Interleukin-2 based immunotherapy in patients with metastatic renal cell carcinoma.

The present thesis consists of 8 published articles focusing on interleukin-2 based immunotherapy in metastatic renal cell carcinoma (mRCC). This disease represents a significant challenge, as the tumor is resistant to current chemotherapy, hormonal therapy and radiation therapy. However, IL-2 based immunotherapy may induce dramatic durable tumor regression by manipulating the immune system, however, only in a minority of patients. Two critical questions have driven the present thesis. First, which properties of the immune system are responsible for the dramatic tumor regression seen in some patients with mRCC following IL-2 administration? And second, can histamine increase the efficacy of IL-2 based immunotherapy by ending the immune suppression induced by phagocyte-generation of reactive oxygen species? 120 Danish patients, 41 UK patients and 20 Swedish patients were treated with low- or intermediate dose IL-2 based immunotherapy in an outpatient setting. As monitoring of the Danish patients, 443 serial blood samples and 225 serial tumor core biopsies were obtained. The regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC is safe and active. In the Danish patients, an estimated 5-year survival rate of 16% was observed. From the blood and tumor analysis, an understanding emerged that IL-2 based immunotherapy is a "targeted therapy" requiring intratumoral immune cells (CD4+, CD8+, CD56+, CD57+ T- and NK cells) for treatment effect. In contrast, monocytes and neutrophils were harmful for the outcome of IL-2 based immunotherapy. In progressing patients, the leukocyte subsets in blood and tumor tissue remained unaffected by cytokine therapy. The fate of a patient with mRCC prior to IL-2 and IFN-alpha based immunotherapy cannot be determined by measuring baseline tumor features of FasL expression or Ki-67 (MIB-1) proliferation marker. We established a biological rationale for the potential use of histamine in conjunction with IL-2 in mRCC. A large confirmatory randomised phase III trial of IL-2 with and without histamine in mRCC appropriately stratified for monocytes and neutrophils in blood and tumor tissue is warranted. In a multivariate analysis, 5 clinical features (PS, bone metastases, lymph node metastases, low hemoglobin and high LDH) plus 3 supplemental immunological factors (intratumoral CD57+ NK cells <50 cells/mm(2), intratumoral neutrophils >0 and blood neutrophils >6.0) were independent prognostic factors of short survival in patients with mRCC receiving IL-2, identifying subgroups with estimated 5-year survival rates of 60%, 25% and 0%, respectively. These features may help to select patients more likely to benefit from IL-2 based immunotherapy.