Research on Immune Checkpoint Inhibitors and Cancer
Immune checkpoint molecules regulate the immune system's balance. Cancer cells can use these checkpoints to evade immune detection, making them targets for therapies designed to enhance the immune response against tumors.
However, a proportion of patients do not respond to existing checkpoint inhibitor therapy; non-response rates in melanoma have been observed approaching 40%.
Development of BEAT Nanotherapy
Researchers at Columbia Engineering have developed an inhalable nanotherapy named BEAT (Bispecific Exosome Activator of T Cells). BEAT utilizes exosomes, which are nanosized vesicles, to deliver therapeutic proteins directly to the lungs, a common site for non-skin melanoma metastases. This therapy aims to activate the immune system against cancers resistant to current checkpoint inhibitor treatments.
Ke Cheng, Alan L. Kaganov Professor of Biomedical Engineering at Columbia Engineering, stated that BEAT employs engineered exosomes to simultaneously block two pathways that suppress immune responses. This tandem exosome engineering method is described as a strategy for local delivery of multiple therapeutic proteins, with potential applicability in autoimmune, infectious, or fibrotic diseases requiring multi-target modulation.
This approach targets the immunosuppressive tumor microenvironment, identified as a source of resistance to checkpoint inhibitor therapy, with one protein. Simultaneously, it targets immune checkpoints with another protein. Local administration of these proteins, rather than systemic delivery, is intended to limit potential effects on healthy tissue.
Exosome Research Background
The Cheng Lab has been engaged in exosome research for 15 years, investigating their use as drug delivery carriers due to their biocompatibility. The researchers have previously developed exosome-mediated inhalation therapies for pulmonary diseases, including COVID-19 and lung cancer, as well as cardiovascular diseases.
Study Findings and Mechanism
A study published in Nature Biotechnology details the exosome system developed by Cheng and colleagues. This system co-displays two therapeutic proteins for treating lung metastases:
- One protein blocks the PD-1/PD-L1 immune checkpoint pathway, which has shown effects on melanoma cells and tumor size.
- The second protein blocks the Wnt/β-catenin signaling pathway, which is associated with immune cell exclusion from tumor tissues.
Results from mouse models indicated that inhaled BEAT exhibited increased retention in the lungs and reduced tumor growth to a greater extent compared to a systemically delivered antibody approach targeting the same pathways. Cheng commented that BEAT, by co-displaying proteins on a single exosome, aims to modulate the tumor microenvironment and recruit T cells to the tumor site. In mouse models of metastatic melanoma resistant to checkpoint inhibitors, inhaled BEAT reversed immune resistance and showed minimal observed side effects.
Collaboration and Future Plans
The research was an interdisciplinary collaboration involving bioengineering, immunology, and nanomedicine experts from 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.
Future plans include validating BEAT in larger animal models and across different cancer types. The researchers also intend to conduct formal toxicology and pharmacokinetic studies to prepare for early-phase clinical trials. Cheng noted that the preclinical safety profile in mice, which showed no detectable liver, kidney, or autoimmune toxicity, suggests potential. Translational efforts with biotech partners could facilitate human testing within several years, contingent upon consistent safety findings.