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Groundbreaking immunotherapy. Novel treatments. And options for even the hardest to treat childhood cancers.
It's all happening at the pediatric hematology, oncology and bone marrow transplant program at the University of Wisconsin Carbone Cancer Center and the American Family Children's Hospital in Madison. The doctors, researchers and support staff are not only treating infants, children and teenagers with cancer, but are also working to get first-in-human clinical trials off the ground, often with therapies developed on the very same campus.
It's perhaps somewhat unexpected to find a complete bench-to-beside operation at a smaller cancer center in a mid-sized Midwestern city. But as one faculty member put it, it's a program that clearly punches above its weight.
"We're doing some pretty unique and possibly paradigm shifting research here," said Paul Sondel, MD, the Reed and Carolee Walker Professor of Pediatric Oncology at UW-Madison. "Our platform is to be one of the places that's taking new, cutting-edge ideas that are coming out of the laboratory and figuring out how to translate that into clinical reality and doing the first in clinical testing of those kinds of ideas."
Treatment for childhood cancer has come a long way. In the 1950s, a diagnosis of childhood leukemia, for example, would have been seen by doctors as a likely death sentence. Now, thanks to decades of research and significant advances in treatment, more than 80 percent of children with cancer in the United States are thought to be cured, with no sign of their original cancer ever coming back.
Without a doubt, that's a statistic to be celebrated. But Sondel says that success often comes with a catch. "Many of those children are facing lifelong medical issues, not only because of the cancer but because of what it took to treat the cancer," he said. That means former pediatric cancer patients are dealing with late effects like organ failure in their 20s and 30s, or even the emergence of secondary cancers that most people aren't at risk for until much later in life.
The goal then is not just to be able to cure all forms of childhood cancer, but do it in a way that gives children the best chance of living a long and healthy life. "If we could use more immunotherapy, we might be able to cut back on some of the chemotherapy and the radiation therapy and avoid some of those long-term side effects," he said.
Immunotherapy is a hot concept in cancer research right now, but the earliest examples of it date back to the late 19th century. With their experiments and research, physician-scientists like William Coley and Paul Ehrlich would lay the groundwork that Sondel would much later build upon at the UW-Madison.
While the body's immune system is usually pretty good at fighting off illness, cancer is a stubborn exception. Otherwise effective white blood cells have a tendency to overlook cancer cells, which lets the disease grow unchecked and thus requires an external form of treatment. But immunotherapy looks to sharpen or suppress various immune functions to help the body fight cancer by itself, or in conjunction with other therapies. For Sondel, finding that right mixture of treatment which balances the short-term and long-term needs of pediatric patients is critical.
"You can't have quality of life without life, but we need to be concerned about quality of life, and from the very beginning, be picking those treatments that are not only curative but also cause the fewest problems downstream," he said.
Of mice and men
Sondel, a physician-scientist, has been a prominent part of the pediatric cancer program at the University of Wisconsin for decades. Among other leadership positions, he was the head of the pediatric hematology, oncology and bone marrow transplant program for many years. He's also lent his expertise to numerous national cancer organizations and is an internationally recognized expert in the field of cancer immunotherapy.
Not bad for a guy whose first job on campus was washing test tubes.
As an undergraduate at UW in the late 1960s, Sondel knew he wanted to become a physician, but also had a desire to understand what was going on behind the scenes of the clinic. "I knew I wanted to understand what research was like and how you use research to make decisions about medical decisions," he said.
Seeking lab experience, he started knocking on doors around campus, hoping he might be able to land a job. Fortunately for Sondel, one of the doors he knocked on belonged to Fritz Bach, MD, the pioneering researcher and physician whose bone marrow transplant work would pave the way for modern immunotherapy. Among other things, Bach developed a compatibility test between organ donors and recipients. That enabled him to then lead one of the world's first successful matched bone marrow transplants, which took place in Madison.
Bach offered Sondel a job in his lab, a move that would set Sondel on a professional course that he's still on today.
In addition to washing the glassware, Sondel was able to get involved with the lab's research, which was turning its attention to leukemia. Early studies in mice had shown that different cancers had specific tumor antigens, or molecules that the immune system could recognize, and a mouse could be immunized against leukemia after a transplant.
