University of California, Irvine cancer researchers have developed a groundbreaking pan-cancer immunotherapy that uses unique Velcro-like binding properties to destroy tumors without harming healthy tissue. The biologically engineered compounds, called glycan-dependent T cell recruiter (GlyTR) compounds, demonstrated safety and effectiveness across a spectrum of cancers in preclinical models.
Revolutionary Glycan-Targeting Approach
The research team, led by Michael Demetriou, MD, PhD, professor of neurology, microbiology and molecular genetics at UC Irvine School of Medicine, reported their findings in the journal Cell. Their approach targets cancer-associated complex carbohydrate chains called glycans using sugar-binding proteins to penetrate tumor cell protective shields and trigger cell death.
"It's the holy grail – one treatment to kill virtually all cancers," said Demetriou, the study's corresponding author. "GlyTR's velcro-like sugar-binding technology addresses the two major issues limiting current cancer immunotherapies: distinguishing cancer from normal tissue and cancer's ability to suppress the immune system."
The GlyTR compounds, designated GlyTR1 and GlyTR2, proved effective in models for breast, colon, lung, ovarian, pancreatic, and prostate cancers, as well as leukemia. The research represents the culmination of a decade of work that began in 2015 when Demetriou collaborated with then-postdoctoral fellow Raymond W. Zhou, the study's first author.
Overcoming Current Therapy Limitations
While many cancer researchers have focused on protein biomarkers for specific cancers, Demetriou and Zhou targeted the unique coating of glycans that surround cancer cells but exist in very low density in normal cells. These complex sugar chains represent the most widespread cancer antigens known but were previously ignored by researchers because they are inert to the immune system.
The GlyTR compounds attach themselves to glycan-dense cancer cells while ignoring low-glycan-density normal cells. Once attached, the compounds identify cancer cells as targets for destruction by the body's immune system. This contrasts with current cancer immunotherapies that attack cells based on specific proteins regardless of glycan density, failing to distinguish tumor cells from healthy tissue.
Current treatments like chimeric antigen receptor (CAR) T cell therapy have largely worked only for blood cancers such as leukemia. The GlyTR technology overcomes the shield that glycans form around solid tumors by targeting the glycans themselves and blanketing tumor cells with the Velcro-like compounds.
Clinical Translation and Funding Support
Clinical-grade GlyTR1 protein manufacturing is already being developed at the NCI Experimental Therapeutics program labs in Maryland, enabling the launch of a phase 1 clinical trial within approximately two years. The trial will test the therapy in patients with a range of metastatic solid cancers, as the highest glycan density is typically seen in patients with refractory/metastatic disease.
"This is the revolutionary approach to cancer treatment our patients have been waiting for," said Farshid Dayyani, MD, PhD, medical director of the cancer center's Stern Center for Clinical Trials and Research. "We are committing all available resources to bring this exciting new trial to UCI Health as fast as possible."
The research has received substantial funding support, including a Cancer Moonshot Initiative grant from the National Cancer Institute in 2018. Demetriou and Zhou received a $2.4 million NCI Small Business Technology Transfer Grant to further develop the GlyTR technology. Earlier this year, the California Institute for Regenerative Medicine awarded Demetriou $4.6 million to support clinical-grade production of GlyTR2 for a second clinical trial.
Industry Impact and Future Directions
"This landmark study is a paradigm shift with the very real potential to change how we treat cancer patients," said Marian Waterman, PhD, former deputy director of research at the cancer center and champion of the project since its inception.
Richard A. Van Etten, MD, PhD, director of the cancer center, emphasized the technology's potential significance: "This novel technology may, for the first time, allow the widespread application of targeted T-cell therapy to solid tumors, which is the 'holy grail' in the immuno-oncology field."
The research team continues to explore GlyTR applications on multiple fronts, with Zhou serving as president of GlyTR Therapeutics Inc., a company founded with Demetriou to advance preclinical development of the immunotherapeutic compounds. Additional funding has come from various sources including the University of California Drug Discovery consortium, the UC Irvine Institute for Clinical and Translational Science, and the Chao Family Comprehensive Cancer Center's Experimental Tissue Shared Resource.
