What is the significance of soluble Interleukin-2 (IL-2)?

From the Guidelines

Soluble Interleukin-2 (IL-2) plays a crucial role in immune responses, primarily regulating T cell activity, and its significance is highlighted by its use in treating certain cancers, such as metastatic renal cell carcinoma and metastatic melanoma, as evidenced by the most recent study 1. The biological importance of IL-2 stems from its central role in T cell proliferation, differentiation of regulatory T cells, and modulation of both immune activation and tolerance mechanisms. Clinically, recombinant IL-2 (aldesleukin/Proleukin) can be administered as a treatment for certain cancers, typically at doses of 600,000-720,000 IU/kg given intravenously every 8 hours for up to 14 doses per treatment cycle, as recommended by the expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy 1. However, IL-2 therapy carries significant toxicity risks, including capillary leak syndrome, hypotension, and multi-organ dysfunction, which must be carefully managed, as noted in the guidelines for hypotension management during IL-2 administration 1 and the considerations for renal function in patients undergoing IL-2 therapy 1.

Key points to consider regarding the significance and use of soluble IL-2 include:

• Its role in immune signaling and T cell regulation
• Clinical applications in cancer treatment, particularly for metastatic renal cell carcinoma and melanoma
• Significant toxicity risks associated with IL-2 therapy, necessitating careful patient selection and monitoring
• The importance of managing side effects, such as hypotension and renal toxicity, to ensure safe administration of IL-2
• The use of IL-2 in combination with other therapies, like tumor-infiltrating lymphocyte cell therapy, and the need for expert consensus guidelines to standardize its administration and management 1.

Given the most recent evidence from 2024 1, the administration of IL-2 should be approached with caution, considering its potential benefits and risks, and should be guided by expert consensus guidelines to optimize patient outcomes in terms of morbidity, mortality, and quality of life.

From the FDA Drug Label

The in vitro biological activities of the native nonrecombinant molecule have been reproduced with aldesleukin. The significance of soluble Interleukin-2 (IL-2) is not directly stated in the provided drug label.

• The label describes the biological activities of the native nonrecombinant molecule, which have been reproduced with aldesleukin, a recombinant form of IL-2.
• However, it does not explicitly state the significance of soluble IL-2. 2

From the Research

Significance of Soluble Interleukin-2 (IL-2)

• Soluble Interleukin-2 (IL-2) plays a crucial role in the immune system, particularly in the growth and proliferation of immune cells such as NK and T cells 3.
• The clinical significance of soluble IL-2 receptor measurement has been established in various immune-mediated diseases, including haemophagocytic lymphohistiocytosis, sarcoidosis, rheumatoid arthritis, and systemic lupus erythematosus 4.
• Soluble IL-2R levels can be used as a biomarker to monitor and predict disease activity and treatment response in these conditions 4.

Therapeutic Applications of IL-2

• High-dose IL-2 treatment has been approved for the treatment of renal cell carcinoma and melanoma, achieving complete and durable responses in a small proportion of patients 5, 6.
• However, the therapeutic potential of wild-type IL-2 is limited by its short half-life and severe vascular toxicity 6.
• Novel engineering strategies are being developed to overcome the toxicity of IL-2 and realize its full potential for patients, including combination therapies with PD-1/L1 pathway blockade 6, 7.

Recent Advances in IL-2 Therapy

• Aerosolized delivery of IL-2 has been developed as a means to provide localized delivery and higher local immune cell activation, with reduced systemic effects 3.
• Combination therapies using aerosol IL-2 with adoptive transfer of T cells or NK cells have shown improved therapeutic effects 3.
• New recombinant IL-2 compounds and delivery systems are being developed, highlighting a possible comeback of recombinant IL-2 therapy 7.