A team of researchers at Columbia Engineering has developed a groundbreaking inhalable nanotherapy that aims to enhance the immune response against checkpoint-resistant melanoma. This innovative treatment addresses a significant challenge in cancer therapy, where approximately 40% of patients do not respond to existing immune checkpoint inhibitors.
Immune checkpoint molecules regulate the immune system and prevent it from attacking the body’s own cells. Cancer cells exploit these checkpoints to evade detection. Current therapies focus on immune checkpoint inhibitors to activate the immune system, but many patients with melanoma remain resistant to these treatments. The newly developed therapy, named BEAT (Bispecific Exosome Activator of T Cells), utilizes engineered exosomes to deliver therapeutic proteins directly to the lungs, a common site for melanoma metastasis outside the skin.
Innovative Delivery Method Targets Multiple Pathways
Unlike traditional antibody drugs that target a single immune checkpoint, BEAT employs a novel method that allows for the simultaneous blockade of two immunosuppressive pathways. This dual-action approach addresses the tumor microenvironment, which often contributes to resistance against checkpoint inhibitor therapies. By administering the proteins locally to lung tissue, the therapy minimizes potential damage to healthy cells.
The research team, led by Ke Cheng, the Alan L. Kaganov Professor of Biomedical Engineering at Columbia Engineering, published their findings in the journal Nature Biotechnology. The study demonstrated that the inhaled BEAT therapy significantly reduced tumor growth compared to systemic delivery methods that use antibodies targeting the same pathways. One protein in BEAT inhibits the PD-1/PD-L1 immune checkpoint pathway, known for enhancing immune responses against melanoma. The second protein disrupts the Wnt/β-catenin signaling pathway, a mechanism that prevents immune cells from penetrating tumor tissues.
Positive Results in Preclinical Models
The results from preclinical trials using mouse models of metastatic melanoma resistant to checkpoint inhibitors revealed that inhaled BEAT effectively reversed immune resistance. Cheng noted, “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.” The therapy showed promising efficacy with minimal side effects, which is a significant concern in cancer treatments.
The project involved collaboration among researchers from various disciplines, including bioengineering, immunology, and nanomedicine, across institutions such as the University of North Carolina at Chapel Hill and North Carolina State University. Moving forward, the team plans to validate the BEAT therapy in larger animal models and explore its applicability across different cancer types.
In addition, they will conduct formal toxicology and pharmacokinetic studies to ready the treatment for early-phase clinical trials. Cheng expressed optimism about the safety profile observed in mice, stating there were “no detectable liver, kidney, or autoimmune toxicity.” If these positive safety findings persist, the researchers aim to initiate first-in-human testing within the next few years through partnerships with biotechnology firms.
The development of BEAT represents a significant advancement in cancer therapy, offering new hope for patients facing melanoma that resists conventional treatments. As the scientific community continues to explore innovative solutions, the potential for transformative therapies remains strong.
