I think we can all appreciate those “wow, this is amazing” moments of life. They can be many and varied, but at some point everyone has those intense feelings of gratitude and satisfaction. I’ve had a few of these moments lately when reading about immunotherapies for my research. I love the idea of using the defenses and machinery that our bodies already possess to fight off foreign invaders, such as cancer. The human body is pretty extraordinary — and the ways we fight off cancer are as well.
One of the steepest learning curves for me has been remembering the names, classes, and side effects of cancer drugs. There are SO many cancer drugs out there, and more get approved for clinical use every single day! With the help of some charts created by my PI (like this one published in the New England Journal of Medicine) and some really extensive notes, I feel way more comfortable with cancer therapies than when I started. Most people have heard of “chemotherapy” as a treatment for cancer. For years, chemotherapy has long been the go-to induction treatment for many types of cancer. I think of chemotherapy as the biological version of carpet-bombing – it is very limited in specificity and comes at a cost of collateral damage. Chemotherapies (literally “chemical treatments”) induce apoptosis, or cell death, of cancer cells through many mechanisms. They may interfere with DNA replication or alter the metabolic machinery necessary for providing fuel for cellular survival and reproduction. Chemotherapy drugs are most efficacious against cells that divide rapidly (i.e. tumor cells) but come with many of the side effects we associate with cancer – fatigue, loss of hair, dry skin, and general myalgia. Traditional chemotherapies are still used but mostly in combination with newer drugs and at lower cumulative dosages.
The advent of targeted therapies for cancer has redefined the specificity of cancer treatment (the word “targeted” gives it away). These are usually small molecules or antibodies that target kinases, or phosphorylating enzymes, that are overexpressed on cancer cells. Targeted therapies may work intracellularly through small molecules that slip inside the cell and stop cancer-promoting enzymes or extracellularly by recognizing receptors involved in tumor pathogenesis. Instead of using a carpet-bombing approach, targeted therapies are designed to selectively target cancer cells. One of the targeted therapies we study is trastuzumab (Herceptin). This is a monoclonal antibody (an immune system molecule that recognizes one complementary receptor) that binds HER2, a kinase expressed on cells. HER2 is overexpressed on HER2+ breast cancer cells, among other HER2+ cancer types. Once trastuzumab binds HER2, it inhibits a signaling pathway that normally promotes cell survival. Trastuzumab is one example among many, many other types of targeted therapies used to treat cancers. Targeted therapies have literally saved hundreds of thousands of lives and will continue to do so as scientists “fine tune” their targeted activity.
Now, immunotherapies. These are the current Holy Grail of cancer treatments. I am still learning a lot about the biology behind immunotherapies. Surprisingly, most immunotherapy treatments don’t care at all about the cancer cells. Instead, they focus on the cells of the immune system. We have cells in our bodies called T cells that essentially patrol for foreign invaders. Dendritic cells, another type of immune cell, “show” the T cells pieces of degraded protein, or polypeptide. The T cell then either recognizes the polypeptide as a normal part of the body or as foreign. If it recognizes it as foreign, the T cell will become activated and initiate an immune response. This is a normal process and keeps our bodies healthy and free of disease. Except in the case of cancer. Like most things, the immune system has its own set of checks and balances. The T cells (those monitoring cells that give approval for an immune response) have a protein called programmed death-1 or PD-1. Other immune cells have the receptor to this protein called programmed death ligand-1 or PD-L1. These two molecules fit together like puzzle pieces. If the T cells inappropriately initiate an immune response, cells with PD-L1 will bind PD-1 and effectively stop the T cells from killing anything.
Unfortunately, some cancer cells overexpress PD-L1 so that the immune system is always put on hold and does not attack them (which it should because they are foreign). The cancer cells become “hidden” from the immune system and continue to thrive and reproduce. But, aha!, some scientists much smarter than me once asked, but why doesn’t the immune system recognize cancer cells as foreign? And after a lot of research, thousands of pipette tips, and some vigilant clinical trials, today people are being cured by their own immune system. A new cancer drug, pembrolizumab (Keytruda) is a PD-1 inhibitor that binds to PD-1 on the T cell that normally functions as a brake (or as a signal to not kill). It is like sliding in another puzzle piece so that the original cannot fit anymore. This means that those pesky cancer cells that overexpress PD-L1 can no longer hide from the immune system. Pembrolizumab and nivolumab (Opdivo) have had remarkable response rates. A recent paper published in the journal Science (here) demonstrated how these immune checkpoint inhibitors may be used to treat cancer cells with a shared genetic deficiency. This recent publication and growing knowledge of immuno-oncology, cancer genetics, and precision medicine are transforming cancer treatment. I think this stuff is pretty cool, and I always leave feeling amazed, humbled, and grateful for the work that people are doing to save lives.