Interleukin 2-Based Fusion Proteins for the Treatment of Cancer

Abstract

Interleukin 2 (IL-2) plays a fundamental role in both immune activation and tolerance and has revolutionized the field of cancer immunotherapy since its discovery. The ability of IL-2 to mediate tumor regression in preclinical and clinical settings led to FDA approval for its use in the treatment of metastatic renal cell carcinoma and metastatic melanoma in the 1990s. Although modest success is observed in the clinic, cancer patients receiving IL-2 therapy experience a wide array of side effects ranging from flu-like symptoms to life-threatening conditions such as vascular leak syndrome. Over the past three decades, efforts have focused on circumventing IL-2-related toxicities by engineering methods to localize IL-2 to the tumor or secondary lymphoid tissue, preferentially activate CD8⁺ T cells and NK cells, and alter pharmacokinetic properties to increase bioavailability. This review summarizes the various IL-2-based strategies that have emerged, with a focus on chimeric fusion methods.

Figure 1

Properties of a next-generation IL-2-based fusion construct. A next generation IL-2-based fusion protein for cancer immunotherapy will encompass the criteria shown to overcome challenges associated with conventional IL-2 therapy. Due to the pleiotropic effects of IL-2 on different IL-2R-bearing immune cells, a biased agonist targeting CD8 T cells and NK cells bearing the intermediate affinity receptor, IL-2Rβγ, will promote antitumor immunity and limit expansion of immunosuppressive Tregs. Furthermore, traditional IL-2 therapy is limited by a short half-life, poor in vivo localization, and off-target activity which all contribute to adverse effects experienced by patients. Strategies that improve the pharmacokinetic and biodistribution profile of IL-2 will increase antitumor efficacy. Lastly, IL-2-based therapy delivered in combination with other treatment modalities will provide the best opportunity to overcome immunosuppression and immune escape that occurs. Tregs: T regulatory cells; TME: tumor microenvironment; dLN: draining lymph node; chemo: chemotherapy; rad: radiation; CPI: checkpoint inhibitor.