Novel delivery platform enhances effectiveness of cancer immunotherapy and reduces side effects

National University of Singapore, Yong Loo Lin School of MedicineSep 16 2024

Immunotherapy is a type of cancer treatment that uses the body's own immune system to help fight cancer. This is by stimulating the immune response to recognize and attack cancer cells more effectively. The treatment involves using substances that boost the immune system, teaching immune cells to target cancer, or using engineered cells to specifically target and kill cancer cells. While it is a key approach in cancer treatment, the effectiveness of immunotherapy is limited by the risk of immune-related side effects, because the immune system, while targeting cancer cells, may also attack normal, healthy tissues. These side effects include inflammation or damage to various organs and tissues, causing a range of symptoms or complications in health outcomes.

A team led by Assistant Professor Minh Le from the Institute for Digital Medicine (WisDM) and Department of Pharmacology at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) has unveiled a novel delivery platform that significantly enhances the effectiveness of cancer immunotherapy while reducing the associated side effects. This innovative approach, leveraging nano-sized particles released by cells, termed "extracellular vesicles" (EVs), represents a major advancement in the field of cancer immunotherapy.

In the study, the researchers developed a technique which modified EVs to carry multiple immune-boosting molecules called 'immunomodulatory ligands', for the treatment of in vivo models of metastatic pancreatic cancer and melanoma. The approach enhanced the therapeutic effectiveness of the ligands-;particularly the subset tumor Necrosis Factor Receptor Superfamily (TNFRSF) agonists, which are key in controlling immune responses against cancer. The team also found that the delivery method enhanced retention of the immune-boosting ligands in the tumor-;allowing for better therapeutic effects to be achieved with lower drug doses, which in turn reduced the risk of side effects that are often seen in current immunotherapeutic treatments.

Published in Molecular Therapy, the study demonstrates that the new EV-based delivery approach can alter the tumor's immune composition to improve treatment outcomes of patients with cancer. Notably, the approach was consistently proven to show better outcomes in terms of tumor-specific immune activation, suppression of tumor burden, overall survival and resistance to tumor rechallenge (or recurrence), compared to the current clinical standard of care, whereby the ligands are administered in their free soluble form without the EV-based delivery platform. This is remarkable as it indicates that the EV-based delivery approach is able to enhance the treatment of existing tumors and prevent the recurrence of the same cancer in the future via the development of tumor-specific immune memory.

Asst Prof. Minh Le said, "We are thrilled to present this novel EV-based delivery system that not only enhances the therapeutic efficacy of immunomodulatory ligands but also significantly reduces systemic toxicity. Our findings pave the way for safer and more effective cancer immunotherapies, potentially transforming the landscape of cancer treatment."

This new delivery platform holds great potential to improve both the effectiveness and safety of current immunotherapies, which often have limited results and major side effects. It also enables the development of advanced treatments that can more precisely target cancer cells while protecting healthy tissues."

Dr. Migara Jayasinghe, first author of the study, from WisDM and Department of Pharmacology at NUS Medicine

The findings of this study have been patented and the research group is now working on advancing this technology to further enhance the broader application of immunotherapeutic ligand-based therapies. Alongside plans to establish a clinical stage start-up, the technologies developed through this study will be commercialized to facilitate access for other researchers in the field and related disciplines.