The Fundamentals—and Future—of Cancer Treatment

When Hippocrates encountered cancer around 400 BCE, he named it karkinos—Greek for “crab”—because of how tumors seem to crawl and grip through the body like a crustacean’s claws. Today, the American Cancer Society estimates that one in two men and one in three women will grapple with some type of cancer during their lifetimes.

But just as the disease itself has persisted, so have our efforts to combat it. Modern medicine’s understanding of cancer has progressed greatly over the last century, thanks to sustained basic research, with scientists now parsing the progression of cancer at the cellular and molecular levels.

“Every breakthrough cancer therapy has started with research in basic sciences,” says Lieping Chen, MD, PhD, United Technologies Corporation Professor in Cancer Research and professor of immunobiology, of dermatology, and of medicine (medical oncology) at Yale School of Medicine (YSM). One example of a breakthrough is immunotherapy—a treatment that harnesses the body’s own immune system to recognize and target cancer cells. What was seen as a groundbreaking approach has now dramatically shifted the landscape of cancer treatment, and it was made possible by Chen’s research.

It has been 26 years since Chen discovered the PD-L1 molecule, a protein expressed on cancer cells that suppresses the immune response and promotes tumor growth. This research revealed that cancer cells actively resist immune attack—not by hiding from the immune system but by hijacking the body’s own regulatory mechanisms to shut down anticancer immune responses. This breakthrough insight led to a shift in treatment from simply trying to boost immune responses to understanding and dismantling cancer’s sophisticated defense systems.

“We have to understand the fundamentals first. That’s what really drives future treatment,” says Chen, who joined YSM 15 years ago, bringing with him rich experience in academia, the pharmaceutical industry, and clinical trials. By integrating basic science research with clinical applicability and pharmaceutical development, Chen’s approach ensures that advances—like immunotherapy—efficiently reach the patients who need them most.

In our conversation with Chen, Yale Medicine Magazine explores immunotherapy, its promising future, and the critical need to bridge translational research in cancer treatment.

That’s an important question, and there are several key factors to consider. While many different types of cancer progress at varying rates, the ultimate cause of death is typically metastasis. Cancer is an extremely unusual organism—once these cells become malignant, they grow aggressively and begin shedding throughout the body. These circulating cells can implant anywhere and establish new tumors, essentially spreading cancer to different organs. That’s what ultimately leads to death.

Some cancers are particularly aggressive and metastasize much more easily than others. Brain cancers, lung cancers, and pancreatic cancers are examples of cancers that progress very rapidly. The most challenging aspect is that for these fast-progressing cancers, we don’t have many effective ways to control them. This represents an urgent medical need—for several types of cancer, we simply don’t have adequate treatment options. That’s what causes so many deaths.

Every breakthrough therapy comes from basic science—that’s absolutely certain, though unfortunately this is often ignored. Certain areas of basic science are clearly disease-relevant. Immunology is a major one—it’s closely related to infection, autoimmune diseases, cancer, and viral infections because the immune system’s role is to defend the body. Many people studying immunology are already thinking about disease applications, but we must understand the fundamentals first.

Basic science drives treatment. Many therapeutic ideas are based on current discoveries, which is why we devote so much effort to fundamental research. It’s not as if basic science knowledge is just sitting there waiting to be applied—there’s still so much we don’t know, and without that knowledge, we can’t develop new ways to treat cancer.

Our lab is somewhat unique because of my training background and work experience. I started as a physician; and after practicing as an oncologist for several years, I became deeply interested in discovering new treatments for cancers that couldn’t be treated with existing methods. This drove me to pursue discovery research. I went back to get a PhD and postdoctoral fellowship in immunology to do basic science. I also worked for eight years in a pharmaceutical company to understand the drug development process.

What sets our lab apart is that we do basic science and are closely involved in translational research and clinical trials. In between basic science and real clinical treatment is a phase people now call translational research. It involves drug development—utilizing basic discoveries to invent drugs. But this area has been largely ignored, creating a gap between clinical practice and basic science.

