Deploying Immunotherapy Against Metastatic Osteosarcoma

Researcher Alex Huang, MD, PhD, is leading efforts from UH Rainbow’s new Center for Pediatric Immunotherapy

Innovations in Pediatrics | Winter 2022

Research under way at the new Center for Pediatric Immunotherapy at the Angie Fowler Adolescent & Young Adult Cancer Institute at UH Rainbow Babies & Children’s Hospital is focused on using one of medicine’s most promising new tools to solve one of the most intractable problems in pediatric oncology – the dismal outcomes for young patients with metastatic osteosarcoma and other sarcomas.

Alex Huang, MD, PhD

“The outcomes for metastatic osteosarcoma are pretty abysmal,” says pediatric oncologist Alex Huang, MD, PhD, Director of the new Pediatric Immunotherapy Center at UH Rainbow. “There is a great need to think out of the box, and we at UH Rainbow believe strongly that immunotherapy is the answer.”

Dr. Huang and his team are approaching this problem by seeking a better understanding of how myeloid immune cells function and interact with these tumors.

“It’s been shown that osteosarcoma patients who have a lot of these infiltrating myeloid cells in their tumor mass tend to have worse outcomes compared with patients whose tumor harbors fewer of these myeloid cells,” he says. “We know the presence of these myeloid cells has a prognostic effect on the long-term outcome from these tumors, but what exactly they do is under intense investigation.”

One specific project in Dr. Huang’s lab is looking at how to block the interaction between a molecule called VCAM-1 in the osteosarcoma tumor and its partner macrophages in the lungs, which appears to be important in disease spread.

“Our research shows that VCAM-1 is absent in primary osteosarcoma tumors that do not metastasize to the lungs,” he says. “So there’s something about this molecule’s presence that allows this tumor to grow better in the pulmonary microenvironment. We propose that the interacting partner on the macrophage in the lung is a molecule called VLA4.”

In animal experiments, the team has shown that when VCAM-1 is genetically removed, or when macrophages are depleted from the lungs, there is no metastasis.

“When you do that, you can prevent pulmonary metastatic disease from happening in animal models, demonstrating that the presence of the VCAM-1 in tumor and the presence of macrophages in the lungs are the two ingredients that are critical to make sure that these tumors metastasize and take hold in the lung tissue microenvironment,” Dr. Huang says.

Seeking a more practical way to block this important molecular interaction, Dr. Huang and his team have looked to existing, FDA-approved antibody therapies that can achieve the same outcome. Specifically, they’re investigating an off-label use of natalizumab, approved for multiple sclerosis and inflammatory bowel disease.

Dr. Huang and his team, including fellow UH Rainbow oncologist Kristen VanHeyst, DO, approached the drug manufacturer about using it in an osteosarcoma clinical trial, and they ultimately got the answer they wanted: yes. After receiving IND approval from the U.S. Food and Drug Administration (FDA), a Phase I/II trial of natalizumab in patients with unresectable pulmonary metastatic osteosarcoma will open at UH Rainbow in the coming days.

“That’s going to be very gratifying,” Dr. Huang says. “This project has gone from mouse studies to patients in record time. It's preclinical to clinical translation. It is an extremely gratifying opportunity for Dr. VanHeyst, our former trainee at UH Rainbow and now faculty, for whom this effort will advance her clinical translational career and build a national reputation, both for her and for Angie’s Institute. Because of this project, she’s also been invited by Children’s Oncology Group to participate in its Bone Tumor Committee.”

Another promising project in Dr. Huang’s lab is the identification of a potent anti-cancer compound in the shell of oat bran – a project pursued jointly with Mei Zhang, PhD, an Assistant Professor of Biomedical Engineering and Case Comprehensive Cancer Center at Case Western Reserve University.