That research led the team to start doing bone marrow transplants to treat the disease in humans. "It was one of the first things that was showing to be successful for those many patients with leukemia who weren't being cured with chemotherapy at the time," Sondel said.
With that experience fresh in his mind, Sondel went off to medical school at Harvard after graduating from UW. But in his classes about tumor and transplant immunology, he realized that what was being taught hadn't yet caught up to the type of research he participated in back in Wisconsin.
So he did what anyone would do in his situation: Take a leave of absence from Harvard to come back to UW-Madison to pursue a PhD in genetics.
While he'd go on to finish medical school at Harvard, work in a lab at the Sidney Farber Cancer Center (now the Dana-Farber Cancer Institute), and do a residency at the University of Minnesota, the pull of UW was strong. He'd return to campus, and after a few years, become a faculty member in 1980. "I joined the faculty because I wanted to be involved in the care of children with cancer, I wanted to do research that could potentially impact children and adults, and I wanted that research to be in the realm of what can we do with the immune system to have an effect against the tumor," he said.
At the time, much of the cancer immunology work being done revolved around how to make bone marrow transplants better. With an allogenic bone marrow transplant, cells are harvested from a matching donor and given to a recipient. While this procedure can be life-saving, it comes with risk, including graft-vs.-host disease, a potentially serious complication in which the donor's immune cells attack the healthy cells of the recipient. On the flip side, the recipient's immune system can flat out reject the graft altogether.
While researchers were brainstorming ways to make the graft work better, Sondel had another idea - might there be some way to get around all of this by using a patient's own immune cells to attack their own cancer?
With that, Sondel's lab made a significant shift towards toward researching and developing therapies that would rely on a patient's own cells, as opposed to the cells of others, to try and tackle cancer.
But in order to do the work he was looking to do, he'd need a little help.
If you build it, they will come
After becoming division head of the pediatric hematology, oncology and bone marrow transplant program in 1990, Sondel was able build up a research operation around this concept of cancer immunotherapy, and get the infrastructure in place to attract researchers to his program.
He likens it to Field of Dreams: A sort-of "if you build it, they will come" phenomenon.
The first major addition to the program came in 1998 with the hire of Ken DeSantes, MD, who was brought on to lead the bone marrow transplant program. DeSantes then became the clinical director of the pediatric hematology/oncology program, and director of the hematopoietic stem cell transplant program at the American Family Children's Hospital. He brought to the program expertise in not only transplant, but cancer immunology as well. DeSantes also had experience with a unique method of radiation delivery called MIBG, which at the time, was not widely adopted in the United States.
"I came with a strong clinical interest," DeSantes said. "I wasn't in the laboratory, but I was very interested in clinical immunotherapy. So having Paul in the lab, and me very interested in clinical research, it was a nice starting point."
That allowed the two to build a strong translational research component, something that's still true to this day. "It's actually quite unusual to have the type of bench-to-bedside clinical trials open that we have here, which I think is pretty unique for a program our size," DeSantes said.
DeSantes now heads the entire UW Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, taking over from Sondel in 2016 when he stepped down from that role after 26 years to become the Research Director of the division.
As the research operation grew and evolved, the team was able to grow alongside it. Of importance to this immunotherapy research mission, Inga Hofmann Zhang and Christian Capitini, both innovative physician scientists focused on immunotherapy or cell therapy for childhood cancer, were all recruited in the last 10 years, joining the team in clinical and research roles. Most recently, the team has benefited greatly from the arrival of Jacques Galipeau to UW, to help translate new technologies and therapies being developed at UW into first-in-human clinical trials.
"I feel like we hit the jackpot," Sondel said about the team.
Speaking of clinical trials, they are a huge part of what sets the program apart. Not only has UW Carbone and the American Family Children's Hospital rolled out numerous clinical trials featuring treatments and therapies developed right here, but the center is often asked to participate in national and international clinical trials as a partner institution.
"It's because of the reputation we have as an institution with extensive experience developing clinical trials focused on cancer immunotherapy," DeSantes said.
Piling into the minivan
In 2019, DeSantes was able to bring his two research interests - immunotherapy and MIBG - together for a first-of-its-kind clinical trial in the United States. The so-called "minivan" trial, which combines MIBG radiation therapy, along with immunotherapy drugs nivolumab and dinutuximab beta, is a collaboration between DeSantes and investigators in Germany and the United Kingdom.
