Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

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.

Intravenous Injection of MVA Virus Targets CD8+ Lymphocytes to Tumors to Control Tumor Growth upon Combinatorial Treatment with a TLR9 Agonist

“…Consistent with work from others on this model (38,39), the requirement of CD8 þ lymphocytes was demonstrated by specific in vivo depletion preceding MVA-MUC1 immunization. We identified two peptides containing H-2 d -restricted epitopes indicating that the human MUC1 protein is weakly immunogenic in BALB/c mice, as frequencies of responding T cells were very low (below 10 À4 ).…”

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

“…In addition, the homing properties of TRAIL exosomes could be improved by inserting tumor-specific receptors or ligands, or applying strategies to avoid their clearance by macrophages (41,42). TRAIL-mediated tumor apoptosis in immunocompetent mice would also allow engaging systemic immunity, ideally promoting an amplified antitumor effect (43,44). Importantly, these experiments would shed light on the potential toxicity generated by systemic administration of TRAIL exosomes.…”

Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK

“…The previous evidence suggests that TRAIL-mediated tumor destruction increases the amount of antigens that could be delivered into the cross-presentation pathway, ultimately leading to enhanced antitumor immunity (4). HSV-TK/GCV therapy is also capable of inducing potent T cell and natural killer cell responses (37).…”

“…Approximately 30% of patients with RCC present with metastatic disease and the 5-year survival rate of these patients is less than 10% (3,4). Despite the recent advances in understanding genetic and epigenetic events involved in the metastasis of RCC, current therapies have shown limited success in improving the overall survival of patients with metastatic RCC.…”