s cytotoxic (cell-targeting) immune response mechanisms, which is essentially what immune checkpoint inhibitors do, enhances the innate risk of autoimmune phenomena, and can compound the toxicity of complementary treatment modalities,” says Dr. J. Wes Ulm, MD, Ph.D., an expert in therapeutic drug development.
The Future of Immune Checkpoint Inhibitors
We are still in the early days of understanding the roles of the various proteins and antibodies in immune checkpoints. At the current rate of research, we can expect further clinical breakthroughs and newer monoclonal antibodies in the near future.
There are already several ICIs that target PD-1 immune checkpoints under review in the US and Europe. Soon, we can realistically expect ICIs to join hands with other treatment modalities like radiation and chemo to drastically improve survival rates of patients across multiple stages and types of cancer.
