Emerging Role for Novel Immunotherapy Agents in Metastatic Renal Cell Carcinoma: From Bench to Bedside

Abstract

Therapies that augment the antitumor immune response have been an established treatment modality for metastatic renal cell carcinoma (mRCC) since the 1980s. An improved understanding of the factors that limit the immune response to cancer have led to the development of novel therapeutic agents. Most notably, monoclonal antibodies that block the programmed death (PD)-1 immune checkpoint pathway have demonstrated encouraging antitumor activity against mRCC in phase I and II clinical trials. However, as monotherapy these agents are unlikely to offer substantial clinical benefit for the majority of patients with mRCC. Combination approaches and improvements in patient selection will be essential to enhance their efficacy and ensure the rational application of immunotherapy. This review summarizes the clinical and preclinical data that support the use of novel immunotherapies for mRCC and looks forward to future directions for this promising therapeutic strategy.

Treatment of renal cell carcinoma: Current status and future directions

“…Patients from these studies were continually monitored for toxicity and clinical outcomes; the most recent ORR was 15%, and complete responses were observed in 7% of patients . Unfortunately, a majority of patients fails to achieve a long‐term disease control, and novel immunotherapy strategies are being developed with interesting clinical data among tumors with higher immunogenicity, including RCC (Table ) …”

“…Because nivolumab, a fully human monoclonal IgG4 antibody specific for PD‐1, has demonstrated a survival benefit in patients with mRCC (see “Second‐line options and beyond,” below), several other checkpoint inhibitors are being tested as single agents (such as T‐cell agonists, T regulatory antagonists, and vaccines) or combined with other therapies . Interestingly, there are preclinical data suggesting synergy between angiogenesis inhibition and immune system activation as well as different ways of stimulating the immune system . After the publication of data from early trials with promising ORRs (range, 40%‐55%) and manageable AEs, several large phase 3 trials are being conducted in the front‐line setting (Table ).…”

“…93 Unfortunately, a majority of patients fails to achieve a long-term disease control, and novel immunotherapy strategies are being developed with interesting clinical data among tumors with higher immunogenicity, including RCC (Table 3). 82,[94][95][96][97][98][99][100][101][102] One of these strategies included IMA901, which is the first therapeutic vaccine consisting of multiple tumorassociated peptides (9 different class I human leucocyte antigens [HLA] [HLA-A*02] and 1 class II HLA), which were confirmed as naturally present in human cancer tissue. 103 IMA901 was studied in a multicenter, randomized, phase 2 study (IMA901-202), in combination with granulocytemacrophage-colony-stimulating factor with or without cyclophosphamide, in 68 patients with refractory mRCC.…”

“…55 Interestingly, there are preclinical data suggesting synergy between angiogenesis inhibition and immune system activation as well as different ways of stimulating the immune system. 94,[109][110][111][112] After the publication of data from early trials [113][114][115] with promising ORRs (range, 40%-55%) and manageable AEs, several large phase 3 trials are being conducted in the front-line setting ( Table 3).…”

Association between B7‑H1 and cervical cancer: B7‑H1 impairs the immune response in human cervical cancer cells

“…B7-H1, also known as programmed death ligand, is a member of the B7 family. The binding of B7-H1 (programmed death-ligand 1) to its receptor, programmed cell death protein 1, can inhibit the proliferation of T cells and the secretion of some cytokines in vitro ( 29 – 31 ). B7-H1 acts as a negative co-stimulatory molecule in the process of T cell activation and may serve a major role in suppressing the immune system during certain events including pregnancy, tissue allografts ( 32 ), autoimmune disease ( 33 ) and other disease states such as hepatitis ( 34 ).…”