Pere Dosta Pons, PhD

Pronouns

He/Him/His

Job Title

Instructor in Medicine

Academic Rank

Instructor

Department

Medicine

Authors

Pere Dosta, Alexander M. Cryer, Michelle Z. Dion, Tsubasa Shiraishi, Steven P. Langston, David Lok, Jianing Wang, Sean Harrison, Shiran Ferber, Santhosh Kalash, Michaela Prado, Alma L. Rodríguez, Adnan O. Abu-Yousif, Natalie Artzi

Principal Investigator

Natalie Artzi

Research Category: Cancer

Tags

Conjugated STING-agonist nanoparticles enhance antitumor immunity in multiple tumor models

Scientific Abstract

Despite prolific advances in cancer immunotherapy, such as immune checkpoint blockade (ICB), many patients do not achieve complete tumor remission. Insufficient antitumor responses have spurred efforts to invoke complementary elements of the immune system, including the stimulator of interferon genes (STING) pathway. STING agonist is a promising activator of antitumor immunity. However, the systemic delivery of STING agonist, based on cyclic dinucleotides (CDNs), yields limited anticancer activity owing to poor serum stability and cellular internalization. To address these challenges, we report the development of a biodegradable, highly potent STING agonist in conjugate nanoparticle formulation for systemic delivery of sub-microgram doses of STING agonists. Here, we show, in multiple models of murine cancer, that the intravenous administration of chemically-modified CDNs covalently bound to poly(β-amino ester) nanoparticles (CDN-NP) results in potent innate and adaptive antitumor immune responses. The combination of CDN-NPs and ICB led to largely curative outcomes, even after tumor re-challenge, in mouse models of melanoma and colon cancer. The NPs activated STING signaling in immune cells in tumor and lymphoid tissues. We demonstrate, in a mouse melanoma model, that cancer-cell STING signaling is not necessary for therapeutic responses, but act as a nanoparticle reservoir, releasing CDN to proximal immune cells.

Lay Abstract

Cancer immunotherapy is changing the way how various types of cancer are treated. Despite prolific advances in immune-oncology, such as immune checkpoint blockade (ICB), many patients do not achieve complete tumor remission. Therefore, understanding how immune cells recognize and kill cancer cells, and enhance their ability to fight against cancer is critical. The stimulator of interferon genes (STING) pathway is a promising activator of antitumor immunity. However, the systemic delivery of STING agonist, based on cyclic dinucleotides (CDNs), yields limited anticancer activity owing to poor serum stability and cellular internalization. To address these challenges, we developed a biocompatible nanoparticle formulation for the systemic delivery of STING agonists. We showed, in multiple models of murine cancer, that the intravenous administration of STING agonist nanoparticles (CDN-NP) results in potent innate and adaptive antitumor immune responses. The combination of CDN-NPs and ICB led to largely curative outcomes, even after tumor re-challenge, in mouse models of melanoma and colon cancer. The combination of more efficient delivery systems and the use of immunomodulatory drugs will open a new avenue for the treatment of a wide range of cancers.

Clinical Implications

The use of more efficient delivery systems will enhance the therapeutic efficacy of currently used drugs while decreasing their side effects.