The human immune system is an evolutionary marvel designed to find and eradicate microscopic invaders that would do us harm. These invaders include cells in our body that mutate to become cancerous. Unfortunately, the immune system does not always succeed in stopping the proliferation of cancer cells throughout the body. Consequently, treatment techniques that help the immune system are rapidly evolving to treat a variety of cancers. In the last two decades, a type of immunotherapy utilizing ‘immune checkpoint inhibitors’ has proven effective in fighting several cancers and continues to inspire research and innovation.
Dr. Kevin Dalby, a professor in the College of Pharmacy, and Department of Oncology at The University of Texas studies the mechanics of cancer cell signaling while working toward the development of potential new therapeutics. The research in his laboratory embraces a diversity of approaches including, biochemistry, cell biology, chemical biology, diagnostics, and enzymology. Like many scientists at the cutting edge of research, he believes that a multi-disciplined approach is instrumental in developing and advancing modern therapeutics such as immune checkpoint inhibitors.
How Checkpoint Inhibitors Work
T cells, a type of immune cell, are an integral aspect of the immune system. They help protect the body from pathogens and cancer by finding and destroying infected cells. Though with high power comes great responsibility. What is to prevent immune cells from attacking healthy cells as they ward off infection? The answer is the presence of immune checkpoints.
Think of immune checkpoints as a brake that is activated to prevent a T cell from inadvertently harming healthy cells. While this is the desired response in most scenarios, tumors can use checkpoints to turn T cells off early when they encounter a tumor, and thus avoid their destruction. T cells rely on protein receptors to determine if a cell is healthy, but cancer cells are deceptive and capable of signaling that they’re harmless.
In 1995, Dr. Jim Allison, then at Berkeley, changed the game when he demonstrated that a monoclonal antibody that bound an immune checkpoint protein called CTLA-4 could bypass an immune checkpoint to activate T cells and inhibit tumor growth in mice. This discovery paved the way for the rapid development of several new cancer therapies within just a few years.
The concept of immunotherapy is quite straightforward: activate the human immune system to combat disease. Immune checkpoint inhibitors are a type of immunotherapy that keeps the T cells engaged. Checkpoint inhibitor drugs stop cancer cells from sending wrong signals, allowing T cells to analyze cells without interference and attack as necessary.
Effectiveness in Treatment
Ipilimumab was the first approved immune checkpoint inhibitor as a result of Dr. Allison’s work. It blocks CTLA-4 allowing T cells to search and destroy per usual. This treatment has helped improve the survival rates for patients suffering from advanced melanoma.
In 2000, scientists identified another immune checkpoint protein, PD-1. The immunotherapy drugs Pembrolizumab and nivolumab block PD-1. They are effective at treating various cancers, including melanoma, kidney, and bladder cancer. Immune checkpoint inhibitors, especially when coupled with additional immune mediators, have revolutionized the treatment for metastatic urothelial carcinoma, the most common type of bladder cancer.
Unfortunately, not all types of cancer are treatable by checkpoint inhibitors, and stimulating the immune system is not without side effects. The most common reactions include fatigue, nausea, diarrhea, and flu-like symptoms. Checkpoint inhibitors are lifechanging for many patients, being the standard of care in some cases. Building on foundational research, oncologists continue to explore new strategies to make checkpoint inhibitors the drug of choice for even more patients.