It has changed dramatically because that represented a fundamental conceptual shift. Before this new thinking, most people understood immunotherapy very straightforwardly: ‘We have an immune system, so why does cancer still grow? It must be because our immune system isn’t powerful enough.’ So all efforts focused on making the immune system more powerful, pushing it to maximum levels until our body could not tolerate the toxicity.

And there were many ways to make the immune system powerful. For example, we could artificially engineer T cells, infuse them back into patients, and make them 10 times, 100 times, sometimes even 1,000 times more powerful than what our bodies naturally produce.

However, this approach wasn’t very successful for the treatment of common cancer for two major reasons. First, there’s toxicity—when you boost the immune system to such high levels, the body can’t tolerate it, so you get severe side effects. Second—and more importantly—we began to understand that when you push the immune system, cancer actually adapts; it doesn’t just sit there waiting to be attacked.

Cancer is genetically unstable and makes DNA replication errors, leading it to grow and proliferate fast. This creates many different types of cells that can quickly adapt to immune attacks and become resistant.

Starting in 1997, we observed immune systems being pushed to high levels, yet cancer remained resistant. When we analyzed why cancers were so resistant, we discovered a series of immune checkpoint molecules—proteins that act like brakes on the immune system preventing cancer cells from damaging it further—and we found that PD-L1 is one of them. Later, we found other such molecules that are now all being used in clinical treatments.

But here is the ironic part—PD-L1 is actually induced by the immune response itself. When the immune system attacks, it releases cytokines and proteins that induce PD-L1 expression on cancer cells. The previous way of thinking was partially wrong—you can’t just keep pushing the immune system because cancer will develop protection mechanisms. This was a completely new concept: Instead of just promoting the immune system, we also had to understand and block the resistance mechanisms that develop as feedback from immune attacks. It took us multiple years to convince ourselves this was how it worked. After many years of research, by 2004 we started working with companies to create antibodies to block PD-L1’s resistance, and clinical trials began in 2006.

We have largely laid out a plan. What we’ve discovered is that most resistance mechanisms happen at the tumor site, in what we call the tumor microenvironment, but not in other parts of the body. When we first proposed this concept in the early 2000s, most people disagreed. This was considered outside-the-box thinking. Now this is well accepted due to increased laboratory and clinical evidence.

There are a lot of basic science efforts trying to discover what’s in the microenvironment, how resistance develops, which particular molecules are responsible, and identifying cellular and molecular mechanisms. This research is very active right now and heading in the right direction. I think it will generate important information to help us design the next generation of drugs. However, these discoveries take time—not days or weeks, but years. For truly successful drugs to emerge, it will probably take at least four to five years.

Being here allows me to do a lot of things I had been dreaming of doing. I believe creating a streamlined process is the most efficient way to discover new drugs and make them available to patients: You make a discovery, then work with companies, and work with clinicians. It’s all connected.

When you separate these three pieces—discovery, translation, and clinical application—it’s very easy to make mistakes. This is why many basic discoveries aren’t translated to clinical applications. I like to connect them all—have everyone at the same table so people understand each other and what we want to do.

This is what I dreamed about, and I can do this at Yale. Right now, my lab is very well linked to clinicians. We work with physicians all the time—we get grants together; meet together; they come to my lab meetings and listen to all these basic discoveries, in addition to regular research training for young physicians.

We also work closely with several companies, including startup companies. I think this is probably the most efficient way to fast-track basic discoveries. So far, it has been good. We continue moving new treatments to clinical trials—probably one new treatment every one to two years, which I’m very happy about.

We have a few discovery platform technologies that were invented in our laboratory that give us significant advantages to move the field forward. As an example, we developed a receptor array platform to identify specific molecules and proteins that cause tumor resistance to immune attack. Our platform allows us to study thousands of genes at once, investigating them simultaneously to see what they’re responsible for and what induces resistance.

We’re still in a learning period, learning how to evaluate which molecules are more important than others, which resistance mechanisms matter most. Then we move to clinical trials to test them. Most immunotherapies can only treat a subset of patients because cancers are so different. Obviously, we’re looking for the targets and medicines that can treat more patients.

I think we’re on the right track. Every trial teaches us something about how to do better next time. And discovery is like this—it takes a while, but once there is a discovery, lots of people jump in and things move very fast. Progress continues toward the next breakthrough drug.