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

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

• Zha, Y; et al. T Cell Anergy is Reversed by Active Ras and is Regulated by Diacylglycerol Kinase-α. Nature Immunology, v. 7(11), 1166-1173, 2006.

July 23, 2019

Proof of concept

Patent Issued

Licensing,Co-development,Investment

Thomas Gajewski

• US: 7,381,401