Small Molecule Immune Response Regulators for the Treatment of Cancer and Autoimmune Disorders

Inventor(s):

    SUMMARY

    • Cancer cells induce a state of T-cell anergy to evade tumor cell clearance. PD-1 checkpoint inhibitors overcome this in some cases, however patient resistance and harmful side-effects limit its utility in others.
    • Diacylglycerol Kinase (DGK) sits in the middle of a complex series of interactions that determine the strength of an immune response to a given antigen. The inventors discovered that downregulation of DGK can alleviate T-cell anergy in an alternate mechanism of action to PD-1 inhibition. 
    • The invention is a series of small molecule inhibitors of DGK. Inhibiting DGK in turn allows the immune system to mount a defense against cancer cells and can be useful in patients who do not respond to traditional checkpoint inhibitors.
    • In ex-vivo proof-of-concept experiments, T cells from anergic mice demonstrated 2.4-4.8 fold increase in T cell activation as measured by IL-2 production when treated with a DGK inhibitors.

     

    FIGURE

    T-cell anergy was induced in murine T-cells by using an anti-CD3 antibody. Treatment with a DGK inhibitor (DGK I) followed by incubation with CD3 and CD23 coated beads reversed T-cell anergy in a dose dependent manner.

    ADVANTAGES

    ADVANTAGES

    • Mechanism of action harnesses a patient’s own immune system
    • Alternative mechanism to current checkpoint inhibition

     

    APPLICATIONS

    • DGK inhibitors: treatment of solid tumors
    • DGK agonists: treatment of autoimmune disorders

     

    PUBLICATIONS

     

     

    • US: 7,381,401

    TECH DETAILS

    Published
    7/23/2019

    Reference ID
    04-T-005

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