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 %, and approximately 20–25 % of patients with metastatic RCC do not respond to treatment and symptoms progress rapidly. 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, 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.
BMC Urol. 2016;16(2) © 2016 BioMed Central, Ltd.