Pioneering the next frontier in cancer immunotherapy
Despite the increasing use of immuno-oncology drugs and targeted therapies, complete and durable responses are observed in only a subset of patients; and most patients’ cancers advance even while receiving therapy. With the aim of improving current standard of care, we are developing our therapeutic candidates as monotherapies and in combination with approved drugs with the goal of curing cancer.
The more fundamental a role in immune suppression a metabolite plays, the more likely it is to be an effective therapeutic target across multiple tumor types, ultimately benefiting more patients. Therefore, our research focuses on immuno-metabolic pathways which have the potential to impact both the adaptive and innate immune system relevant in a broad range of tumor types.
Activation of metabolic pathways can lead to a number of local changes that promote tumor survival. These immune suppressive pathways have broad effects including decreased T cell expansion and tumor infiltration and increased immune suppressor cells such as myeloid-derived suppressor cells (MDSCs) and T regulatory cells.
What is an immunosuppressive metabolite?
Immunosuppressive metabolites are molecules that are formed by a breakdown of a ‘precursor’ that function to suppress an immune response. These metabolites inhibit the activity of effector immune cells such as cytotoxic T-cells or by increasing the activity of regulatory immune cells such as myeloid-derived suppressor cells. Multiple metabolic pathways are upregulated in cancer leading to increased concentrations of immunosuppressive metabolites enabling cancer cells to evade recognition of effector immune cells.
Common characteristics of an immunosuppressive tumor microenvironment
- Secretion of immunosuppressive molecules
- Generation of immunosuppressive metabolites
- Infiltration of regulatory immune cells
- Incidence of anergic effector T cells
- Expression of immune-activating molecules
- Penetration of proinflammatory helper and effector immune cells
- Tumor antigen presentation
Tackling the protective tumor micro-environment
Tumors cause a number of structural and chemical changes in the surrounding area, referred to as the “tumor micro-environment” or TME. These changes in the surrounding cells and tissues promote tumor survival. At Kyn Therapeutics, we are focused on reversing these changes to enhance immunity, and allow responding immune cells to reach the tumor.
Key publications in immunometabolism
Muller, A. J., Manfredi, M. G., Zakharia, Y. and Prendergast, G. C. (2018). Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Seminars in Immunopathology, 40(159), pp.1-8.
Triplett, T. et al. (2018). Reversal of indoleamine 2,3-dioxygenase–mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nature Biotechnology, 36, pp.758-764.
Liu, Y. et al. (2018). Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell, 33(3), pp.480-494.
Prendergast, G., Malachowski, W., DuHadaway, J., and Muller, A. (2017). Discovery of IDO1 Inhibitors: From Bench to Bedside. Cancer Research Reviews, 77(24), pp.6795–6811.
Cheong, J. and Sun, L. (2017). Targeting the IDO1/TDO2–KYN–AhR Pathway for Cancer Immunotherapy – Challenges and Opportunities. Trends in Pharmacological Sciences, 39(3), pp.307-325.
Wang, D., and DuBois, R. N. (2016). The role of Prostaglandin E2 in Tumor Associated Immunosuppression. Trends in Molecular Medicine, 22, pp.1-3.
Munn, D. and Mellor, A. (2016). IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends in Immunology, 37(3), pp.193-207.
Platten, M., von Knebel Doeberitz, N., Oezen, I., Wick, W. and Ochs, K. (2015). Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors. Frontiers in Immunology, 5(673), pp.1-7.
O’Callaghan, G. and Houston, A. (2015). Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? British Journal of Pharmacology, 172(22), pp.5239-5250.
Biswas, S. (2015). Metabolic Reprogramming of Immune Cells in Cancer Progression. Immunity, 43(3), pp.435-449.
Adams, J. L., Smothers, J., Srinivasan, R., & Hoos, A. (2015). Big opportunities for small molecules in immuno-oncology. Nature Reviews Drug Discovery, 14(9), pp.603-622.
Murray, I., Patterson, A. and Perdew, G. (2014). Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nature Reviews Cancer, 14(12), pp.801-814.
Kalinski, P. (2012). Regulation of Immune Responses by Prostaglandin E2. The Journal of Immunology, 188(1), pp.21-28.
Opitz, C. A. et al. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature, 478(7368), pp.197-203.