Science & Opportunity
Immuno-Oncology Today: An Unmet Need
Despite the dramatic success of first-generation immuno-oncology agents, most patients still do not respond to these treatments. It is now recognized that cancers use multiple pathways to evade the immune system in the tumor microenvironment, suppressing a full range of innate immune cells such as dendritic cells, macrophages, and NK cells, as well as adaptive immune cells, mainly T cells. A novel approach is needed to overcome this broad suppression of the human immune system.
Adopted from Chen Daniel S. et al. Immunity
"A novel approach is needed to overcome cancer's broad suppression of the human immune system."
Unique glycan patterns on tumor cell surfaces have been observed for decades, and the correlation between certain patterns and poor clinical outcomes was widely known, but the precise function of the glycans was not clearly understood. Glycans are notoriously complex, and tools to study them were limited, making progress in this area of scientific research very challenging.
Recent advances in glyco-chemistry tools have led to the discovery of the mechanism by which tumor-specific glycans suppress the immune system. The Siglecs (sialic acid–binding immunoglobulin-like lectins) are a large family of glyco-immune checkpoint receptors found on innate immune cells and tumor-infiltrating T cells, which inhibit immune activation after sensing sialic acid-containing glycan patterns. Tumors evolve to express hypersialylated glycan patterns on their surfaces, which engage Siglecs on innate and adaptive immune cells, resulting in a broad, comprehensive suppression of the anti-tumor immune response.
Targeting glyco-immune checkpoints such as the Siglecs offers two distinct advantages over first generation immuno-oncology efforts. First, since glycan-mediated immunosuppression impacts both innate and adaptive immune cells concurrently, drugs that target this axis have the potential to overcome resistance to first generation agents that only target a single cell type. Second, the identification of distinct tumor surface glycan patterns creates the potential to match an individual patient to the right drug.
"Glyco-Immune Checkpoints are hard-wired, glycan-sensing pathways that tumors exploit to inhibit a broad swath of immune cells."
Palleon Pharmaceuticals is the leading biotechnology company developing drugs to treat cancer by targeting glyco-immune checkpoints, which are glycan-sensing inhibitory receptors found on innate and adaptive immune cells. Tumors upregulate certain glycan patterns – such as those that contain terminal sialic acids – or sialoglycans – to facilitate innate and adaptive immune cell evasion by engaging inhibitory Siglec receptors.
Palleon has demonstrated that inhibiting the Siglec-Sialoglycan axis can result in single agent efficacy in pre-clinical tumor models, and that patients may potentially be identified and stratified by their specific tumor glycan pattern signature, or tumor glyco-code. Palleon has three distinct platform technologies, which enable drug development in this field, and the first program is planned to enter clinical trials in 2020.
"Glyco-Immune Checkpoint Inhibitors offer the potential to overcome resistance to existing therapies and select patients who are likely to respond."