Effects of Stimulating Interleukin-2/Anti-Interleukin-2 Antibody Complexes on Renal Cell Carcinoma

Kyu-Hyun Han; Ki Won Kim; Ji-Jing Yan; Jae-Ghi Lee; Eun Mi Lee; Miyeon Han; Eun Jin Cho; Seong Sik Kang; Hye Jin Lim; Tai Yeon Koo; Curie Ahn; Jaeseok Yang


BMC Urol. 2016;16(2) 

In This Article


Renal cell carcinoma (RCC) is the most common primary malignancy of the renal parenchyma, comprising 3 % of all adult malignancies, and its incidence has been increasing.[1,2] Although early RCC can be cured by surgery, one-third of RCC patients exhibit metastasis at diagnosis. Metastatic RCC has poor prognosis, with a 5-year survival rate of only 10 %,[3] and approximately 20–25 % of patients with metastatic RCC do not respond to treatment and symptoms progress rapidly.[4] Sorafenib is one of target drugs against RCC that prolongs patient survival, but rarely leads to complete remission;[5–7] moreover, long-term sorafenib treatment can exacerbate RCC by creating ischemic conditions.[8,9]

RCC is considered as an immunogenic tumor owing to its spontaneous regression, variable growth, late metastasis, high degree of T cell infiltration, and high incidence in immunosuppressed patients. However, RCC can also suppress the anti-tumor immunity of naïve and memory CD4+ T, natural killer (NK), and dendritic cells,[10] and evade the cytotoxic effect of NK cells.[11,12] Therefore, a drug that potentiates immune response may be effective in the treatment of RCC. Indeed, high doses of interleukin (IL)-2 have been shown to suppress RCC progression without inducing tumor ischemia, leading to complete remission in 10–20 % of patients.[13,14] Blockade of CTLA4, a T-cell inhibitory receptor with ipilimumab, and increasing T-cell proliferation and cytotoxic effects with PD-1/PD-L1 axis inhibition also induced regression of renal cell carcinoma in some patients.[15,16] However, high-dose IL-2 therapy also induces systemic inflammatory responses, including capillary leak syndrome, heart failure, and pulmonary edema, thereby hindering the broad application of high-dose IL-2 therapy in the treatment of advanced RCC.[17,18]

Recently, immune complexes (IL-2C) composed of with low-dose IL-2 and stimulating anti-IL-2 antibody (S4B6) have been shown to enhance immune responses via selective structural interactions.[19–23] Stimulating IL-2C can preferentially expand memory CD8+ T and NK cells—while more weakly affecting regulatory T cells—via the interaction of anti-IL-2 antibodies (S4B6) and CD25 binding region of IL-2, leading to inhibition of both leukemia and melanoma.[19,23] Interestingly, the half-life of IL-2 is increased in IL-2C; as such, low-dose IL-2C has immune enhancing effects that are comparable to those of high-dose IL-2 therapy without accompanying serious side effects such as capillary leak syndrome.[19,23] Low-dose IL-2C therapy is therefore expected to be an effective and safe treatment for immunogenic tumors.

Here, we investigated the efficacy and safety of low-dose IL-2C treatment for RCC in a syngeneic murine model. We found that IL-2C treatment enhanced anti-tumor immunity against RCC without causing pulmonary edema, although it did not have sufficient potency to suppress tumor growth.