Inhalable nanotherapy can activate the immune system against checkpoint-resistant melanoma

Immune checkpoint molecules play a crucial role in keeping the immune system in balance and preventing an attack on the body's own cells. Cancer cells can use these checkpoints to hide from the immune system, making them a key focus for treatments that boost the immune response against cancer. Immune checkpoint inhibitors are proteins that release this brake on the immune system and unleash our immune cells to attack tumors. 

However, a significant proportion of patients fail to respond to checkpoint inhibitor therapy, with non-response rates in melanoma approaching 40%. Now, researchers at Columbia Engineering have developed an inhalable nanotherapy that can activate the immune system against cancers resistant to current checkpoint inhibitor therapies. BEAT (Bispecific Exosome Activator of T Cells) 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. 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." 

 Ke Cheng, Alan L. Kaganov Professor of Biomedical Engineering at Columbia Engineering

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. 

Over the past 15 years, the Cheng Lab has been developing exosomes for use as drug delivery carriers with favorable biocompatibility and safety profile. The researchers have recently developed exosome-mediated inhalation therapy for several pulmonary diseases, including COVID-19 and lung cancer, as well as cardiovascular diseases. 

In the current study, published today in the journal Nature Biotechnology, 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 where immune cells are unable to infiltrate tumor tissues. 

The 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 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 work was an interdisciplinary collaboration involving researchers in bioengineering, immunology, and nanomedicine at Columbia University (Departments of Biomedical Engineering and Medicine, Herbert Irving Comprehensive Cancer Center), University of North Carolina at Chapel Hill, and North Carolina State University.

For next steps, 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."