Learn how researchers at the Wyss Institute are inventing new ways to fight and treat cancer
By Lindsay Brownell
(BOSTON) — More than 18 million people around the world are told, “You have cancer” every year. In the United States, nearly half of all men and more than one third of all women will develop some kind of cancer during their lifetimes, and over half a million die from it annually. Despite the billions of dollars of investment and hundreds of new treatments that have been thrown at the disease over the last few decades, cancer refuses to be beaten.
Why is cancer such a formidable foe? After all, it’s been known since the 1970s that unrepaired genetic damage can cause cells to grow uncontrollably, which has been viewed as cancer’s root cause. But this understanding has not pointed the way to an obvious treatment, as research into cancer biology has revealed it to be one of the most complex and insidious human diseases for a variety of reasons.
First, cancer can be caused by any number of factors, from viral infections to exposure to carcinogenic chemicals to simple bad genetic luck. One patient’s lung cancer might be caused by an entirely different constellation of mutations than another patient’s, and a drug that targets a certain mutational profile only benefits a subset of patients. And, cancer cells often spontaneously develop new mutations, limiting the effectiveness of genetically targeted drugs. Second, cancer is caused by the body’s own cells malfunctioning, so it is more difficult to design drugs that will target only cancerous cells while sparing healthy ones. Third, while genetic mutations can drive cancer formation, cancers can stop growing and remain dormant for years, suggesting that there are more factors in play than gene mutation. And finally, cancer has a number of different “tricks” that allow it to hide from the body’s highly vigilant immune system, which allows it to grow undetected and unchecked, often until it is too late.
Cancer treatment regimens through the 19th and 20th centuries were largely limited to the aggressive triumvirate of surgery, radiation, and chemotherapy, all of which carry traumatic side effects and can bring patients to the brink of death in the name of saving them. As our knowledge of the disease has grown more nuanced over the decades, a paradigm shift is happening in the field of cancer treatment, centered around the recognition that attacking a complex disease with blunt tools is not the most effective approach. A surge of new therapeutic strategies including immunotherapy, nanotechnology, and personalized medicine is giving hope to patients for whom traditional therapies have failed and offering the potential of long-lasting cures.
Scientists at the Wyss Institute with expertise in diverse fields ranging from molecular cell biology and immunology to materials science, chemical engineering, mechanobiology, and DNA origami are at the forefront of several of these novel approaches. Their research, united by the common principle of emulating the way Nature builds, has the potential to make existing treatments better, create new ones, and even prevent cancer from arising in the first place.
Better drug delivery is in our blood
Chemotherapy has been the backbone of cancer treatment for the last half-century, because it infuses drugs into the bloodstream to kill rapidly dividing cancer cells throughout the body. However, since chemotherapy systemically targets all fast-growing cells, it can also damage the intestines, bone marrow, skin, hair, and other parts of the body, and in some cases must be given at such a high dose that it nearly kills the patient in the course of treatment. Efforts to make chemotherapy drugs less toxic have included encapsulating them in nanoparticles that release them only when they reach their intended location, but less than 1% of nanoparticle-encapsulated drugs actually reach their targets, as the human liver and spleen aggressively filter them out of the blood.
Samir Mitragotri, Ph.D., decided to apply his chemical engineering background to solving the problem of keeping drugs in the bloodstream long enough to do their job, and found that he had been beaten to the punch: red and white blood cells circulate through the blood several times a day, seemingly escaping detection and destruction by the liver and spleen.
“I thought, ‘If these cells are naturally not cleared from the bloodstream, maybe we can use them to help the nanoparticles stay there as well, rather than creating some new and expensive disguise to protect the nanoparticles,’” says Mitragotri, who is a Core Faculty Member at the Wyss Institute and the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).
