Abstract
Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC.
Highlights
Patients with metastatic renal cell carcinoma (RCC) face a dismal prognosis and have limited therapeutic options
To determine the extent to which local administration of Ad5mTRAIL+CpG at the primary tumor site would stimulate T cell-mediated eradication of metastatic RCC, we developed a murine model based on intrarenal (IR) injections of Renca tumor cells engineered to express Luciferase
We evaluated the efficacy of an Ad5mTRAIL+CpG combinatorial immunotherapy in a more physiologically relevant orthotopic Renca model, where IR tumor challenge gives rise to spontaneous lung metastases [20,22,34]
Summary
Patients with metastatic renal cell carcinoma (RCC) face a dismal prognosis and have limited therapeutic options. Immunotherapy with high dose IL-2 has a 20% response rate, including a 5–10% complete response rate, but is poorly tolerated and has significant side effects that limit its use to specialized centers with highly selected patients [2,3,4,5]. While newer treatments, such as the multikinase inhibitors sunitinib and sorafenib, show small improvements in survival, complete responses are rare with these agents [6]. Co-administration of CpG with TRAIL provides the stimulatory signal APCs need to initiate protective immunity to tumor-derived antigens. Both TRAIL and CpG have shown minimal toxicity in Phase I clinical trials, making them excellent candidates for antitumor immunotherapies [9,15]
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