VRK2 kinase inhibitors for enhanced cancer immunotherapy

This technology is a combination immunotherapy strategy that integrates VRK2 inhibition and PD-1 blocking antibodies to enhance the efficacy of anti-tumor responses in cancer patients.

Unmet Need: Improving resistance and durability in immune checkpoint blockade therapy

PD-1 blocking antibodies are widely used cancer immunotherapies, but clinical efficacy is limited by a short duration of response and a high percentage of non-responders. Additionally, systemic immune checkpoint inhibition can lead to significant adverse inflammatory side effects and immune-related toxicities. There is an urgent need for adjunct therapies that target specific downstream effectors in PD-1 signaling pathways to enable more selective and potent enhancement of checkpoint blockade without broadly disrupting immune tolerance.

The Technology: Targeted inhibition of a downstream PD-1 effector to boost checkpoint blockade efficacy

This technology combines VRK2 kinase inhibitors with PD-1 blocking antibodies to enhance T cell-mediated anti-tumor immunity. It was demonstrated that VRK2 is required for PD-1-mediated inhibition of cytokine secretion. Pharmacological inhibition of VRK2 (using the small molecule AZD-7762) in combination with anti-PD-1 antibodies inhibits the PD-1 signaling cascade at multiple points, resulting in more robust T cell activation and improved tumor clearance compared to PD-1 blockade alone.

This technology has been validated in human primary T cells and a syngeneic mouse adenocarcinoma tumor model.

Applications:

• Adjunct immunotherapy for solid tumors (e.g., adenocarcinoma, lung, bladder)
• Combination treatment with existing PD-1/PD-L1 blockers
• Therapeutic strategy for checkpoint inhibitor-resistant cancers
• Drug screening platform for identifying VRK2 inhibitors
• Research tool for studying PD-1 signaling pathways and downstream effectors

Advantages:

• Synergistic efficacy of combination therapy
• Mechanistic precision through specific targeting of downstream effector
• Enhanced safety profile by avoiding broad immune activation
• Leverages small molecule inhibitors that can be administered orally

Lead Inventor:

Adam Mor, M.D., Ph.D.

Patent Information:

Patent Pending (US20220370408)

Related Publications:

• Peled M, Tocheva AS, Adam K, Mor A. “VRK2 inhibition synergizes with PD-1 blockade to improve T cell responses.” Immunol Lett. 2021 May;233:42-47. doi: 10.1016/j.imlet.2021.03.007

• Tocheva AS, Peled M, Strazza M, Adam KR, Lerrer S, Nayak S, Azoulay-Alfaguter I, Foster CJR, Philips EA, Neel BG, Ueberheide B, Mor A. “Quantitative phosphoproteomic analysis reveals involvement of PD-1 in multiple T cell functions.” J Biol Chem. 2020 Dec 25;295(52):18036-18050. doi: 10.1074/jbc.RA120.014745.

Tech Ventures Reference:

• IR CU21245

• Licensing Contact: Cynthia Lang