Mitragotri’s lab has found that nanoparticles attached to red blood cells are indeed ignored by the liver and spleen in mice, and that the nanoparticles are eventually sheared off and deposited into tissues when the blood cells make the particularly tight squeeze through the tiny capillaries that deliver blood to organs. By injecting blood-cell-bound nanoparticles into a blood vessel directly upstream of whole human lungs, they were able to get 41% of them to accumulate in the lung tissue – a far cry above 1%.
“Simply by changing which blood vessel we inject the nanoparticles into, we can deliver a much higher dose of a drug to its intended organ, and rely on the body’s natural clearing mechanism to get rid of any particles that don’t reach the target. We can even get some nanoparticles to target the brain, which has been a huge problem when trying to deliver drugs to the brain,” says Mitragotri.
Despite its bad reputation, chemotherapy is unlikely to be going anywhere soon, as research has found that new therapies work best when given in combination with chemotherapy. But technology like blood-cell-bound nanoparticles could help reduce the dose that must be administered, improve chemotherapies’ efficacy, and improve the quality of life for cancer patients worldwide.
Mitragotri has also found success in applying this nanoparticle “backpack” strategy to a type of white blood cell called monocytes, which differentiate into immune cells called macrophages that fight diseases including cancer. Not only are monocytes able to carry their nanoparticle drug loads with them as they infiltrate tissues (which could help deliver drugs to tumors that are deep inside organs), but nanoparticles could one day be used to control the monocytes themselves.
“One of the sneaky things tumors can do is turn macrophages ‘off’ in a similar way that they turn other immune cells off, such that up to half of a tumor can be made of dormant macrophages,” Mitragotri explains. “If we can deliver a chemical signal to monocytes via a nanoparticle backpack that keeps them in the ‘on’ state after they differentiate into macrophages, they could be much more effective at attacking a tumor rather than becoming part of it.”
Creating a safe space for immune cells
By exploring how controlling immune cells might help kill cancer, Mitragotri is dipping his toes into the burgeoning immuno-oncology movement, which reasons that modifying a patient’s immune system (which is already designed to hunt down and kill malfunctioning cells) so that it can overcome cancer’s evasive tactics is better than trying to design a novel drug for every different kind of known cancer. A number of immunotherapy approaches have been approved by the FDA in recent years, including “checkpoint inhibitor” drugs that take the brakes off of immune cells that have been inactivated by cancer cells, and T-cell therapies that involve removing a patient’s T cells, engineering them to attack the cancer, multiplying them, and infusing them back into the body.
A newer tactic, cancer vaccines, attempts to modify a patient’s immune system from within so that it not only attacks existing tumors, but creates an immune “memory” to destroy any future cancerous growths. However, engineering that process to take place completely within the body has proven to be a challenge, and the only cancer vaccine approved by the FDA so far (Provenge, in 2010) was a commercial failure due to its hefty $93,000 price tag and complicated, days-long treatment process that requires multiple infusions (though the vaccine is still approved for use in patients and clinical trials are ongoing)
One person was enthralled rather than disappointed by Provenge’s public struggle: David Mooney, Ph.D., a Founding Core Faculty member of the then-newly-created Wyss Institute for Biologically Inspired Engineering at Harvard University.
“My lab has had a longstanding interest in cell-based therapies for diseases like cancer. We thought the concept of training the body’s own immune system to fight cancer was really beautiful, but we wondered if there was a way we could simplify it by moving that whole process into the body instead of doing parts of it in a lab, like Provenge required,” says Mooney, who is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS.
The body already has a natural immune-training ground in the form of its lymph nodes, which harbor immune cells called dendritic cells that become activated and initiate an immune response when they detect evidence of an invading pathogen from the lymph vessels. Cancer cells, however, secrete immunosuppressive signals that can disrupt this immune activation process and protect themselves from the body’s defenses. A materials scientist and chemical engineer by training, Mooney realized that if he could construct and implant an artificial lymph node made from a material that was distinct from the rest of the body (and therefore protected from cancer’s influence), it might provide a safe haven in which to activate dendritic cells, which would then unleash the immune system’s attack on the cancer.
