Scientists Develop Inhalabale Nanotherapy to Fight Melanoma Resistant to Checkpoint Inhibitors

Researchers at Columbia Engineering have developed an inhalable nanotherapy called BEAT (Bispecific Exosome Activator of T Cells) that can activate the immune system against cancers resistant to current checkpoint inhibitor therapies. BEAT uses tiny bubbles, called exosomes, to directly deliver therapeutic proteins to the lungs — the most common non-skin metastasis site in melanoma. 

“Unlike existing antibody drugs that block a single immune checkpoint, BEAT uses engineered exosomes — the body’s own nanosized vesicles — to simultaneously block two pathways that suppress immune attack,” said Ke Cheng, PhD, Alan L. Kaganov professor of biomedical engineering at Columbia Engineering. “The tandem exosome engineering method opens a new way to deliver multiple therapeutic proteins locally — a platform that could apply to autoimmune, infectious or fibrotic diseases where multi-target modulation is needed.”

Dr. Cheng and his colleagues created an exosome system that co-displays two therapeutic proteins to treat lung metastases. One protein blocks the PD-1/PD-L1 immune checkpoint pathway, a process that has been shown to boost the immune response against melanoma cells and shrink tumors. The other protein blocks the Wnt/β-catenin signaling pathway that drives immune exclusion in tumors, a phenomenon in which immune cells are unable to infiltrate tumor tissues. 

Results demonstrated that, compared to a systemically delivered approach with antibodies targeting the same pathways, inhaled BEAT showed better retention in the lungs and dramatically suppressed tumor growth to a larger extent. “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,” said Dr. Cheng. “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 novel approach allows for simultaneous targeting of the immunosuppressive tumor microenvironment — a common source of resistance to checkpoint inhibitor therapy — with one protein and immune checkpoints with the other. In addition, administering the proteins locally rather than systemically serves to limit damage to healthy tissue. 

Next, Dr. Cheng and his colleagues aim to validate BEAT in larger animal models and across different cancer types. They also plan to conduct formal toxicology and pharmacokinetic studies to prepare for 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.”