Bispecific antibodies and chimeric antigen receptor (CAR) T cells demonstrate potent cancer immunotherapy in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies needed to maximize cancer killing also detect low antigen expression in normal tissue, which causes toxicity in healthy tissue. Identifying cancer-restricted cell-surface protein antigens remains an ongoing challenge.
In a new study published in Cell titled, “Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens,” researchers from the University of California (UC), Irvine, have reported that targeting cancer-associated glycans with binding proteins can trigger tumor cell death without toxicity to surrounding tissue. The biologically engineered immunotherapies, known as glycan-dependent T cell recruiter (GlyTR) compounds, were shown to be safe and effective in models for a spectrum of cancers, including breast, colon, lung, ovaries, pancreas and prostate.
“It’s the holy grail—one treatment to kill virtually all cancers,” said Michael Demetriou, MD, PhD, a professor of neurology, microbiology and molecular genetics at the UC Irvine School of Medicine and corresponding author of the study. “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.”
Both bispecific antibodies and CAR T cells trigger T cell-mediated killing of cancer cells by targeting a cell-surface cancer antigen using modified antibodies. However, applying this strategy to the majority of cancer types, particularly solid cancers, is limited by a lack of safe targetable protein antigens. High-affinity antibodies required for potent cancer killing also detect low target expression in normal tissue to generate potential on-target, off-cancer toxicity. The identification of antigens that are restricted to cancer is needed for broader application.
GlyTR bispecific proteins fuse a carbohydrate-recognition domain (CRD) from a lectin to a single-chain variable fragment (scFv) from an antibody targeting CD3, a protein complex on T cells essential for their activation by the T cell receptor (TCR). Lectins use high binding avidity, or velcro-like binding, to achieve specificity for glycan targets. High-avidity binding of lectins results from the high density of glycan targets on the cell surface and multiple CRDs in the lectin. The authors tested the hypothesis that multivalent GlyTR immunotherapy should allow safe pan-cancer activity by targeting high-TACA density cancer cells while evading the risk of on-target, off-cancer toxicity by ignoring lower-expressing normal tissue.
Tumor-associated carbohydrate antigens (TACAs) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. While these complex sugar chains are the most widespread cancer antigens, research on the role of glycans in immunotherapy were limited because these glycans are inert to the immune system.
The study showed that GlyTR1 and GlyTR2 bind immunosuppressive multiple TACAs to overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Results supported the notion that density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapies.
Future directions will test the therapy’s safety and effectiveness in humans. According to Demetriou, clinical grade GlyTR1 protein manufacturing is already being developed at the NCI Experimental Therapeutics program labs in Maryland, which would enable the launch of a Phase I clinical trial within two years.
