We will discuss the past and current developments to overcome tumor mediated immune evasion in metastatic kidney cancer. Broadly, these include (1) T cell modulation, for example, with cytokines and immune checkpoint inhibitors, (2) adoptive cellular immunotherapy, and (3) vaccination.
Cytokine Therapy: The two principal cytokines with proven efficacy in metastatic renal cancer are interferon-alpha (INF-α) and high-dose interleukin 2 (IL2). IL2 is a potent stimulator of T cell proliferation and differentiation, while INF-α has antiangiogenic effects, promoting antigen presentation and dendritic cell maturation. However, their exact mechanism of action is unknown.
Immune Checkpoint Inhibitors: In a single institution phase II study of ipilimumab in metastatic kidney cancer, 5 of 40 responses were noted in the higher dose group (3 mg/kg every 3 weeks) compared to 1 of 21 responses in the lower dose group (3 mg/kg followed by 1 mg/kg every 3 weeks). To our knowledge, there are currently no other studies of single agent ipilimumab in kidney cancer and the ongoing trials are evaluating the efficacy of combining ipilimumab with PD-1 blockade in kidney cancer . A phase III study of ipilimumab and the anti-PD-1 antibody nivolumab versus sunitinib is currently recruiting patients with previously untreated advanced or metastatic kidney cancer (CheckMate 214). Although a phase I study of another CTLA-4-directed monoclonal antibody, tremelimumab in combination with sunitinib, showed RR of 43% in metastatic kidney cancer the combination was not recommended for further investigation due to rapid onset renal failure noted in a subset of patients.
Nivolumab (previously BMS 936558 and MDX-1106) is a fully humanized PD-1 blocking antibody. Promising responses, some durable, have been reported in phase I and II studies in melanoma, non-small-cell lung cancer, and, more recently, renal cell cancer. Nivolumab (previously BMS 936558 and MDX-1106) is a fully humanized PD-1 blocking antibody. Promising responses, some durable, have been reported in phase I and II studies in melanoma, non-small-cell lung cancer, and, more recently, renal cell cancer.
Adoptive cellular immunotherapy (ACI) entails in vitro expansion of immune effectors (autologous or allogeneic lymphocytes) with antitumor activity and reinfusing them into the tumor bearing host. First described in kidney cancer in 1992, ACI has thereafter been evaluated in several clinical studies with or without cytokines. Conflicting data on efficacy, significant cost, and a labor intensive process of preparation has limited the pace of development of ACI in kidney cancer.
Vaccines carry tumor antigens on a vehicle that may be a cell, peptide, or a vector. They are designed to enhance innate or adaptive immunity depending on the antigen and vehicle. Examples include autologous tumor cell vaccines, dendritic cell (DC) based vaccines, and peptide based vaccines. Results from ongoing trials of DC vaccines in kidney cancer are the most promising and are discussed here. Phase I studies of vaccines containing DCs transfected with tumor RNA or pulsed with tumor lysate found them to be safe and effective with high efficacy in kidney cancer either alone or in combination with cytokines.
Although much progresses have been made, more efforts are still needed for the research of Kedney cancer immunotherapy.
Raman R et al. Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review. BioMed Research International. 2015;2015:367354.
Fishman M. et al. Immunotherapy of metastatic renal cell cancer. Cancer Control. 2002;9(4):293–304.