First-in-Class Suppressor of VISTA
(Oral, Small Molecule VISTA/PD-L1 Antagonist)
Immune cells and certain human cancers express a ligand on their cell surface referred to as Programmed Cell Death Ligand-1 (PD-L1) which binds to its cognate receptor, Programmed Cell Death Protein-1 (PD-1) present on the surface of the immune system’s T cells. Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability to mount an effective immune response against the tumor. It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD-1 antibodies or anti-PD-L1 antibodies can lead to T cell activation that result in the observed anti-tumor effects in the tumor tissues. Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.
In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells1. One such regulator is V-domain Ig suppressor of T-cell activation (VISTA) that shares structural similarity with PD-L1 and is also a potent suppressor of T cell functions. The expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as on the surface of myeloid hematopoietic cells within the tumor microenvironment. Recent animal studies have demonstrated that combined targeting/blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors2.
As part of the collaboration with Aurigene, in October 2015, Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. Preclinical ex vivo data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production -a cytokine that is produced by activated T cells and is a marker of T cell activation- by T cells that are specifically suppressed by PD-L1 or VISTA. In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models. In preclinical toxicology studies, CA-170 appeared safe when administered at multiple dose levels using a once daily oral dosing schedule.
For more information on current trials click here.
Posters and Presentations
1Le Mercier I, et al., Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. (2015) 6:418. https://doi.org/10.3389/fimmu.2015.00418
2Liu J, et al., Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6682-7. https://doi.org/10.1073/pnas.1420370112