The goal of the trial, which is ongoing, is to try and improve the cure rate for children with relapsed or refractory neuroblastoma. It's a disease that, fortunately, has recently seen advances in treatment. "About half the kids now with high risk neuroblastoma are cured," DeSantes said. "So there are fewer children relapsing."
Still, children can and do relapse, and this trial is aimed at those who haven't responded well enough to conventional therapy. Researchers will also be assessing the combination's ability to create long-lasting immunity that could prevent the disease from coming back later in life.
One of the key parts of this trial is the MIBG therapy, which is already being used as a standalone treatment option for the disease. Metaiodobenzylguanidine, or MIBG, is a substance that concentrates in neuroblastoma and a few other types of tumors. By attaching a radioisotope - in this case, iodine-131 - to an MIBG sample and infusing in into the patient, the drug goes where the cancer is, and ideally, takes it out. However, there's a catch. "It's a very complex therapy to administer, because, for a few days, the patients become extremely radioactive," DeSantes said.
That's because iodine-131 is a highly radioactive gamma emitter, meaning it radiates outside the body. Because of this, patients must be isolated in a special lead-lined facility for several days after receiving the treatment.
While it's a much more targeted form of radiation therapy, it's still radiation. And if the goal is to use less radiation therapy in pediatric cancer care, MIBG therapy by itself may not be the long-term answer. But combining it with immunotherapy drugs is an approach that researchers believe has merit, based in part on research from Sondel's lab, and that's where the minivan trial comes in. It's the first time the two antibodies and targeted radiation have been combined to target the disease, and represents a potentially less toxic alternative to the standard treatment.
"It's a great concept that mixes immunotherapy research done here with radiation therapy work done here, together with immunotherapy work done by a collaborator of ours in Germany," Sondel said. "You put these concepts together, and you get this minivan trial, which we're very excited about."
Moving beyond MIBG
MIBG compounds, however, target only neuroblastoma cells, as well as the cells of some rarer forms of cancer. That means that MIBG therapy, and the minivan treatment combination, have limited uses.
The question then becomes: can a similar method be used to treat other types of cancer?
That's one of the things that Diane Puccetti is looking trying to answer. Puccetti, an associate professor of pediatrics at UW-Madison, is the principal investigator on a Phase I clinical trial that is evaluating the use of CLR 131, a radiolabeled phospholipid ether analog, to treat children with relapsed solid tumors.
To say the least, it can be a challenge to get targeted radiation to a tumor, especially if the cancer has metastasized.
CLR 131 enters via lipid rafts, cholesterol-rich subdomains of the plasma membrane that are important in cell signaling. Because cancer cells replicate so quickly, they do a lot of signaling and therefore have a lot of lipid rafts, especially compared to normal cells. The lipid rafts pick up the radiolabeled phospholipid, take them to the cancer cells, and get down to business. In fact, researchers compare CLR 131 to a “Trojan horse,” as it sneaks inside a cancer cell before going on the attack.
Unlike MIBG, the compound's applications are significantly broader. In clinical testing, researchers are evaluating CLR 131’s use in neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma and other solid tumor cancers. The broad applicability of the compound to so many cancers is something researchers say is an enormous advantage in pediatric oncology.
It's another clinical trial that was originally developed and only available at American Family Children's Hospital. Now, several other hospitals nationally and internationally have joined this trial. It's also a homegrown technology. CLR 131 was developed at UW-Madison by associate professor Jamey Weichert, PhD, and colleagues in the Department of Radiology.
Efforts are also underway to push this approach even further, with researchers radiolabeling a related phospholipid analog with isotopes other than radioactive iodine. The advantage there is that patients would not have to be isolated in a lead-shielded room for up to several days after treatment - a big improvement over radioactive iodine.
Being cooped up for that long is hard enough for adults, and it's certainly very difficult for kids. Plus, any parent or caregiver who wants to enter the room must do so wearing safety equipment to protect themselves from radiation exposure, and even then, they can't stay long.
Finding an alternative isotope that prevents the radiation from leaving the body - an alpha or beta emitter - while still having the same effect against the tumor is an approach of great interest. It could also potentially be done on an outpatient basis, meaning the patient could go home instead of being confined for days at the hospital.
