CD137, also known as 4-1BB or TNFRSF9, is a protein found on the surface of immune cells, particularly T-cells. It functions like a “gas pedal” for these cells, accelerating and strengthening their activity. CD137 belongs to the tumor necrosis factor (TNF) receptor family, regulating immune responses.
The Role of CD137 as an Immune System Accelerator
The immune system’s T-cells require two distinct signals to become fully active and mount a strong response. The first signal occurs when a T-cell receptor recognizes a specific antigen, like a “key in the ignition” for the T-cell. This initial recognition alone is often not enough for a robust and lasting immune reaction.
The second signal, co-stimulation, is provided by molecules like CD137, acting as the “gas pedal.” When CD137 on the T-cell binds to its partner molecule, CD137L (also known as 4-1BBL or TNFSF9), found on other immune cells like antigen-presenting cells, it delivers this crucial second signal. This co-stimulation leads to increased proliferation, enhanced survival, and stronger production of immune-signaling molecules like interferon-gamma. This two-signal process ensures that T-cells are activated effectively and maintain their function for a sustained period, contributing to a more powerful immune response.
How CD137 Helps the Body Fight Cancer
For T-cells to effectively eliminate cancer cells, they need strong activation to overcome the often suppressive environment within tumors. Engaging CD137 on tumor-specific T-cells provides the necessary acceleration. This boost helps T-cells attack the tumor more effectively and for longer durations.
Cancer cells can sometimes evade the immune system by creating an environment that suppresses T-cell activity. Boosting the CD137 signal unleashes these T-cells, enabling them to recognize and destroy malignant cells. This mechanism improves T-cell proliferation, survival, and their ability to differentiate into memory cells, which can provide long-term protection against cancer recurrence. CD137 stimulation primarily enhances the anti-tumor functions of CD8+ T cells, which are highly effective at directly killing cancer cells.
Medical Therapies That Activate CD137
Harnessing the power of CD137 has led to the development of specific medical therapies for cancer. One approach involves engineered drugs called agonist antibodies. These antibodies are designed to mimic the natural CD137L, “pressing the gas pedal” on T-cells to stimulate a strong anti-tumor response.
Agonist antibodies, such as urelumab and utomilumab, bind to CD137 on activated T-cells, triggering pathways that promote T-cell proliferation, survival, and the production of substances that kill cancer cells. Another application of CD137 is in Chimeric Antigen Receptor (CAR)-T cell therapy. In this advanced therapy, scientists engineer a patient’s own T-cells to express synthetic receptors (CARs) that specifically recognize cancer cells. The internal signaling part of the CD137 molecule is often incorporated into these CAR constructs, providing a built-in co-stimulatory signal. This integration makes the engineered CAR-T cells more potent, persistent, and effective at killing tumor cells, addressing a limitation of earlier CAR designs that lacked this sustained activation.
Safety and Research in CD137 Treatments
While CD137-activating therapies offer promise in cancer treatment, a primary challenge involves managing potential side effects from over-activating the immune system. Because CD137 acts as a powerful “on” switch for immune cells, therapies targeting it can lead to systemic adverse events.
Risks include liver toxicity, also known as hepatotoxicity, which can be severe. Another concern is cytokine release syndrome (CRS), an inflammatory response resulting from an excessive release of signaling proteins by activated immune cells. CRS can cause a range of symptoms, from fever and fatigue to more severe manifestations like low blood pressure, difficulty breathing, and organ dysfunction, sometimes requiring intensive care. Ongoing research aims to develop safer ways to target CD137, such as creating antibodies designed to activate CD137 only within the tumor environment, maximizing anti-cancer effects while minimizing systemic side effects. This localized activation strategy could potentially reduce the risk of widespread immune over-activation and improve the overall safety profile of these therapies.