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.
Science & Opportunity
Most patients do not respond to first-generation immuno-oncology drugs.
The Scientific Opportunity
The convergence of two fields has catalyzed a new strategy for fighting cancer.
The alteration of glycans — the sugar molecules expressed on every cell surface — has been observed on cancer cells since the 1960’s. By the early 1990’s certain tumor-specific glycan patterns, such as an increase in the density of sialic acids (hypersialylation) were shown to correlate with poor clinical outcomes in patients with many different types of cancer. However, scientists struggled to understand their functional role because glycans are notoriously complex, and few tools were available to make progress in this area of scientific research.
Stanford Professor and Palleon Co-Founder Carolyn Bertozzi recently created new scientific tools for studying the function of tumor cell surface glycans, which yielded an unexpected result. Tumors exploit a previously unappreciated axis of immunosuppression through alteration of their cell surface glycans, which impairs multiple types of innate and adaptive immune cells critical to the anti-tumor response. Immune cells are “tricked” by the proliferation of these tumor-specific glycan patterns, such as hypersialylation, which makes them unable to detect and destroy cancer cells. Tumor cell evolution alters cell surface glycans in such a way as to take advantage of this hard-wired vulnerability in the immune response. This mechanism of immunosuppression appears to be present in the majority of cancer types.
In parallel, Co-Founder Paul Crocker, a world leader in glycan-dependent regulation of immune responses at the University of Dundee in Scotland, was a pioneer in the discovery of the Siglecs, which is a family of cell surface proteins expressed on key immune cells that recognize sialic acid-containing glycan structures. Many of the Siglecs down-regulate immune responses and play a functional role in recognizing “self” versus “non-self”. Remarkably, many Siglecs drive immune cell suppression through the same biochemical signaling pathways that are used by well-known immune checkpoint receptors, such as T cell-associated PD-1 and CTLA-4. Tumors exploit the Siglecs by covering their surfaces with a high density of sialic acids, which allows them to evade both innate and adaptive immunity.
The Siglecs are notable for their expression across a range of innate and adaptive immune cells, as well as the significant differences between species. These evolutionary differences create a barrier to drug development, since the pharmaceutical industry has relied historically upon mouse models for new drug discovery, and mouse Siglecs do not match those of humans. Dr. Crocker is at the forefront of understanding the structure and function of the human Siglecs, building a foundation upon which drug discovery in this area is now feasible.
The convergence of scientific discovery in these two different fields has catalyzed the development of drugs that target Glyco-Immune Checkpoints.
The integration of glycoscience and human immunology paves the way for new class of drugs in oncology: Glyco-Immune Checkpoint Inhibitors
Palleon Pharmaceuticals has integrated technologies and insights from world scientific leaders in the diverse fields of glycoscience and human immunology to create the first Glyco-Immune Checkpoint Inhibitors to treat cancer.
Glyco-Immune Checkpoints are different from other checkpoints in several important ways:
- They are activated by binding to cell-surface glycans rather than to other proteins.
- They are expressed in a wider range of immune cells involved in the anti-cancer response, including innate immune cells such as dendritic cells, macrophages, NK cells, as well as adaptive immune cells such as T cells.
- The evolution of tumor cell surface glycans which exploit Glyco-Immune Checkpoints, appears to be a prominent feature in most types of cancer.
These unique features offer a number of advantages to Glyco-Immune Checkpoint Inhibitors:
- The potential to impact multiple immune cell types involved in a coordinated anti-tumor immune response, offering the possibility to overcome multi-layered immunosuppression to address resistant patient populations.
- The prospect of selecting patients who are most likely to respond to therapy by identifying the unique glycan signatures of tumor cells from tissue biopsies or from secreted glycoproteins detected in the blood.
- The possibility of creating a much wider range of rational combination therapies to treat cancer.