Researcher leading the field in cancer immunotherapy

It's 3:30 in the morning and immunologist Jennifer Wu, Ph.D., who will soon be a full professor in the Department of Microbiology and Immunology, is not sleeping. That is not an uncommon occurrence for her — sleep often eludes her these days. Her mind races with myriad thoughts and possibilities, and she just can’t seem to turn them off. 

There is a question that consumes her, and if she could, she would work 24/7 to solve it.

“I can’t sleep anymore. I’m just too excited to sleep,” she said, while her computer and cell phone persistently pinged, alerting her of incoming messages. “Sometimes I get in the car, and I’m not even sure where I’ve ended up. I constantly think about it. My mind races nonstop. I can’t stop thinking about this.”

What could be so important that she can’t let her work go? It’s not like she’s trying to cure cancer — well, except for the fact that that is actually exactly what she’s trying to do.

Wu believes the body should be able to heal itself of even the most aggressive and deadly tumors, and that it can be accomplished through a relatively new field of study called immunotherapy.

Cancer immunotherapy, harnessing the body’s immune system so it recognizes cancer as a threat and attacks it, was considered science fiction barely a decade ago. Having been named Science Magazine’s 2013 Breakthrough of the Year, cancer immunotherapy is a promising alternative or companion to traditional methods of fighting cancer: chemotherapy, radiation and surgery. A subject that was met with a healthy dose of skepticism has not only shot to the front of the class, it’s the teacher’s pet. And rightfully so; it offers a lot of hope. 

“Early on,” Wu said, “we couldn’t figure it out — it’s a very complicated system, and we had very limited understanding of how tumor cells and the immune system interact. But we knew we were on to something.”

“At first, medical people were skeptical. They would ask, ‘So you really think the immune system would attack a tumor?’ Then they would say, ‘No, we can just cut it out.’”

Today, cancer immunotherapy is perhaps the most exciting development in cancer research, as avant-garde researchers like Wu explore the possibility that it might very well be the solution to eradicating cancer. And with two recent National Institutes of Health R01 grants totaling $3,419,810, along with a $560,625 Department of Defense Research Award last year to combat deadly prostate cancer, and a separate nearly–$300,000 NIH small business grant to fund the groundbreaking work of her startup company, CanCure, LLC, she’s become a bit of a superstar in the cancer immunotherapy field.

A call to arms

Wu describes the immune system as the body’s defense system — a massive army of ground soldiers that defend the body against infectious organisms like bacteria, viruses and funguses that invade the body’s systems and cause diseases. The immune system, a set of strategic reactions and responses, launches a complex defense plan known as the immune response when the body comes under attack.

To carry out such a complicated mission, these defender cells, which consist of different types of white blood cells, charge into action and destroy the invaders as soon as they are detected. The body makes somewhere around a billion of these cells every day in the bone marrow. One single teaspoon of blood contains tens of millions of white blood cells.

The immune system consists of multiple battalions of cell types to sense and attack invaders. Among them, the natural killer (NK) cell and T cell are the ones that directly kill the invaders. B cells produce antibodies to attack the intruders. NK cells are armed with multiple sensors called receptors to directly sense abnormal cells and are naturally licensed to kill them. They are the first line of defenders of the immune system. T cells, B cells and the other immune troops then quickly assemble and rally on the battlefield. Together these immune defenders go into high gear and deliver lethal blows directly to the intruders and clear them out. 

But sometimes the process goes awry. For some reason, the typically aggressive patrols tend to ignore cancer cells, allowing them to hide from the immune system or even block its natural ability to attack. Rather than attack tumors, they retreat, and tumors are able to grow viciously and spread.

So exactly what happens to cause the immune system to stop doing its job? That is the question keeping Wu up at night.

“When we are born, we have a perfect immune system. When we’re young, we do not develop cancer — well, rarely.  When we start to develop cancer, we’re aging. We catch colds very easily. So, what’s wrong with the immune system — why is it not working anymore?”

When she was a postdoctoral trainee, her mentor discovered a tumor–specific molecule called “MIC” that was induced by cellular stress during mutation and only abundant in tumor cell surface, but not found in normal cells. The MIC molecule has a particularly important job — to rouse the immune system. It can be detected by the activating receptor or the immune sensor, NKG2D, which licenses NK cells to kill. NKG2D can also power up the capacity of T cells to kill tumor cells. “This molecule MIC is supposed to tell the immune system, ‘Hey! I’m abnormal. I’m cancer. Come get me!’” Wu explained.

