4-1BB agonism: adding the accelerator to cancer immunotherapy
Cariad Chester1,2, Siddhant Ambulkar3, Holbrook E Kohrt3
1Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford University, 269 Campus Drive, CCSR 1140, Stanford, CA, 94305-5151, USA. cchester@stanford.edu.
Abstract:
The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8(+) T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously "removing the brakes" via blocking inhibitory signaling and "stepping on the accelerator" via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.
Insights
Checkpoint inhibitors are effective cancer treatments. Targeting 4-1BB (CD137) with agonistic antibodies, combined with checkpoint blockade, may enhance antitumor immunity by co-stimulation and removing inhibitory signals.
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.
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