Researchers at Columbia Engineering have developed an inhalable nanotherapy designed to activate the immune system against melanoma that is resistant to current checkpoint inhibitor therapies. The therapy, known as BEAT (Bispecific Exosome Activator of T Cells), uses exosomes—tiny bubbles—to deliver therapeutic proteins directly to the lungs, which are a common site for melanoma metastasis outside the skin.
Immune checkpoint inhibitors are treatments that help the immune system recognize and attack cancer cells by releasing natural brakes on immune responses. However, nearly 40% of melanoma patients do not respond to these therapies. The new approach aims to address this challenge by targeting both the immunosuppressive tumor microenvironment and immune checkpoints simultaneously with two different proteins delivered via exosomes.
According to Cheng, one of the lead researchers, "By co-displaying them on a single exosome, BEAT can 'reprogram' the tumor microenvironment and recruit cancer-killing T cells directly to the tumor site." He added, "In mouse models of metastatic melanoma resistant to checkpoint inhibitors, inhaled BEAT completely reversed immune resistance, outperforming dual antibodies and showing minimal side effects."
The research team included experts in bioengineering, immunology, and nanomedicine from Columbia University’s Departments of Biomedical Engineering and Medicine as well as collaborators from Herbert Irving Comprehensive Cancer Center, University of North Carolina at Chapel Hill, and North Carolina State University.
Previous work by Cheng's lab has focused on developing exosomes for drug delivery in pulmonary diseases such as COVID-19 and lung cancer. In this study published in Nature Biotechnology, they engineered an exosome system displaying two therapeutic proteins: one blocks the PD-1/PD-L1 pathway—which is known to boost immune response against melanoma—and another inhibits Wnt/β-catenin signaling that prevents immune cells from entering tumors.
Results showed that inhaled BEAT was retained better in lung tissue compared to systemic antibody delivery and led to greater suppression of tumor growth. Local administration also limited potential damage to healthy tissues.
Looking ahead, Cheng stated that his team plans further validation in larger animal models and other cancer types. They will also conduct toxicology and pharmacokinetic studies before moving toward early-phase clinical trials. "While the approach is still preclinical, its safety profile in mice - no detectable liver, kidney, or autoimmune toxicity - is promising," he said. "Translational work with biotech partners could enable first-in-human testing within several years if these safety findings hold."
