Velcro-like immunotherapy destroys most cancers without attacking healthy tissue, landmark study shows

Next step: Testing groundbreaking therapy’s safety and effectiveness in patients

Irvine, Calif. —  A new, highly potent class of immunotherapeutics with unique Velcro-like binding properties can kill diverse cancer types without harming normal tissue, University of California, Irvine cancer researchers have demonstrated.

A team led by Michael Demetriou, MD, PhD, reported that by targeting cancer-associated complex carbohydrate chains called glycans with sugar-binding proteins, they could penetrate the protective shields of tumor cells and trigger their death without toxicity to surrounding tissue.

Their biologically engineered immunotherapies — glycan-dependent T cell recruiter (GlyTR, pronounced ‘glitter’) compounds GlyTR1 and GlyTR 2 — proved safe and effective in models for a spectrum of cancers, including those of the breast, colon, lung, ovaries, pancreas and prostate, the researchers reported today in the journal Cell.

“It’s the holy grail — one treatment to kill virtually all cancers,” said Demetriou, a professor of neurology, microbiology and molecular genetics at the UC Irvine School of Medicine. and the paper’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 researchers were awarded a Cancer Moonshot Initiative grant from the National Cancer Institute in 2018 for this study.

Breakthrough research

The study’s publication, the culmination of a decade of research, is a watershed moment for UC Irvine and the UCI Health Chao Family Comprehensive Cancer Center.

“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 Demetriou, a UCI Health neurologist, began working on the concept in 2015 with his then-postdoctoral fellow, Raymond W. Zhou, the study’s first author.

Added Richard A. Van Etten, MD, PhD, director of the cancer center and also an early supporter of the GlyTR project, “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.”

Current treatments, such as chimeric antigen receptor (CAR) T cell therapy, use the body’s own white blood cells to attack cancer. They have largely worked only with blood cancers, such as leukemia. The GlyTR technology also proved effective in targeting leukemia, the study shows.    

Unorthodox approach

While many cancer researchers have sought protein biomarkers for specific cancers, Demetriou and Zhou aimed at a more abundant target, the unique coating of glycans that surround cancer cells but are found in very low density in normal cells.

These complex sugar chains are the most widespread cancer antigens known, but were generally ignored by researchers because they are inert to the immune system. 

To solve this problem, Demetriou and Zhou engineered the GlyTR compounds to attach themselves to the sticky surface of glycan-dense cancer cells while ignoring low-glycan-density normal cells. Once attached, the GlyTR compounds identify the cancer cells as targets for killing by the body’s immune system.   

In contrast, current cancer immunotherapies attack cells based on specific proteins regardless of their glycan density and thereby fail to distinguish tumor cells from healthy tissue. A second impediment to developing broadly active cancer immunotherapies is the shield glycans form around solid tumor cells.

By target glycans and blanketing the sticky surface of the tumor cells with the Velcro-like compounds, the GlyTR technology overcomes both obstacles.  

Human trials

The next step will be testing the therapy’s safety and effectiveness in humans. Clinical grade GlyTR1 protein manufacturing is already being developed at the NCI Experimental Therapeutics program labs in Maryland, Demetriou said.

That will enable the launch of a phase 1 clinical trial, which could begin within about two years. It will test the therapy in patients with a range of metastatic solid cancers. The highest glycan density is typically seen in patients with metastatic disease, a population with the greatest unmet need for effective treatments.

“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.”

Future research

Meanwhile, Demetriou’s team continues to explore GlyTR on other fronts. He 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. 

Demetriou’s lab also has received funding from several NCI grants and a previous Discovery award from CIRM. His glycan research won early support with a 2017 pilot project award from cancer center’s first UC Irvine Anti-Cancer Challenge, an annual fundraising event that has since raised more than $6 million for potentially groundbreaking studies like Demetriou’s.

Additional support has come from the University of California, Irvine/Office of the President, the University of California Drug Discovery consortium, the NCI Experimental Therapeutics Program, the UC Irvine Institute for Clinical and Translational Science, and the Chao Family Comprehensive Cancer Center’s Experimental Tissue Shared Resource.

Michael Demetriou, MD, PhD, is a UC Irvine School of Medicine professor in the departments of Microbiology & Molecular Genetics and Neurology, where he serves as chief of the division of Multiple Sclerosis and Neuroimmunology. He is also a UCI Health neurologist who specializes in the treatment multiple sclerosis. His research has long been focused on the role of complex sugar molecules called glycans in cell function and disease. The Demetriou lab’s work on glycans, which play a significant role in the pathogenesis of multiple sclerosis, provided a springboard for the cancer immunotherapy research.

Raymond W. Zhou, PhD, is a project scientist in the UC Irvine School of Medicine’s Department of Neurology. As a postdoctoral fellow in the Demetriou lab, Zhou applied his expertise in glycobiology and immunology to cancer immunotherapy. He is co-architect of the GlyTR technology used to create the pan-cancer immunotherapeutics described in the research study published in Cell. He is also president of GlyTR Therapeutics Inc., which he founded with Demetriou to advance preclinical development of the immunotherapeutic compounds.

About the University of California, Irvine: Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UC Irvine, visit www.uci.edu.