Yale researchers have developed a breakthrough antibody-RNA therapy platform that successfully targets treatment-resistant cancers, demonstrating significant tumor reduction and improved survival in preclinical studies. The engineered antibody TMAB3, combined with immune-stimulating RNA, overcomes a major challenge in cancer treatment by delivering therapeutic payloads directly to hard-to-reach tumors while sparing healthy tissue.
The study, published July 16 in Science Translational Medicine, provides evidence that TMAB3 can form antibody/RNA complexes capable of localizing to tumors and penetrating stubborn diseased cells across multiple cancer types. "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," said senior author Peter Glazer, MD, PhD, Robert E. Hunter Professor of Therapeutic Radiology and Genetics at Yale School of Medicine.
Targeting "Cold" Tumors Across Multiple Cancer Types
The research team tested their platform against three types of "cold" tumors that typically resist standard treatments and immunotherapies: pancreatic cancer, medulloblastoma (brain cancer), and melanoma (skin cancer). These tumor types are notoriously difficult to treat due to their immunosuppressive microenvironments and resistance to conventional therapies.
In pancreatic ductal adenocarcinoma animal models, the treatment significantly reduced tumor size and extended survival by boosting the presence of CD8+ T cells that attack cancer cells. The medulloblastoma models showed similar responses, with the treatment successfully crossing the blood-brain barrier to reach and shrink tumors while extending survival without triggering harmful immune reactions in healthy brain tissue.
Animal models with melanoma demonstrated pronounced suppressed tumor growth with an absence of severe side effects or toxicities, highlighting the therapy's safety profile across different cancer types.
Engineering Approach and Humanization
The research team employed computer modeling to modify the antibody, enabling it to bind effectively to RNA while maintaining its targeting capabilities. Crucially, they also "humanized" the antibody to prevent the body from attacking it as a foreign invader, representing a critical step toward potential clinical application.
The collaborative effort involved 29 contributors, primarily from Yale's Department of Therapeutic Radiology and departments of genetics, molecular biophysics and biochemistry, biomedical engineering, pathology, and medical oncology, with additional contributions from the University of Illinois Urbana-Champaign.
Clinical Translation Potential
"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," said Luisa Escobar-Hoyos, PhD, senior author and associate professor of therapeutic radiology and molecular biophysics and biochemistry at Yale School of Medicine.
The platform's ability to deliver RNA payloads with precision while avoiding systemic toxicity represents a significant advancement in cancer therapeutics. The researchers suggest that with further development, this platform could support personalized immuno-RNA therapies tailored to individual patients' cancer profiles.
Path Forward
The successful preclinical results across multiple cancer types position this antibody-RNA platform as a promising candidate for clinical development. Escobar-Hoyos noted that the platform could move toward first-in-human clinical trials with continued development, potentially offering new hope for patients with treatment-resistant cancers.
The research was supported by multiple National Institutes of Health awards, the Damon Runyon Cancer Research Foundation, the American Association for Cancer Research, and other funding organizations, underscoring the significant investment in advancing this novel therapeutic approach.