His lab has created just that: a cancer vaccine that is essentially an artificial lymph node containing signals that attract dendritic cells and activate them with proteins found on a patient’s tumor cells. The activated dendritic cells then travel to the body’s closest lymph node, where they train other types of immune cells to recognize and destroy the tumor. The vaccine is a spongy disk about the size of an aspirin tablet that is implanted into a patient using a simple incision, and biodegrades in the body to be safely excreted. Additionally, training the dendritic cells to recognize the proteins found on a tumor can provide protection against future recurrences of cancer, even if they occur elsewhere in the body.
Dramatic responses in mice with cancer who received the vaccine spurred Mooney and collaborators at the Dana-Farber Cancer Institute (DFCI) to start a Phase I clinical trial with support from the Wyss Institute and DFCI to see if it had the same effect in human patients – a feat usually undertaken by hospitals and pharmaceutical companies, but rarely inside academia. All told, it took just three years from the first publication about the cancer vaccine to its being implanted into the first patient as part of a clinical trial; a process that usually takes six to seven years of preclinical development in traditional pharmaceutical and biotech environments. Their results attracted the attention of drug giant Novartis, who licensed the technology from the Wyss Institute in 2018 and took the reins of future clinical trials, with plans to develop the cancer vaccine into a treatment for multiple kinds of cancer.
“The Wyss Institute was just starting, and we knew we wanted to focus on translating discoveries from the lab to the clinic, so we saw the cancer vaccine not only as a treatment with real potential to help lots of patients, but also as an opportunity to create a path for moving novel therapies out of academia and into the real world faster,” says Mooney. “There is no way I could have run a clinical trial out of my laboratory, so being able to build a team inside the Wyss to do the experiments and manufacturing needed for the FDA application, and partnering with DFCI to organize and run the clinical trial, was really what allowed us to get to the point where we’re implanting the vaccines in cancer patients so quickly.”
One such patient, profiled in a recent Boston Globe article, remains cancer-free nearly two years after getting the vaccine for advanced melanoma. Mooney is not content to rest on his laurels, however. “Cancer is a complex disease, and it’s unlikely there will be a single answer for all people and all kinds of cancer, so we need to keep exploring different approaches,” he says.
One such exploration is a partnership with another Wyss faculty member, William Shih, Ph.D., who has long been interested in how his research on DNA molecules that self-assemble into defined three-dimensional (3D) structures, or what is known as DNA origami, can improve the precision with which cancer therapy is delivered. Shih and Mooney are working on a joint project to see if DNA origami-based nanostructures can be incorporated into the cancer vaccine to enhance its ability to create a sustained immune response against cancer.
“When dendritic cells are activated, either in a lymph node or in the cancer vaccine, they have a decision to make: do they initiate an antibody response, where antibodies are produced that bind to a specific pathogen and mark it for destruction, or do they initiate a T-cell response, where they send T cells to destroy the pathogen directly? We want to nudge them toward the T-cell response, because it’s a more effective way to kill cancer cells,” explains Shih, who is also a professor at DFCI and Harvard Medical School (HMS).
Shih’s DNA origami nanostructures take advantage of the fact that DNA is a very stable and predictable compound thanks to the strong bonds between its four chemical bases. By constructing strands of DNA whose sequences of bases along their length are precisely known, Shih and his lab have been able to design 3D DNA structures that effectively build themselves (much like automatic Lego blocks) and whose properties can be tuned down to the nanoscale.
For the cancer vaccine, Shih’s lab has designed a DNA “cask” structure that presents a densely packed, precisely arranged display of ligands that are usually found on pathogens like bacteria or viruses and are recognized by the body’s immune system as “foreign.” These ligands essentially produce a “danger” signal that is recognized by dendritic cells, and can make them choose to initiate a T-cell immune response more often than an antibody response. “Our initial data suggest that the precise patterning of ligands we’re able to achieve with DNA origami make a big difference in activating the dendritic cells the way we want them to be activated,” Shih says. “We have this miracle drug [the cancer vaccine] – let’s make it better.”
