University of Colorado Cancer Center members Michael Leibowitz, MD, PhD, and Dan Regan, DVM, PhD, have received an $800,000 grant from the V Foundation for Cancer Research, co-founded by ESPN and legendary basketball coach Jim Valvano, to study a new potential treatment for pediatric osteosarcoma that spreads to the lungs.
“These tumors tend to occur in the limbs and sometimes in the pelvis,” says Leibowitz, assistant professor of pediatric hematology, oncology, and bone marrow transplantation at the CU School of Medicine. “Initially these patients get chemo, then surgery, then additional chemo, and most do fairly well. However, a certain percentage of those patients that present with nonmetastatic disease will relapse and recur with metastatic disease, and the prognosis for those patients — as well as patients who present with lung metastatic disease — is dismal.”
Some patients also have localized osteosarcoma in areas like the pelvis where there are so many nerves that removing them surgically is simply too risky, Leibowitz says. In either case, the standard of care for patients with lung metastatic osteosarcoma or osteosarcoma in areas where surgery is impractical is toxic chemotherapy that can damage organs like the kidney and heart.
“In those situations, where a patient cannot receive the standard of care therapy, we don’t really have many good alternative therapies,” Leibowitz says. “We’ve been giving the same chemotherapy to these patients for over 40 years. There have been no advances. The medicines that we have now are very toxic; not everybody can tolerate them. And when patients relapse or have a tumor in a location where you can’t get standard of care, the prognosis is absolutely dismal. That’s what motivated me to work on developing safer, less toxic, and more effective therapies for these patients.”
Two-drug combination shows promise
Regan, a faculty member at Colorado State University (CSU) in Fort Collins and a researcher at the Flint Animal Cancer Center, previously identified a two-drug combination for metastatic osteosarcoma that showed success in targeting a type of immune cell called a macrophage that tumors use to grow and spread. First tested in dogs at CSU, the combination of the blood pressure drug losartan and the anti-cancer drug sunitinib — both of which are FDA approved — is now in a clinical trial in pediatric patients at Children’s Hospital Colorado.
“We’re working with the Children’s Hospital team on the human trial, and we get a lot of those samples sent to our lab for immune-based correlative analyses,” Regan says. “We’re escalating the dose of losartan throughout the trial, and we’re about halfway through right now. Although we are still early in the time course of the trial, we do seem to be modulating some of our intended targets based on the immune-based analyses.”
Adding CARs to the mix
For the new study funded by the V Foundation and other entities, Regan and Leibowitz plan to build upon that two-drug combination by adding CAR T-cell therapy to the mix, using genetically engineering canine blood cells from the patients to seek out and destroy cancer cells. Leibowitz is utilizing chimeric antigen receptor (CAR) T cells that target a population of cells called cancer-associated fibroblasts. The fibroblasts secrete a signal that recruits macrophages to work on behalf of the tumor cells.
“We think there will be synergy between the CAR T product and Dan’s two-drug product,” Leibowitz says. “In addition, the CAR T cell, by eliminating these cancer-associated fibroblasts, will also deplete a physical barrier around tumors that we call stroma. We hypothesize that this will enable immune cells like T cells to get into the tumor and increase anti-tumor efficacy.”
For the four-year study, researchers in Fort Collins will study dogs who have naturally developed osteosarcoma and lung metastases by treating them with CAR T cells produced in Leibowitz’s lab on the CU Anschutz Medical Campus. Known as “comparative oncology,” the practice of studying cancer in dogs as a precursor to treating it in humans makes perfect sense from a scientific standpoint, Regan says.
“The major benefit of this comparative oncology approach is that we can jump ahead a little bit,” Regan says. “We can test things in dogs that you might not necessarily jump right into a human clinical trial. Dogs also have a shorter lifespan than humans, so their progression of cancer is much more accelerated. You know if things are working or not working much more quickly.”
In his initial trial of the losartan-sunitinib combination in dogs, Regan saw 50% of patients achieve longer-term disease stabilization and 25% that saw regression of tumors. It’s a good start, he says, but he’s hopeful that adding the CAR T product to the mix leads to even better results.
“It’s a good backbone,” he says of the previous study, “but I think we can build on it. In the setting of metastatic disease, where basically nothing works, it’s a big success to have 25% regression. But could we get 50% regression with the addition of CAR T cells? That would be a huge ask, but that’s what we’re trying to find out.”
Thankful for support
Both researchers say they are grateful to the V Foundation for supporting the research that could have life-saving repercussions for pediatric patients down the line.
“It’s not always easy to get financial support for this type of comparative oncology approach, so getting buy-in from an organization like the V Foundation is encouraging and motivating, and we’re really grateful and appreciative for that,” Regan says. “Mike and I clearly believe in the utility of this approach to hopefully accelerate therapeutic development for this rare cancer, and getting this grant shows that the foundation also potentially believes in that potential.”
The V Foundation support is “incredibly humbling,” Leibowitz adds. “We’re grateful for the support, because, quite honestly, without monetary support, it would be very difficult to perform a trial like this. We’re going to learn a lot about the biology of this disease, and how these interventions change the tumor microenvironment. Regardless of if this is successful or not, I think it will lead to more interesting questions, and perhaps new and different targeted therapies. It’s incredibly exciting.”