If working optimally, the immune system should recognize and fight cancer cells, killing them as they develop. “We asked a very fundamental question: Why? If the immune system is strong, and there are lots of mechanisms in place to identify and kill cancer cells, why did the tumor develop? That is the conundrum.”

So she and the team set out to answer the question.  They took plasma from various cancer patients and ran tests to see if they could figure it out. “Surprisingly,” she said, “we found the molecule MIC in the circulation, just wandering around the body.” At that time, they thought that the “wandering” molecule (named soluble MIC or sMIC) was the culprit that made T cells not function to their maximum power.

After completion of her post–doctoral training, Wu led her own research team to further understand how this sMIC molecule was actually moving freely around a patient’s body, undetected, seemingly invisible, with no attackers on its heels. Then they realized some cells are smarter than others – so smart, in fact, they’d developed covert ways of operating — from hiding, to hibernating, to actually outright fooling and disabling the immune system.

“How do these smart cancer cells go undetected?” she asked. “We hypothesized that the ‘not smart’ tumor cells get killed because they tell the immune system, ‘I’m here, come kill me.’ They’re not very bright. However, the smart cells, the ones that kill people, they take off their coats and say, ‘Let me get rid of this thing, so I can run around and not be seen by the immune system.’  That was our initial hypothesis, 12 years ago.”

For the last 12 years, five of them spent running her laboratory at MUSC, Wu led her team and dug deeper to more fully understand how tumor cells manage to trick the very powerful immune system by hiding or changing their appearance and viciously sabotaging the immune system.

The sMIC released by tumor cells, she explained, disarm the soldiers in the body in multiple ways. “The NK cell — which is the frontline defender that has the ability to kill tumor cells — it’s as though sMIC make them disappear. They’ve been disarmed, disabled, and even disappeared from the force.”

She further explained that the molecule sMIC can also make the overall climate unfavorable for immune attack, encouraging tumor cells to thrive.

“You wonder,” she continued, “is this what’s happening to make the immune system not work? If this is the reason, how can we make it work? How can we reverse it? That’s my question. How can we overcome cancer? How can we catch the smart cancer cells?”

Wu’s team discovered a way.

Immune cells have accelerators and brakes that speed up or slow down the cell’s ability to combat intruders. What if there were a treatment that removes the brakes and fuels–up the accelerator from these cells on patrol and deploys them to do their job?

Disabling the brakes

For decades, clinicians and scientists assumed that cancer was beyond the reach of the body’s ability to use its own natural defenses to fight. But research like Wu’s demonstrates the immune system is indeed capable of identifying and killing cancer cells, along with a new class of drugs called checkpoint inhibitors, which harness the immune system’s own ability to fight off cancer cells. These emerging sciences are indeed the revolution to traditional medicine. While traditional cancer drugs like chemotherapeutic agents act with foreign chemicals to attack cancer cells, immunotherapies also called “biotherapies” instead stimulate the body’s own immune cells to kill the cancer.

One of the most exciting advances in cancer immunotherapy involves releasing the innate brakes that keep the immune system from running rampant. This approach, called checkpoint blockade or inhibitors, relies on the fact that the immune system already knows how to fight cancer — it just needs a little boost.

T cells have receptors on their surface that accomplish different things. Some act like a gas pedal on a car telling them to go. But because they are so powerful, they also have a built–in brake system that tells them to stop, so they don’t attack normal cells or tissue, accidentally causing an autoimmune disease like rheumatoid arthritis or lupus. Many cancers, however, have learned to step on the brakes and use them to suppress the immune system's response to disease to avoid destruction. Checkpoint inhibitors are able to block that action, thereby depriving cancer of an all–important protective defense. Several checkpoint inhibitors are FDA–approved, and fortunately, many cancers have responded to them.