A neighborhood watch for cancer
Immunology is all the rage for treating cancers after they occur, but every cancer arises from what was once a normal cell. What if we could tease out exactly what promotes the development of cancer, and find a way to reduce the chances that cancer will form in the first place? That’s a tall order, as there are hundreds of substances that are known to cause cancer, hundreds more that are suspected but not proven carcinogens, and other factors such as lifestyle and genetics all conspiring to damage our DNA.
But there are some causes that play an outsized role in cancer’s development, like chronic inflammation, which is associated with nearly 25% of all human cancers. Research being undertaken by the Wyss Institute’s Founding Director Donald Ingber, M.D., Ph.D., is now investigating the possibility of treating the inflammation of connective tissue and blood vessels (known collectively as the stroma that surrounds and supports organs) rather than directly attacking tumors themselves.
“Understanding how stromal tissues can influence the development of cancer has intrigued me personally since the time I was a graduate student,” says Ingber, who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS. “We and others have shown that changes in the physical structure and composition of the stroma can promote cancer formation and, conversely, that putting cancerous cells into a healthy stromal environment can suppress tumor growth, suggesting that targeting the tumor microenvironment could lead to new cancer reversal therapies.”
Ingber is part of a global research team tackling this problem from multiple angles as part of Cancer Research UK’s Grand Challenge competition, which was announced earlier this year. Key to the project is Ingber’s Organ Chip technology, which allows researchers to carry out human organ-level experimentation in vitro. Each Organ Chip is a microfluidic culture device containing hollow microchannels that can be lined with living human organ-lining epithelial cells and stromal cells, which experience physical conditions similar to those found in the body including blood flow, breathing motions in the lung, peristalsis in the intestine, etc. The Wyss Institute has created Organ Chips that faithfully mimic the lung, kidney, intestine, bone marrow, brain, and more, allowing researchers to grow tumor cells within the natural tissue and organ microenvironments found in the body, and then test treatments without the need to expose animals or patients to potentially harmful conditions.
“Our Organ Chips have shown us time and time again that in order for organ cells to function normally, they have to be provided with the right microenvironment. For this project, we will build models of different stages of cancer progression using cells isolated from human patients to understand how interactions between stromal cells and organ-lining cells change as inflammation-associated cancers form, as well as develop new ways to combat this response,” says Ingber. By combining Organ Chips with bioinformatics and machine learning approaches, the team hopes to identify new stromal-targeted treatments that can change inflamed tissue back into healthy tissue, thereby preventing cancer progression, or that induce cancerous or precancerous tissues to revert to a more normal state. By studying human cancer progression in vitro, the team also hopes to identify new diagnostics that can be used to identify the small subset of patients with inflammation-associated pre-malignant conditions, such as Barrett’s esophagus or ulcerative colitis, who might progress to cancer.
“Treating cancer is ultimately going to need to be a multifaceted approach, because the disease itself is so multifaceted,” adds Ingber. “The Wyss Institute was founded on the basis of bringing people together from different disciplines to tackle big problems in medicine through communication and collaboration among experts with a broad range of different perspectives. Doing that within the Wyss Institute has led to advances like Organ Chips, and doing that at a larger scale, such as with the Grand Challenge, allows whole institutions to put their resources together and drive real change for millions of patients living with devastating diseases like cancer worldwide.”
Whether targeting blood cells, the immune system, or stromal tissue, all of these projects are guided by the principle of using existing biological elements as the basis for new therapies, rather than trying to invent new cures from scratch.
“The human body is a marvel of biological engineering that has been tuned over millions of years to be able to fight off threats and heal itself. When we can recognize its inherent abilities and work with them rather than against them, we are taking full advantage of all the experimentation that evolution has already done for us. We believe this type of interdisciplinary, bioinspired approach can help create more new treatments for cancer and other complicated diseases much more effectively than traditional drug development strategies,” says Ingber.