Made here, tested here
Cooking up a new technology or treatment in the lab is one thing. Getting them to the next level - human testing - is a whole different beast. That's where Jacques Galipeau, MD, comes in.
"My mandate here is to MacGyver those technologies into first-in-human clinical trials," said Galipeau, a professor of oncology and the director of the Program for Advanced Cell Therapy at UW-Madison.
MacGyver, of course, was the title character of a popular 1980s television series who had a knack for coming up with creative and clever solutions to solve a problem at hand. But while MacGyver's tools of the trade often entailed duct tape and paper clips, Galipeau's tools are much more complex and sophisticated.
"I'm interested in a flavor of immunotherapy called cell therapeutics, where the weapon used is taking your own cells and manipulating them in a petri dish, and giving that back as a pharmaceutical," he said.
Unlike other members of UW team of pediatric cancer researchers, Galipeau isn't a pediatric oncologist. But the work he does could have direct implications for pediatric cancer patients.
Launched in 2016, the Program for Advanced Cell Therapy, or PACT, looks to develop and utilize personalized cell technologies to improve health outcomes in children and adults with unmet medical needs. One of those needs is how to treat both adults and children who are suffering from a life threatening viral complication of a bone marrow transplant. And that's where PACT faces its first big test.
Cytomegalovirus, or CMV, is a fairly common virus in children and adults, but a healthy immune system usually keeps it in check. However, when a patient's immune system is suppressed, which must happen for a successful bone marrow transplant, CMV can run unchecked in the body.
In the program's first ever clinical trial, researchers are testing whether viral-specific white blood cells from a bone marrow stem cell donor - in this case, the cells that fight CMV - can be safely given to a recipient. Those cells are collected via a cell processing system developed at UW, and are infused into the patient receiving the transplant.
The trial is currently open to adult patients, and after three have been treated, the trial can then open up to children, as per an FDA requirement. "This is the first of what we hope to be many clinical trials where we deploy first-in-human technologies that were discovered and developed here," Galipeau said.
The applications here also go beyond just cancer. PACT's second clinical trial, which is currently enrolling patients, will take a similar approach with patients facing complications from a kidney transplant.
Working alongside Galipeau on these trials is PACT's medical director, Inga Hofmann Zhang, MD, who also is the director of the pediatric bone marrow transplant program.
"One of my focuses now is really to grow that program," she said. "The goal is to build a comprehensive clinic that is really building a platform for translational research."
In addition to her cell therapy work, Hofmann Zhang, an assistant professor at UW-Madison, is working to build what she calls a "Wisconsin-centric" network of data, rooted in genomics. "It's like a molecular tumor board, but it's focused on inherited predispositions of hematological malignancies and bone marrow failure," she said. "We'll be building a referral-based platform, building expertise, building collaborations with centers around the state or neighboring states, and with that, we're going to start collecting local patient samples."
Information will come from both pediatric and adult patients. The hope is to use it to develop treatments that could help fight diseases like pediatric myelodysplastic syndrome, or MDS, which is a rare bone marrow disorder that prevents the formation of blood cells, and can lead to leukemia.
Hofmann Zhang is also heading up numerous clinical trials that deal with bone marrow failure. One trial is looking at unrelated donor transplant vs. immune therapy in pediatric severe aplastic anemia, a condition where the bone marrow doesn't produce enough blood cells. Another is a phase II trial that's testing the effectiveness of the drug Eltrombopag in children with the disease, as well as studying how the body processes the drug.
It's all in a day's work for someone who describes herself as a personal growth and development junkie. "I'm very passionate about expanding things and doing new things, whether that's research or whether that's building clinical programs," she said.
Turning T-cells into CAR T-cells and beyond
One emerging cancer treatment option for kids and adults that's getting a lot of attention these days is CAR T-cellular therapy.
The concept involves reengineering a patient's own white blood cells, or T cells, in a lab. There, they are modified with special receptors, known as chimeric antigen receptors or CARs. These new supercharged CAR T-cells are then injected back into a patient, where they seek out and hunt cancer cells. The therapy is approved to treat specific blood cancers, such as leukemia and lymphoma, in both adults and children.
