Role of vaccine therapy for renal cell carcinoma in the era of targeted therapy

Abstract

Abbreviations & Acronyms AE = adverse event APC = antigen presenting cells BCG = bacillus Calmette-Guérin CA = carbonic anhydrase CA9 = carbonic anhydrase IX CPA = cyclophosphamide CR = complete response CTLA = cytotoxic T lymphocyte antigen CTL = cytotoxic T lymphocytes DC = dendritic cell DFS = disease-free survival GM-CSF = granulocyte-macrophage colony-stimulating factor GMTV = genetically modified tumor vaccines HLA = human leukocyte antigen HR = hazard ratio IFN = interferon IL-12 = interleukin-12 IL-2 = interleukin-2 KHL = keyhole limpet hemocyanin LMI = large multivalent immunogen MHC = major histocompatibility complex MR = minor response mRCC = metastatic renal cell carcinoma mTOR = mammalian target of rapamycin MUC = mucin MVA = modified vaccinia virus Ankara N/A = not applicable NK = natural killer OS = overall survival PADRE = Pan-DR-binding peptide PD = progressive disease PFS = progression-free survival PR = partial response RCC = renal cell carcinoma RECIST = Response Evaluation Criteria in Solid Tumors SD = stable disease TAA = tumor-associated antigens Th1 = T helper 1 Th2 = T helper 2 Treg = regulatory T cell TRIST = TroVax Renal Immunotherapy Survival Trial TUMAP = tumor-associated peptides VEGF = vascular endothelial growth factor VHL = von Hippel-Lindau WT1 = Wilms tumor 1 Abstract: Renal cell carcinoma is the most common malignant tumor originating from the kidney. Compared with other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiotherapy. However, it is well known that renal cell carcinoma represents one of the most immune-responsive cancers and several immunotherapeutic strategies have been investigated in the management of renal cell carcinoma with variable degrees of success. The development of immunotherapy with a-interferon or high-dose interleukin-2 is the best established treatment, and is associated with durable disease control. Although the lack of defined antigens in renal cell carcinoma has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of renal cell carcinoma for more than 30 years. At present, there are three types of cell-based vaccines in renal cell carcinoma treatment: autologous tumor-cell vaccines, genetically modified tumor vaccines and dendritic cell-based vaccines. A further type is peptidebased vaccination with tumor-associated antigens as possible targets, such as carbonic anhydrase IX, survivin and telomerase that are overexpressed in renal cell carcinoma. In the present article, we review data from completed clinical trials of vaccine therapy, and discuss future trials to assess the current knowledge and future role of vaccine therapy for renal cell carcinoma in the era of recently developed targeted therapy.

Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

“…Early stage RCC patients with localized tumors have a good prognosis after surgical removable of the primary tumor; however, approximately 30% of all patients first diagnosed with RCC already have metastatic disease [ 1 ]. Patients with RCC are unusually resistant to radio and cytotoxic drug therapies compared to responses observed for other solid tumors, and immunotherapies have provided some limited benefits for patients with RCC metastasis [ 5 – 8 ]. Recent developments of targeted therapies for treating RCC have primarily focused on clinical applications of receptor tyrosine kinase inhibitors, neutralizing antibodies against vascular endothelial growth factor (VEGF) and mTOR pathway inhibitors [ 9 – 13 ].…”

Dendritic Cell Vaccines Presenting Autologous Tumor Antigens from Self-renewing Cancer Cells in Metastatic Renal Cell Carcinoma

“…28 Others have conducted small studies of autologous DCVs in mRCC, as summarized elsewhere. 24,25,29,30 Antigen sources have included shared peptides, 31 allogeneic cell lines, 32 autologous tumor cells, 33 autologous tumor lysate, 34 and autologous tumor RNA. 35 The treatment used in this report differs in the use of autologous tumor cells that are self-renewing ex vivo, which may preferentially present antigens associated with tumor stem cells and early progenitor cells and/or rapidly proliferating cells.…”

Inhibition of BRD4 Suppresses Cell Proliferation and Induces Apoptosis in Renal Cell Carcinoma

“…However, a considerable proportion of patients with RCC already have metastatic disease at diagnosis [26]. RCC is unusually resistant to chemotherapy and radiotherapy compared to other solid tumors, and novel immunotherapies have supplied some limited benefits for patients who suffer from advanced RCC [27-30]. Therefore, alternative therapeutic strategies are still necessary to be explored to increase the survival rate of patients with RCC.…”