Cancer Immunotherapy Platform Technology
Imprime PGG is a yeast-derived biologic that acts as a PAMP or Pathogen Associated Molecular Pattern. PAMPs bind to pattern recognition receptors on innate immune cells (monocytes, macrophages, dendritic cells, neutrophils) and provide the critical “non-self” danger signals that trigger a coordinated immune response to infectious pathogens, such as bacteria, viruses or fungi. These immune responses involve both arms of the immune system—the innate and adaptive—and the combination may be essential to enhancing cancer immunotherapies. Most cancer immunotherapies are centered on adaptive immunity, activating T cells to recognize specific tumor antigens and kill cancer cells. However, there are limitations to this approach.
The Immune System and Cancer
Cancers arise from normal tissue and thereby lack the “non-self” signals (PAMPs) that spark innate immune activation and a coordinated immune attack. Moreover, cancers often re-educate myeloid cells (macrophages and myeloid derived suppressor cells) to promote an M2 immune suppressive state—a state akin to wound healing. This environment actively suppresses the killing function of the immune system while also promoting continued tumor growth. Cancers can also directly defeat a T cell based attack by expressing a checkpoint protein called PD-L1, which binds to the PD-1 receptor on an attacking T cell, sending a “do not kill” signal that shields the cancer cell from destruction.
Advances in Cancer Immunotherapy: Checkpoint Inhibitors
Checkpoint inhibitor (CPI) therapies (pembrolizumab/KEYTRUDA®, nivolumab/Opdivo®, atezolizumab/Tecentriq®) block the PD-L1: PD-1 interaction and unleash the killing function of T cells. CPIs are remarkably effective and can impart long-term disease control, but only in approximately 15-30% of treated patients. In responsive patients, there is ample evidence of ongoing T cell based anti-cancer immunity—T cell infiltration, an adaptive immune signature and PD-L1 positivity. In non-responsive patients, an active immune response is lacking. T cells are not yet involved and there is no PD-L1: PD-1 interaction for CPI therapy to disrupt. Significant research is now focused on ways to enhance T cell-based anti-cancer immunity.
The Next Wave of Cancer Immunotherapy: An Integrated Immune Response
An alternate, promising approach is to leverage the natural response cycle of the immune system. When faced with a pathogenic threat, the immune system reacts first by activating the innate immune system and driving the maturation of antigen-presenting cells, which then enlist T cells and other cells of the adaptive immune system. This integrated immune attack involving the concerted action of both arms of the immune system is most effective at eradicating the threat of an invading pathogen.
CPIs and other T cell based therapies are dependent upon the establishment of an anti-cancer immunity cycle, which requires: (1) effective antigen presentation; (2) a permissive (i.e. non-suppressive) immune microenvironment; (3) a sufficient antigen debris field. Tumors in patients who do not respond to single agent CPIs lack one or more elements of this anti-cancer immunity cycle. Combination therapies that trigger one or more elements of this cycle may be particularly effective in combination with CPIs.
Imprime PGG acts therapeutically as an immunological ignition switch that turns on the innate immune system, thereby enabling an integrated—innate and adaptive—immune response to cancer. Specifically, Imprime PGG:
- Binds to innate immune cells, including macrophages, neutrophils, and dendritic cells.
- Activates direct tumor-killing functions of innate effector cells.
- Promotes a shift in the tumor microenvironment to favor cancer destruction.
- Enhances dendritic cell maturation and antigen presentation to T cells.
- Facilitates T-cell based anti-cancer immunity.
Imprime PGG: A Unique PAMP
Other PAMPs, including TLR and STING agonists, can be used therapeutically to activate the innate immune system, drive maturation of antigen-presenting cells and elicit an anti-cancer T cell attack. However, TLR and STING agonists are limited clinically as these inspire intolerable, often life-threatening cytokine storms when administered systemically (i.e. intravenously). As such, TLR and STING agonist therapies are limited to clinical settings amenable to direct tumor injection. By contrast, Imprime PGG has been administered intravenously to more than 400 human subjects to date and is well-tolerated.