With Christian Capitini, MD, at the helm, UW participated in the first multi-center CAR T clinical trial ever developed, which tested the effectiveness of CAR T-cells in treating patients with relapsed or refractory B-cell acute lymphocytic leukemia or ALL. That trial, Capitini said, was critical in achieving the FDA approval of the therapy for ALL in 2017.
"We're continuing in those clinical trials now, studying those CAR T-cells in non-Hodgkin's lymphoma, and seeing if they work in other cancers in children," said Capitini, an assistant professor of pediatrics at UW-Madison.
While it's clear that CAR T-cells can work for some patients, it's still a relatively new treatment, and as such, some questions remain about the long-term impact of these cells being in the body. Researchers like Capitini want to know more about what these cells do and where they go after they've been introduced in a patient.
To do that, Capitini's lab is turning to something called fluorine-19 MRI to track the cells as they move through the body. By adding a non-radioactive isotope of fluorine to CAR T-cells, researchers will be able to track the cells using a specially designed, clinical-grade MRI coil. In addition, because nothing is radioactive, the tagged cells won't decay, meaning long-term tracking is possible.
In a mouse model, it's an approach that Capitini has seen work to track so-called natural killer cells, or NK cells, which are another form of white blood cell. But before human testing can begin, more data is needed, and on something bigger than a mouse.
That's where man's best friend can lend a helping paw.
"Companion animals like pet dogs develop bone cancer at much higher rates than humans, and because osteosarcoma is the most common bone cancer in children, it's obviously even more common in dogs," Capitini said.
To be clear, these dogs are not lab animals. They are people's pets and companions who happen to have cancer. And much like a human clinical trial patient, there are strict protocols that must be followed in any testing. "We thought it would be a great way to test out the clinical coil to make sure that the results we saw with the mouse coil could be extrapolated, and then that could potentially lead to a first in human trial," Capitini said.
However, with specially designed MRI coils, reengineered cells and several rounds of testing, the costs of this kind of research add up quick. While cancer research requires a lot of money to begin with, cell therapy and immunotherapy have their own unique expenses.
"When you're growing cells out of the body for weeks at a time, they need nutrients and other kinds of support that is different than when you thaw something out of the freezer and give it to a patient," Capitini said. "There are a lot of upfront costs in these trials, and that makes it even more challenging to get it to the first-in-human stage."
You might think federal grants are footing the bill. While the UW team does compete for and receive peer-reviewed, competitive federal funding, it's philanthropic gifts, big and small, that really make this research possible.
Philanthropy leads the way
It's hard to not be excited when former Badgers and Bucks show up at the American Family Children's Hospital. It's even more exciting when they have a big announcement to make.
In October 2019, the Midwest Athletes Against Childhood Cancer Fund, or MACC Fund, announced a $10 million gift to American Family Children's Hospital and the UW Carbone Cancer Center. The money - $2 million per year over the next five years - would all go to advancing pediatric cancer research.
It's a gift that has been described in many ways and has elicited numerous superlatives from the researchers who get to put the funds to use.
"Transformative," Galipeau said.
"Huge," said Capitini.
No matter how you want to describe it, a gift of this amount give researchers the ability and resources to try out novel ideas that wouldn't be covered by grant funds.
For as important as federal grants are, they can only take a research operation so far. Only about 8 percent of grants that are submitted to the NCI are funded. And only 4% of the NCI's total budget is allotted to funding pediatric cancer research. There's lots of competition, and even more paperwork to fill out. Plus, there's somewhat of a limit on what federal dollars can be used for. "The grants we get from the government are enabling us to finish things that we've already shown are working," Sondel said. "Philanthropy helps us to generate the support we need to do those new ideas that are novel and risky."
"It allows you, in a timely fashion, to move the needle to generate those pilot data that then allows you to pivot towards long-term sustainable federal funds," Galipeau added.
Once a trial does get to that stage, philanthropic support can also help researchers go the extra mile, and do an in-depth biological analysis of the results. That information, Hofmann Zhang says, is critical in understanding why a trial worked the way it did. "Without collecting more research-type of samples and asking laboratory-types of questions, a trial, in my opinion, is incomplete and insufficient to help us really move forward," she said.
While big donations, such as the recent gift from the MACC Fund, grab a lot of the headlines, the truth is that there are many foundations, organizations and individuals who make philanthropic gifts that make a huge difference. "Having the additional income guaranteed through philanthropy has just been a tremendous asset," DeSantes said. "Without it, there's no way we'd be able to do the type of clinical research we're currently doing."
