Researchers from Columbia Engineering have made significant progress in cancer treatment by developing an inhalable nanotherapy designed to activate the immune system against melanoma, particularly in cases resistant to current checkpoint inhibitor therapies. This innovative approach, known as BEAT (Bispecific Exosome Activator of T Cells), utilizes engineered exosomes to deliver therapeutic proteins directly to the lungs, the primary site for non-skin metastasis in melanoma patients.
Immune checkpoint molecules regulate the immune response, preventing the body from attacking its own cells. Cancer cells exploit these checkpoints to evade the immune system, leading to a focus on immune checkpoint inhibitors, which are proteins that help release this “brake” on immune activity. Despite their promise, nearly 40% of melanoma patients do not respond to these therapies.
How BEAT Works
The innovative BEAT therapy employs tiny bubbles called exosomes to block two pathways that suppress immune responses. This dual action is particularly important as it addresses both the immunosuppressive tumor microenvironment and the immune checkpoints simultaneously. The engineered exosomes are the body’s own nanosized vesicles, allowing for a targeted and less invasive treatment method that minimizes damage to healthy tissues.
Over the past 15 years, the laboratory led by Ke Cheng, the Alan L. Kaganov Professor of Biomedical Engineering at Columbia Engineering, has been at the forefront of developing exosomes for drug delivery with a strong safety profile. Recent research has also explored exosome-mediated inhalation therapies for various pulmonary diseases, including COVID-19 and lung cancer.
The current study, published on March 15, 2024, in the journal Nature Biotechnology, showcases a system that simultaneously displays two therapeutic proteins specifically targeting lung metastases. One protein inhibits the PD-1/PD-L1 immune checkpoint pathway, known to enhance immune response and tumor reduction in melanoma. The other targets the Wnt/β-catenin signaling pathway, which often prevents immune cells from entering tumor tissues.
Significant Findings
The results indicated that inhaled BEAT demonstrated superior retention in the lungs compared to traditional antibody therapies and significantly suppressed tumor growth. In mouse models of metastatic melanoma resistant to checkpoint inhibitors, BEAT was able to reverse immune resistance effectively, outperforming dual antibodies and presenting minimal side effects.
“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. This breakthrough emphasizes the potential of inhalable nanotherapy as a transformative approach in oncology.
The interdisciplinary research involved collaboration among experts in bioengineering, immunology, and nanomedicine from Columbia University, the University of North Carolina at Chapel Hill, and North Carolina State University.
Looking ahead, Cheng and his team aim to validate BEAT’s efficacy in larger animal models and across a variety of cancer types. They will also undertake formal toxicology and pharmacokinetic studies to advance the therapy toward early-phase clinical trials. Cheng noted that while BEAT remains in preclinical stages, its safety profile in mice—showing no detectable liver, kidney, or autoimmune toxicity—holds promise for future applications.
If these findings are confirmed, collaborations with biotechnology partners could pave the way for first-in-human testing within the next few years. The research underscores the potential of innovative therapies to tackle resistant cancers in a more effective and targeted manner.
