CI-8993

First-in-Class Antagonist of VISTA

Monoclonal Antibody VISTA Antagonist

V-domain Ig suppressor of T-cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-1/PD-L1 and suppresses T cell activation. VISTA relieves negative regulation by hematopoietic cells and enhances protective anti-tumor immunity, and VISTA is highly expressed on myeloid cells and T cells. Preclinically, VISTA monoclonal antibody treatment increased the number of tumor-specific T cells in the periphery, and enhanced the infiltration, proliferation and effector function of tumor-reactive T cells within the tumor microenvironment (TME). VISTA blockade alters the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells (DCs) within the TME leading to enhanced T cell mediated immunity. VISTA monoclonal antibody administration as a monotherapy has been shown to suppress the growth of both transplantable and inducible melanoma in preclinical models.

Clinically, VISTA is strongly expressed in several tumor types including pancreatic cancer, mesothelioma, and prostate cancer. VISTA creates an immune blocking signal that is independent of, and complementary to, PD-1 and CTLA-4. VISTA is uniquely expressed on myeloid-derived suppressor cells in addition to T cells, and regulates naïve T cell quiescence and peripheral tolerance. Additionally, treatment of patients with cancer such as NSCLC and prostate cancer with PD-1 or CTLA-4 checkpoint inhibitors induces increased VISTA expression in tumor samples as a compensatory reaction to treatment with PD-1 and CTLA-4 directed therapy.

In January 2020, Curis entered into an option and license agreement to acquire exclusive, worldwide rights from ImmuNext to develop and commercialize anti-VISTA antibodies for the treatment of cancer including ImmuNext’s lead compound, CI-8993. CI-8993 is a clinical-stage human IgG1 kappa monoclonal antibody designed to antagonize the VISTA signaling pathway.

CI-8993 was originally developed as part of a license and collaboration agreement between ImmuNext and Janssen Biotech, Inc (Janssen). In 2016, Janssen initiated clinical development of CI-8993 in a Phase 1 study evaluating safety, pharmacokinetics and pharmacodynamics of ascending doses of CI-8993 in patients with advanced solid tumors. The study enrolled 12 patients, in which one patient experienced transient dose-limiting side effects related to cytokine release syndrome. Janssen opted to close the study for “business reasons” and ImmuNext regained control of the asset.

In the years since the original CI-8993 study, the advent of CAR-T therapy and broad expansion of immunotherapy have led to an evolution within the oncology community toward the safe management of “on-target” side effects such as cytokine release and immune-mediated toxicity. For example, in 2018, the National Comprehensive Cancer Network (NCCN) developed its Guidelines for Management of Immunotherapy-Related Toxicities. We expect to employ such side-effect management strategies as part of our upcoming Phase 1a/1b clinical trials.

VISTA Publications:

webVISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance
webA New VISTA on combination therapy for negative checkpoint regulator blockade
webVISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy
webVISTA Regulates the Development of Protective Antitumor Immunity
webVISTA is an immune checkpoint molecule for human T cells