Osteosarcoma is the most common bone cancer in children and adolescents and occur in young as well as older adults. While outcomes for localized disease have improved over time, patients with metastatic or relapsed tumors still face limited treatment options. Even with aggressive surgery and intensive chemotherapy, survival rates for advanced osteosarcoma have remained largely unchanged for decades. This lack of progress has fueled interest in new therapeutic approaches, including immunotherapies that can more precisely target cancer cells.
One such approach is chimeric antigen receptor (CAR) T cell therapy, which has transformed the treatment landscape for several blood cancers but has proven far more challenging to apply to solid tumors. A major hurdle is finding targets that are broadly present on cancer cells but largely absent from healthy tissues. In a new study in Cancer Research Communications led by investigators in Dr. Soheil Meshinchi’s lab, researchers describe how an unexpected target may help overcome this barrier in osteosarcoma.
“This study represents the culmination of a translational effort that began with Project Stella,” said Meshinchi, referring to a Fred Hutch-based discovery initiative focused on identifying actionable targets in a uniformly fatal form of infant acute myeloid leukemia (AML). Using a large-scale, multi-omic discovery platform, the team identified folate receptor alpha (FOLR1) as a highly and selectively expressed antigen in infant AML, with minimal expression in normal blood-forming cells. That discovery led to the development of a Fred Hutch-engineered, FOLR1-directed CAR T cell therapy that is currently being tested in patients.
As the CAR T therapy moved through development, the team began to ask whether FOLR1 might also be relevant in other cancers. “We systematically evaluated FOLR1 expression across additional malignancies and made an unexpected but striking observation,” Meshinchi explained. “Osteosarcoma exhibited uniform and high-level FOLR1 expression.”
To explore whether this expression could be therapeutically exploited, the researchers analyzed FOLR1 levels across patient tumor samples, osteosarcoma cell lines, and patient-derived xenograft models. They found that the vast majority of osteosarcoma specimens expressed FOLR1 at both the transcript and protein level, supporting its potential as a clinically relevant target.
The team then tested the Fred Hutch-developed FOLR1 CAR T therapy against osteosarcoma models in the lab. In cell culture experiments, the CAR T cells showed strong activation and efficiently killed FOLR1-expressing osteosarcoma cells, including primary patient samples. In mouse models of both localized and metastatic disease, the therapy drove potent antitumor responses, in some cases achieving complete and durable tumor eradication.
“These results provided the scientific rationale to repurpose a CAR T therapy initially designed for leukemia into a solid tumor indication with a significant unmet need,” said Meshinchi.
Importantly, the work has already moved beyond the preclinical stage. The findings directly enabled the launch of an active clinical trial testing FH FOLR1-CART in patients with relapsed or refractory osteosarcoma at Fred Hutchinson Cancer Center and Seattle Children’s Hospital. “This is an incredibly aggressive malignancy with no major therapeutic advances in over half a century,” Meshinchi noted. The first patient has already been treated in the trial, which is led by study author Dr. Michelle Choe as principal investigator.
For Meshinchi, the study underscores the power of discovery-driven translational research. “This work highlights how an unbiased target discovery effort in a rare, lethal leukemia can unexpectedly unlock therapeutic opportunities in solid tumors,” he said. What began as an effort to treat infant AML has now yielded a CAR T cell therapy with potential relevance far beyond its original indication.
That broader impact may only be beginning. The team has identified FOLR1 expression in several additional solid tumors, including lung, ovarian, pancreatic, uterine, and renal cell carcinomas, as well as select pediatric brain tumors, laying the groundwork for future studies. “FOLR1-CAR T is a prime example of how a single, well-validated target can bridge pediatric leukemia and solid tumor oncology,” Meshinchi said. “Our hope is that this approach can ultimately expand treatment options for patients who currently have very few.”
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Michelle Choe and Soheil Meshinchi contributed to this research.
The spotlighted research was funded by Wipe Out Kids’ Cancer, the Kuni Foundation, the Sam Day Foundation and the National Institutes of Health.
Choe M, Kirkey D, Lira I, Hawkins G, Blankenfeld M, Menashe S, Ries RE, Wrightson B, Root C, McKay CN, Peplinski JH, Glabman R, Davis LE, Malhotra SV, Gorlick R, Loggers ET, Meshinchi S. 2025. Preclinical Evaluation of Folate Receptor-α Chimeric Antigen Receptor T Cells Exhibits Highly Efficient Antitumor Activity against Osteosarcoma. Cancer Research Communications. DOI: 10.1158/2767-9764.CRC-25-0086.
Science Spotlight writer Jenny Waters is a postdoctoral research fellow in the Hsieh lab at Fred Hutch. She studies how mRNA translation coordinates bladder cancer transformation and metastasis by post-transcriptionally regulating expression of oncogenic proteins. Outside of the lab, Jenny enjoys spending time with her dogs, convincing her husband to join her on trail runs, and pretending every steep hill is just a "gentle incline."
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