GITR (glucocorticoid-induced tumor necrosis factor receptor) is an immune checkpoint cell surface receptor induced within 24-72h on naïve T cells upon engagement with an antigen presenting cell . When GITR engages with its ligand GITR-L effector T cell proliferation is induced. In the pancreatic cancer microenvironment there is a shortage of GITR-L. Therefore one way to improve immune response is with GITR activating antibodies.
In a well known analogy, checkpoint antibodies take the breaks off the immune system, however in the case of pancreatic cancer because it is non-immunogenic, the clinician must also put their foot down so to speak. Mesothelin is a membrane bound glycoprotein that is universally overexpressed in pancreatic cancer. In a preclinical mouse model of pancreatic cancer full length human mesothelin cDNA was used as a vaccine in combination with activating GITR antibodies . In GITR antibody alone treated tumours all remained. In mesothelin alone treated tumours half were eliminated and in GITR antibody and vaccine treated mice 94% had eliminated tumours. This strikingly demonstrates the power of the combination of pancreatic cancer vaccines with immune checkpoint antibodies.
A mesothelin vaccine in combination with GM-CSF immune system stimulation has successfully completed phase II clinical trial . Merck, Bristol-Myers Squibb, and Pfizer are developing GITR antibodies.
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- Gaffney, Mary C., Peter Goedegebuure, Hiroyuki Kashiwagi, John R. Hornick, Reuben I. Thaker, Timothy Eberlein, and William G. Hawkins. ‘DNA Vaccination Targeting Mesothelin Combined with Anti-GITR Antibody Induces Rejection of Pancreatic Adenocarcinoma’. Cancer Research 66, no. 8 Supplement (15 April 2006): 329–329. http://cancerres.aacrjournals.org/content/66/8_Supplement/329.2.
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