“It turns out that a constituent of the oat bran in the outer shell of the oat is highly immunogenic and can stop tumor growth in mouse models of osteosarcoma, melanoma and pancreatic cancer by eliciting robust anti-tumor immune responses,” Dr. Huang says. “The biopolymer Dr. Zhang has identified, BG34-200, possesses an unusual capacity to enter myeloid immune cells via CD11b molecule and trigger them to become potent, immune-stimulating cells that promote tumor immunity. BG34-200 was shown to be highly effective when administered intravenously in reducing early pulmonary metastatic osteosarcoma in immune competent mouse models. It appears to change the whole tumor microenvironment from a cold tumor microenvironment to a hot tumor microenvironment, increasing the number of T cell infiltration, increasing the function of these myeloid cells from an immune-suppressive to an immune-stimulating phenotype.”

On the strength of these data, Dr. Huang and Dr. Zhang received Orphan Drug Designation/Rare Disease Designation for BG34-200 from the FDA for the treatment of osteosarcoma in August 2020. The team is working with the National Cancer Institute’s Comparative Oncology Program to develop a canine trial, evaluating the molecule in pet dog patients with progressive pulmonary metastatic osteosarcoma, with the goal of seeking FDA IND approval in 2022 or 2023.

In addition to projects initiating in their own lab, Dr. Huang and his team are also engaged in collaborative projects around the globe aimed at improving outcomes for patients with metastatic osteosarcoma. They recently lent their scientific expertise to the Korean pharmaceutical company MedPacto in its quest for Orphan Drug Designation for its orally bioavailable TGF-inhibitor vactosertib, which was ultimately approved by the FDA in August 2021.

“This drug targets another very immune-suppressive molecule in the tumor microenvironment called TGF beta,” Dr. Huang says. “It is known to be a very important molecule to target but historically it’s been very difficult to do. Vactosertib is very potent as a TGF inhibitor, cutting across both mouse and human osteosarcoma cell lines. This drug has an effect directly on the tumor itself, but also has an effect on the immune system that surrounds the tumor cells.”

Joint experiments between MedPacto and Dr. Huang’s lab have demonstrated the efficacy of vactosertib in osteosarcoma models. The team confirmed the superior efficacy of vactosertib in significantly inhibiting osteosarcoma tumor growth and metastasis in experimental mice, both as monotherapy and in combination with checkpoint inhibitors.

“We see again a very potent inhibition of the osteosarcoma growth, and we see changes in the immune microenvironment of these tumors – increasing activity of NK cells, anti-tumor macrophages, increasing T cells,” Dr. Huang says. “And what’s even more exciting is if you combine vactosertib with anti-PDL1 antibody, which historically does not work well for osteosarcoma as a single agent, we now have a synergistic effect. This suggests that vactosertib not only targets cancer cells directly, but also activates immune cells such that they can respond to anti-PDL1 antibody.”

For Dr. Huang, all these research developments give him hope that he and his team can help create a better future for the young osteosarcoma patients he sees in his practice every day.

“We are witnessing the explosion of cellular and immunotherapy as a potentially powerful weapon against a variety of human diseases, including cancer,” he says. “Our goal is to improve the therapeutic options and outcomes for pediatric and AYA patients whose lives could be positively impacted by thoughtful and innovative applications of immunotherapy.”

For more information on the new Center for Pediatric Immunotherapy at the Angie Fowler Adolescent and Young Adult Cancer Institute at UH Rainbow Babies & Children’s Hospital, please visit https://www.uhhospitals.org/rainbow/services/pediatric-cancer-and-blood-disorders/conditions-and-treatments/pediatric-immunotherapy or email your question to Peds.Innovations@UHhospitals.org.

Contributing Expert:
Alex Huang, MD, PhD
Director, Pediatric Immunotherapy Center
Theresia G. and Stuart F. Kline Family Foundation Chair in Pediatric Oncology
UH Rainbow Babies & Children’s Hospital
Professor of Pediatrics
Professor of Pathology and Biomedical Engineering
Case Western Reserve University