4-1BB agonism: adding the accelerator to cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Checkpoint inhibitors have validated immunomodulatory agents for cancer therapy.
• 4-1BB (CD137), a co-stimulatory target in the tumor necrosis factor receptor superfamily, activates T cells and NK cells.
• Ligation of 4-1BB enhances T cell and NK cell pro-inflammatory cytokine secretion and cytotoxic functions.

Purpose of the Study:

• To explore the potential of targeting 4-1BB (CD137) as a co-stimulatory immunotherapeutic agent.
• To investigate combination strategies involving 4-1BB agonism and checkpoint blockade for enhanced anticancer effects.
• To evaluate the complementary mechanisms of simultaneous immune activation and inhibition removal.

Main Methods:

• Utilized agonistic monoclonal antibody (mAb) therapy targeting 4-1BB.
• Evaluated antitumor effects in murine tumor models.
• Considered combination therapeutic strategies, specifically with checkpoint blockade.

Main Results:

• Agonistic anti-4-1BB mAb therapy demonstrated potent antitumor effects in preclinical models.
• Combination therapy of 4-1BB agonism with checkpoint blockade offers a complementary approach to activate antitumor immunity.
• This strategy simultaneously "removes the brakes" (checkpoint blockade) and "steps on the accelerator" (4-1BB agonism).

Conclusions:

• 4-1BB agonism is a promising co-stimulatory target for anticancer therapeutics.
• Combination strategies, particularly with checkpoint blockade, are crucial for optimizing 4-1BB-targeted therapy efficacy.
• Understanding 4-1BB biology is key to advancing combination cancer immunotherapy, despite potential toxicities.