High-dose interleukin-2 therapy related adverse events and implications on imaging

High-dose interleukin-2 (HDIL-2) therapy was initially approved by the U.S. Food and Drug Administration for metastatic renal cell carcinoma (mRCC) and metastatic melanoma. IL-2 is able to promote CD8+ T cell and natural killer (NK) cell cytotoxicity to increase tumoricidal activity of the innate immune system. HDIL-2 therapy is associated with a wide spectrum of immune-related adverse events (irAEs) that can be radiologically identified. HDIL-2 toxicity can manifest in multiple organ systems, most significantly leading to cardiovascular, abdominal, endocrine, and neurological adverse events. The collective impact of the irAEs and the rise of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors led to the demise of HDIL-2 as a primary therapy for mRCC and metastatic melanoma. However, with innovation in ICIs and the creation of mutant IL-2 conjugates, there has been a drive for combination therapy. Knowledge of the HDIL-2 therapy and HDIL-2 related adverse events with radiology relevance is critical in diagnostic image interpretation.

High-dose interleukin-2 (HDIL-2) was initially approved for the treatment of metastatic renal cell carcinoma (mRCC) and metastatic melanoma in 1992 and 1998, respectively. IL-2 was discovered as a cytokine, known as T cell growth factor. The majority of IL-2 is produced by CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and activated dendritic cells. IL-2 has numerous functions which include differentiation of CD4+ T cells, promoting CD8+ T cell cytotoxicity, and promoting NK cell cytotoxicity (1). When given intravenously at high doses, IL-2 therapy gained success in a subset of patients with metastatic melanoma or mRCC who achieved complete and durable responses (1). However, the high toxicity profile of HDIL-2 restricted this therapy to a minority of patients in highly specialized centers.Currently HDIL-2 has been relegated to a limited role in systemic therapy of mRCC and metastatic melanoma patients. Based on National Comprehensive Cancer Network (NCCN) guidelines, HDIL-2 has been useful for patients with favorable, intermediate, and poor risk clear cell mRCC patients who have excellent performance and normal organ function (2). Additionally, HDIL-2 is recommended as a second line regimen for metastatic or unresectable melanoma. HDIL-2 is contraindicated in patients with inadequate organ reserve, poor performance status, or with untreated/active brain metastases (3).Although HDIL-2 was more commonly used in 1990s, with the innovation in immune checkpoint inhibitors (ICIs), there has been a reemergence of HDIL-2 treatment as a combination therapy. The leading theory with including ICIs is the fact that these agents work downstream during the effector phase in a tumor. With IL-2 secretion activating tumor-specific T cells, HDIL-2 therapy could potentially work synergistically with ICIs (4). One study found that there was durable antitumor activity in metastatic melanoma and mRCC patients with HDIL-2 therapy after the patient had received programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor compared to patients who had just received IL-2. Thus, HDIL-2 remains an option for patients who have progressed on ICIs (5). With additional data, combination therapy may be the new norm for metastatic melanoma and mRCC treatment.New innovations to make HDIL-2 therapy safer has also surfaced with the creation of IL-2 conjugated with 6 releasable polyethylene glycol (PEG) chains (4). The mechanism behind PEGylated IL-2 revolves around the idea that the drug selectively binds to the IL-2Rabg isoform which preferentially activates effector T cells, which limits the side effect profile. Unfortunately, there has been mixed data revolving around this therapy. There were attempts to look at the relationship between adverse events observed with HDIL-2 and treatment effectiveness. Curti et al. (6) concluded that those who experienced adverse events had increased survival and better tumor control following treatment with HDIL-2.The purpose of this pictorial review is to describe typical and atypical HDIL-2 related adverse events that can be identified on imaging. It is crucial for radiologists to be familiar with the adverse events associated with HDIL-2 therapy, which has a potential to be more commonly used in the future.