Yale Researchers Develop Novel Antibody-RNA Therapy for Resistant Cancers

A specially engineered antibody that can accurately deliver RNA treatments into hard-to-reach and hard-to-treat tumors significantly improved survival and reduced tumor sizes in animal models, it was reported July 16 in Science Translational Medicine.

The study provides evidence that, once injected into the bloodstream, the antibody TMAB3, combined with a type of RNA that stimulates an innate immune reaction, can localize to tumors and penetrate and destroy stubborn diseased cells in pancreatic, brain, and skin cancers.

"Delivery of RNA-based therapies to tumors has been a challenge. Our finding that TMAB3 can form antibody/RNA complexes capable of delivering RNA payloads to tumors provides a new approach to overcome this challenge,” says senior author Peter Glazer, MD, PhD, a member of the Yale Cancer Center, and Robert E. Hunter Professor of Therapeutic Radiology and Genetics at Yale School of Medicine (YSM).

In addition to Glazer and Yale first authors Elias Quijano, PhD; Diana Martinez-Saucedo, PhD; Zaira Ianniello, PhD; and Natasha Pinto-Medici, PhD, there are 25 other contributors, most from Yale’s Department of Therapeutic Radiology and from the departments of genetics, molecular biophysics and biochemistry, biomedical engineering, pathology, and medical oncology and three from the University of Illinois Urbana-Champaign.

Specifically, animal models of three types of “cold” tumors that are usually resistant to standard treatments and the best immunotherapies—pancreatic cancer, medulloblastoma (a type of brain cancer), and melanoma (skin cancer)—had significant responses to the precision treatment, that homed in on cancerous cells, largely avoiding healthy tissue.

Results:

• In the animal model for pancreatic ductal adenocarcinoma the treatment significantly reduced the size of the tumors and extended survival by boosting the presence of CD8+ T cells that attack cancer cells.

• The medulloblastoma animal models responded similarly. The treatment made it past the blood-brain barrier to reach and shrink the tumors and extended survival, without triggering an immune reaction that can be caused by collateral treatment of healthy tissue.

• Pronounced suppressed tumor growth and an absence of severe side effects or toxicities were noted in the animal models with melanoma.

Researchers used computer modeling to modify the antibody, enabling it to bind to RNA, and also "humanized” it so the body wouldn't attack it as an invader, a step toward possible clinical use.

“This work lays the foundation for translating RNA-based therapies into the clinic. By achieving targeted delivery to tumor cells without systemic toxicity, we open the possibility of developing treatments that are not only tumor-specific but also adaptable to the immunologic context of each patient’s cancer,” says YCC member Luisa Escobar-Hoyos, MSc, PhD, senior author and a YSM associate professor of therapeutic radiology and molecular biophysics and biochemistry. “With further development, this platform could support personalized immuno-RNA therapies and move toward first-in-human clinical trials.”

The research reported in this news article was supported by the National Institutes of Health (awards R35CA197574, K99-R00 CA226342 (LFE-H), R01CA274355, DP2CA280625, R01CA149128, T32GM007205); the Damon Runyon Cancer Research Foundation; the American Association for Cancer Research; Pew Cancer Research Scholars; Cancer Research Institute-Clinic & Laboratory Integration Program (CLIP); Yale Cancer Center; Blavatnik Fund for Innovation at Yale; Gennao Bio Sponsored Research Grant to Yale; and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.