New Immunotherapy Approach Hits the Sweet Spot with Solid Tumors

By Deborah Borfitz 

October 15, 2025 | Glycans, the complex sugar chains found at abnormally high levels on the surface of cancer cells, have historically been difficult to target effectively with traditional antibody therapies. One of the biggest reasons is that T cells can’t present glycans to B cells so they can make antibodies that bind strongly and stably to the target antigen, says Michael Demetriou, M.D., Ph.D., professor of neurology, microbiology and molecular genetics at the UC Irvine School of Medicine and a UCI Health neurologist. 

In a strategic reversal, he and his colleagues have succeeded in targeting tumor-associated glycans via a “Velcro-like” high-avidity binding mechanism that portends a new class of pan-cancer immunotherapeutics that utilize sugar-binding proteins (lectins) in lieu of antibodies to target glycan antigens, as reported recently in Cell (DOI: 10.1016/j.cell.2025.09.001). These have been termed glycan-dependent T cell recruiter (GlyTR, pronounced “glitter”). In models of a spectrum of cancers—including those of the breast, colon, lung, ovaries, pancreas, and prostate, as well as leukemia—GlyTR therapeutics proved effective and left normal tissue unharmed. 

The glycans being targeted are also highly immunosuppressive and thus GlyTR therapeutics can overcome many of the strategies solid tumors use to evade immune detection, disable effector immune cells, and resist therapies, says Demetriou. Liquid cancers, in contrast, typically lack a complex, immunosuppressive tumor microenvironment that enable them to be effectively treated with antigen-targeted immunotherapies like premade bi-specific antibody molecules (bispecifics) as well as chimeric antigen receptor T (CAR T) cells that use the body’s white blood cells to attack cancer. 

In their latest proof of principle study, researchers employed biologically engineered immunotherapies known as GlyTR1 and GlyTR2, targeting two of the most common, co-occurring changes in cancer. It serves as a demonstration of the feasibility of a platform that is applicable to multiple other glycans. 

Demetriou is co-founder of GlyTR Therapeutics, launched in 2016 to develop antibody-independent, antigen-targeted immunotherapeutics. A companion diagnostic is being developed in parallel that uses immunofluorescence to measure tumor-associated glycan levels. At roughly six times the density of a normal T cell, big safety and efficacy margins have been seen with the lectin targeting approach, he says. 

A decade ago, no one knew it was possible to target glycans by fusing a sugar-binding protein to an antibody. “In this case, we made a bispecific where on one end there is an antibody that will bind to the T cell and on the other end there is one of these lectins,” explains Demetriou. “Amazingly enough, the first iteration we made worked and so that got us quite excited and we’ve been iteratively making that better over time.” 

Closest to the clinical trial stage is GlyTR1, which targets β1,6-branched N-glycans that are commonly abnormally over-expressed on the surface of cancer cells, says Demetriou. The β1,6-branching is driven by an enzyme that is critical to cancer progression, especially metastasis. 

High-Avidity Binding 

One of the reasons neither CAR T cells nor bispecifics have been effective in solid cancers is that there has never been good targets that are also not expressed in normal tissue, Demetriou says. As these therapies require an antibody that has high affinity for the target to be effective in killing cancer, they come with the risk of off-cancer toxicity to normal tissue. “This has led the field to look for that one needle in the haystack [antigen] ... that is unique to cancer.” 

Such candidates have proven near impossible to find, “whereas glycans were sitting there, well known to be changed in cancer but not previously targetable,” he continues. Using lectins, he and his team are not only going after a sugar chain rather than a protein antigen but also using a different binding mechanism. 

The analogy to Velcro, which features fuzz on one side and an array of little hooks on the other, is an apt one since a deficiency in either of the two parts of the fastener will greatly weaken the interaction. “You need two to tango,” as Demetriou says. 

Since the cell surface has a very high density of glycans that is 1,000 to 10,000 times greater than protein antigens, the researchers developed GlyTR therapeutics with multiple sugar-binding domains to achieve immunotherapeutics with high-avidity binding. In terms of activity, this created the equivalent of a high-affinity antibody but without impacting normal, low-density tissue, he says. 

“The higher the density, the better” when it comes to the glycans, Demetriou says, pointing to the possibility of combination therapy in the future to synergistically make such immunotherapies better yet. It’s a direction GlyTR Therapeutics plans to take in the development of bispecifics as well as CAR T cells. 

The Moonshot 

Demetriou’s glycan research won early support with a 2017 award from UCI Health Chao Family Comprehensive Cancer Center’s (CFCCC) first UC Irvine Anti-Cancer Challenge Pilot grant. This enabled preliminary testing leading to a Cancer Moonshot Initiative grant from the National Cancer Institute (NCI) in 2018 funding the latest published study. 

This was followed in 2023 and 2025 with two $2.4 million “Fast Track” Small Business Technology Transfer grants from the NCI to further develop the GlyTR technology with Raymond W. Zhou, Demetriou’s onetime postdoctoral fellow and cofounder of GlyTR Therapeutics. These awards are looking to extend the half-life of GlyTR1 and assess the combined activity with therapies already approved by the Food and Drug Administration to reverse immune cell exhaustion (i.e., checkpoint blockade). 

As an awardee of the NCI Experimental Therapeutics Program, clinical-grade GlyTR1 protein manufacturing is already being developed for use in a planned phase 1 clinical trial at the CFCCC of UC Irvine, which could begin in about two years. GlyTR Therapeutics has licensed the GlyTR technology from the university for commercialization purposes. 

Earlier this year, the California Institute for Regenerative Medicine also awarded Demetriou $4.6 million to support clinical-grade production of GlyTR CAR T cells by contract drug manufacturing organizations for a second first-in-human clinical trial his lab will be doing in conjunction with the UC Irvine CFCCC and the Sue and Bill Gross Stem Cell Research Center. This study is expected to start in 2027 and will feature “a version of GlyTR2 that’s more potent than what we have in the paper,” he notes. 

Basket Trials 

Both phase 1 trials are designed as basket trials enrolling patients with different types of solid cancers that are refractory or metastatic, which is both the patient population with the highest density of the target and those in the greatest need, says Demetriou. They will have a traditional “3+3 design” for determining the maximum tolerated dose of the immunotherapies whereby the first group of three patients is given a low starting dose and, if no toxicity is seen, the next three-patient cohort is treated at a higher dose level. 

But if toxicity is seen in 1 out of 3 participants, the same dose level is expanded to include three more patients, for a total of six patients at that dose, he says. The process continues until the maximum tolerated dose is established and thereafter gets extended to other patients to look for early efficacy signals as a secondary goal. 

The primary focus of the phase 1 trials is of course patient safety, says Demetriou, and “there’s always the possibility that glycan expression happens somewhere we don’t know about that could cause some toxicity.” Overactivity of the immune system—e.g., cytokine release syndrome, as happens with current CAR T cell therapies and bispecifics—is another potential toxicity that is related to tumor burden. 

Primary tumors generally have standard local treatments like surgery or radiation available, which can be curable, says Demetriou. But the density of the glycan target within a primary tumor may vary from patient to patient, meaning that GlyTR technology could ultimately prove to be of some value earlier in the disease process. 

The immunotherapeutics will be co-developed with the companion diagnostic test, as recommended by regulatory authorities. Biomarker detection is “fairly straightforward,” involving staining tumor tissue with GlyTR proteins to determine the abundance of glycans relative to normal tissue.