Pediatric Cancer Dream Team
Some grants, however, are a little out of the ordinary. In a good way.
In the fall of 2012, Sondel and Capitini were sitting at a conference in Germany when they got wind of an intriguing announcement. The St. Baldrick's Foundation, one of the world's leading childhood cancer foundations, was teaming up with the group Stand Up to Cancer to fund a so-called "Dream Team" grant. The mandate was clear: Propose what you want but do something to revolutionize pediatric cancer research.
For Sondel and Capitini, they immediately thought about what an immunology dream team might look like. They discussed the idea with immunotherapy colleagues at other institutions and floated the idea of a collaboration. But they also got to talking with colleagues who were studying the genetics of childhood cancer, who were also interested in pursuing the grant.
With millions of research dollars up for grabs, it was clear the competition would be fierce. It was at that point they realized: Why not combine the two ideas?
"For the first time, let's take these two fields that are really cutting-edge in pediatric cancer research and see if we can use genetics to inform what we're doing in immunotherapy, and propose a new concept called immunogenomics," Sondel said.
Genomics and immunotherapy, it turns out, are a pretty good match for each other. Researchers can use genomics to determine the best targets for immunotherapy, meaning a higher likelihood of killing the cancer cells, as well as leaving the healthy cells unharmed.
The idea worked. While over 100 separate pediatric centers competed for the grant, the University of Wisconsin, along with six other collaborating institutions, was awarded the multi-million dollar grant, and the Dream Team was born.
According to St. Baldrick's, the Dream Team has treated more than 930 patients on 34 clinical trials, helped get the first gene therapies approved by the FDA, and discovered new immunotherapy targets.
The Dream Team has been so successful that St. Baldrick's renewed their financial commitment to the grant, even though it wasn't intended to be renewable. Stand Up To Cancer also stayed on to provide expertise and guidance.
"We're now finishing the sixth year of our four-year grant that actually has become an eight-year grant, Sondel said.
The Dream Team designation has reaped other benefits, as well. When the National Cancer Institute announced a competition to create a network for pediatric cancer clinical trials, which would provide funding to accelerate and improve clinical trials, the Dream Team's member institutions were able to show that they already had the infrastructure in place to make it happen.
As a result, they were awarded that grant, as well.
"These two grants complement each other," Sondel said. "It's enabling the institutions that are a part of this Dream Team to do the discovery research and to translate that into early clinical trials, which we hope will become treatments that will provide more cures and allow us to cut back on chemotherapy."
The future is now
It's easy to look back at the successes that the pediatric cancer program at UW has achieved over the years. But as a new decade kicks off, it's clear that the members of the program are only looking forward.
For Sondel, he knows that the immunotherapy research being done here is solid. What's next, however, is finding new ways to augment it with contributions from other scientific fields. "We've got more momentum here and it's reaching out into separate disciplines that interact with immunotherapy to help it work better," he said.
Hofmann Zhang said she's eager to keep building up the bone marrow transplant program, increasing the amount of patient samples to research, and filling an important need to those dealing with bone marrow failure. "I think we can offer something super unique to this area, which doesn't really exist, but we know that there are patients that need those services," she said. "I think now we have some critical manpower to move that forward."
Over at the Program for Advanced Cell Therapy, Galipeau is looking to go big in the new year. "We're thinking in 2020 that we can open up at least another three different studies, he said. "The technologies we're thinking of moving forward with are ones that can genetically weaponize your own immune cells to fight off cancer."
In a similar vein, Capitini sees a promising future for CAR T-cell therapy and pediatric patients. "In 2020, we plan to be participating in other multi-center CAR T-cell trials for pediatric solid tumors," he said. "We're hoping that this technology will be expanded to a lot of different cancers in children."
He also added, "I'm hoping through more philanthropic support that we'll be able to grow the program further, bring in more experts and faculty to expand what we're doing, but also importantly, to provide as many clinical trials as possible. We're not limited to one type of immunotherapy, and I think we have a very nice portfolio to offer patients. We are very big proponents of combination therapy, and we think that combining cell therapy with antibody therapies is really going to be the home run."