Next step is testing ‘holy grail’ therapy’s safety and effectiveness in patients
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 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 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.
Landmark research
The study’s publication, the culmination of a decade of research, is a watershed moment and source of pride 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 centre and champion of the project since Demetriou and his then-postdoctoral fellow, Raymond W. Zhou, the study’s first author, began working on the concept in 2015.
Added Richard A. Van Etten, MD, PhD, director of the cancer centre 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 tumours, which is the ‘holy grail’ in the immuno-oncology field.”
Current treatments, such as chimeric antigen receptor (CAR) T therapy, use the body’s white blood cells to attack cancer. They have largely worked only for blood cancers, such as leukaemia. The GlyTR technology also proved effective in targeting leukaemia, 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, Velcro-like, to 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 tumour cells from healthy tissue.
A second impediment to developing broadly active cancer immunotherapies is the shield glycans form around solid tumours.
By targeting glycans and blanketing the tumour 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 refractory/metastatic disease, a population that also has the greatest unmet need for treatment.