While ecstatic about these new pharmaceutical advancements, Wu looks at it more like a one-two punch. “What we’re trying to do right now, is not only release the immunological brake with an FDA–approved drug, we are also trying to power up the immune system. If the accelerator or the engine is broken, releasing the brake won’t go too far. That is why only a subset of patients responded to releasing the brakes alone. We are working on fixing the broken engine and also fueling-up the accelerator to make a majority, if not all, patients respond to immunotherapy. We have a great solution to it.”

Stealth mode

So a cancer cell is able to disable the immune system? “Yes, we believe it can disable it,” Wu said.” For example, the sMIC, a soluble protein released by cancer cells, gets into your bloodstream, disables the immune system by multiple approaches, and allows cancer cells to thrive — that’s what we found.”

Wu’s work was the first ever to show that tumor cell released sMIC makes tumor–killing NK cells disappear or dysfunctional and creates a hostile environment to hamper T cell function, thus allowing tumors to enter a dormant stealth mode to metastasize, or spread. Immune cells, including NK and T cells, normally should recognize these faulty cells and eliminate them in a process termed immunosurveillance.

Wu’s research team was the first to demonstrate that antibody targeting sMIC protein can repair the damage to the immune system, and even more impressively, to revive and refuel the immune accelerator. An antibody is a blood protein produced in response to a specific antigen — a toxin or other foreign substance that induces an immune response in the body — which it works to counteract.

“Over the last couple of years, we developed a therapeutic antibody, and we tried to determine if we could target the immune system. It worked out great. We showed that we can target this molecule to actually restore the immune system and use a body’s own ability to fight cancer. That is a great success.”

It’s nearly impossible for Wu to contain her excitement, and she can hardly wait to get this development to the point where it can help patients, which she believes will happen in the very near future. That day can’t come soon enough for her.

“I can’t stop thinking about the hope this could offer to patients. Patients are always at the forefront of my mind. I just want to tell cancer patients, ‘This is a great hope — our recent advances in the cancer immunology field offer great hope.’ I want them to know, we don’t just work 9 to 5. We aren’t just working with test tubes. It’s about them. Finding a solution for them is our lives, our passion. We live in it. We always look at the patient and ask, ‘What is wrong with the patient?’ If we understand that, we can come back and address that question. This question drives our lives.”

The NIH: joint chiefs of health care

Wu’s two recent prestigious NIH grants, totaling nearly $3.5 million, will help her to lead her team to bring clarity to these questions and drive innovation and cures. Highly competitive in nature, these grants underscore the significance and importance of her work.

The first grant allows her team to study how tumor–released sMIC makes NK cells, the first–line defenders, disappear or malfunction in cancer patients and to find ways to restore NK cell immune defensive power. NK cells control the spread of cancer cells and recently have been found to control the way stubborn cancer stem cells thrive. The loss of NK cell defense caused by sMIC may contribute to cancer cell spreading and also evolving into a deadly disease. 

The second grant will delve into supercharging the cancer–killing T cells to attack cancers. In most immune responses, the activation of T cells requires the presence of an additional stimulus. Wu has a solution to supercharge the cancer–killing T cells and make them produce the maximum response — more than ever.

The third NIH grant Wu received this year supports the work of her startup company, CanCure, LLC, which she launched in 2015. CanCure is an anticancer drug development company that aims to bring to fruition cancer treatment drugs that can restore the patient’s own natural immune function to fight cancer and to shepherd them through FDA approval. Wu secured CanCure with the NIH small business grant, the largest amount offered during Phase I development, to advance an antibody–based cancer immunotherapy she’s developed to use in humans. This therapy targets all cancer types, at all stages, including metastatic cancers — cancers that have spread to other organs and failed to respond to current standard care. It is a first–in–class cancer immunotherapy in that the therapy not only showed great efficacy by itself in shrinking tumors that are non–responsive to current FDA–approved immune checkpoint inhibitors, but also generates synergistic therapeutic effect when used in combination.

Wu is extremely optimistic.

“Why am I so passionate?” she asked. “Ultimately I want to understand, because I want to help people. I’m a cancer immunologist, and I love it. The bottom line is, I’m trying to understand how cancer develops in patients, so we can develop therapies to fight cancer and help patients.”

She needs to do this, she said, to help humanity. “The most exciting part of this, you see, is we are just about to walk to the end of the tunnel, and we see the light at the end of that tunnel. There is hope. We must have that. We must have hope.”