Interleukin-2 (IL-2) is a naturally occurring protein produced by the body’s immune system. As a cytokine, it signals and regulates immune responses. IL-2 stimulates immune cells, making it a therapeutic agent for certain advanced cancers. It represents an early effort to harness the body’s defenses against malignant cells.
How IL-2 Fights Cancer
IL-2 works by activating and expanding immune cells that recognize and eliminate cancer cells. When administered, IL-2 stimulates the proliferation and differentiation of various immune cells, particularly cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. These activated immune cells become more effective at identifying and destroying cancerous cells throughout the body.
The binding of IL-2 to its receptors on immune cells initiates signal transduction pathways. These pathways mediate the effects of IL-2 on cell proliferation, activation, differentiation, and survival, enhancing the body’s natural defense system against tumors. This immune-mediated approach distinguishes IL-2 from other cancer treatments.
Treating Specific Cancers with IL-2
High-dose IL-2 therapy, known as aldesleukin, is primarily used for advanced cancers, specifically metastatic renal cell carcinoma (mRCC) and metastatic melanoma. It was the first immunotherapy approved by the U.S. Food and Drug Administration (FDA) for these conditions, receiving approval for mRCC in 1992 and metastatic melanoma in 1998. This treatment is administered through intravenous (IV) infusions.
The treatment protocol for high-dose IL-2 usually involves two cycles, each lasting approximately 10 days. Patients receive high doses of IL-2 every 8 hours for 5 days, followed by a rest period. After each cycle, a longer break occurs before repeating the process, provided the cancer shows signs of response or stabilization. While a small percentage of patients, around 7% to 9%, may experience complete and durable regressions, these outcomes are not common.
Understanding IL-2 Treatment Side Effects
IL-2 therapy can lead to significant side effects due to its systemic activation of the immune system. Many patients experience flu-like symptoms, including fever, chills, fatigue, and muscle aches. These symptoms can occur hours to days after the infusion and may be managed with medications such as acetaminophen.
More serious complications can arise, such as capillary leak syndrome (CLS). CLS involves an increase in capillary permeability, leading to fluid leakage from blood vessels into surrounding tissues. This can cause sudden drops in blood pressure, swelling, and reduced organ perfusion. Kidney dysfunction, cardiac arrhythmias, and respiratory insufficiency are also possible, often secondary to CLS. Due to the potential severity of these adverse reactions, high-dose IL-2 therapy requires close monitoring in specialized hospital settings with expertise in immunotherapy.
The Evolving Landscape of IL-2 Therapy
While high-dose IL-2 remains a treatment option for metastatic melanoma and renal cell carcinoma, its use has been limited by significant toxicities and relatively low overall response rates. Newer immunotherapies, such as immune checkpoint inhibitors, have changed the treatment landscape. This prompts ongoing research to improve IL-2 formulations and expand its applications. Efforts focus on developing modified versions of IL-2, often called “muteins” or “super-IL-2,” to enhance efficacy and reduce toxicity.
These novel IL-2 variants aim to selectively activate anti-tumor immune cells while minimizing the expansion of immunosuppressive regulatory T cells and associated side effects. Researchers are also exploring IL-2’s use in combination therapies, such as with PD-1/L1 checkpoint inhibitors, which have shown improved anti-tumor efficacy. Clinical trials are investigating these next-generation IL-2 receptor agonists and combination strategies across a wider range of cancers and autoimmune disorders.