The Past, Present and Future of Immunotherapy for Metastatic Renal Cell Carcinoma

Abstract

The treatment of renal cell carcinoma (RCC) has evolved tremendously over the past decades. Localized disease is often curative with surgical resection of the malignancy. However, in cases where the primary tumor has metastasized, immunotherapy is becoming a more prevalent means to combat metastatic renal cell carcinoma (mRCC). Cytokine and checkpoint inhibitor immunotherapy have been demonstrated to stimulate the immune response through a number of different mechanisms. These drugs have been used as a monotherapy, combination therapy, or as successive treatments to systemic therapies. This review summarizes the success of previous and current therapeutic targets, while also leading to the direction of future therapies. This review might be helpful in improving the management of mRCC.Renal cell carcinoma is the most common malignancy of the kidney, comprising 2-3% of all cancers in adults, and the seventh leading cause of cancer in men and ninth in women (1). At the time of diagnosis, it is estimated that 25% of patients will have a metastatic disease; anywhere from 20% to 50% will develop metastatic disease after surgical intervention and will require systemic therapy (2). Immunotherapy is an increasingly popular and studied treatment modality that utilizes the body's own immune system to combat metastatic cancer. Advancements in biotechnology and knowledge of molecular targets have expanded the arsenal available to urologists to treat metastatic renal cell carcinoma (mRCC).

Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes

“…3a). Such a poor response to chemotherapeutics is a typical feature of RCC (Barbieri et al 2017;Chang et al 2019;Piva et al 2016). Combined treatment of Renca cells with VPA or MS-275 and L-OHP or HU augmented cytotoxic effects of HU significantly (Fig.…”

“…Furthermore, HDACi counteracted the acquired resistance of RCC cells against the mammalian target of rapamycin-inhibitor everolimus and the glucose-regulating biguanide metformin (Juengel et al 2014;Wei et al 2018). In light of the chemoresistance and the poor prognosis of metastatic RCC (Barbieri et al 2017;Chang et al 2019), these findings suggest that HDACi pose an interesting therapeutic option for this cancer type.…”

“…The HDACi trichostatin-A (TSA) and butyrate suppressed TGFβ-induced EMT (Yoshikawa et al 2007) and VPA prevented the TGFβdependent activation of the EMT-associated transcription factor SMAD4 (Mao et al 2017). Such effects could be particularly relevant to tumors that are or become resistant to standard cancer drugs such as renal and lung tumors (Barbieri et al 2017;Chang et al 2019;Dietrich and Gerber 2016;Foy et al 2017).…”

Incidence of Pericardial Effusion in Patients with Advanced Non-Small Cell Lung Cancer Receiving Immunotherapy

“…Immune checkpoint inhibitor-based immunotherapy demonstrated an impressive clinical efficacy in the fight against several cancers with various compounds currently approved for the treatment of many forms of malignant tumors [1][2][3][4]. There is a widespread consensus that this therapy should now be considered as a cornerstone in anticancer treatment [14].…”

Management of Patients With Metastatic Renal Cell Cancer and Bone Metastases

“…Systemic therapy options for patients with metastatic RCC (mRCC) currently include tyrosine kinase inhibitors (targeted therapy), which target vascular endothelial growth factor receptors (VEGFR), mammalian target of rapamycin (mTOR) and other pathways (4)(5)(6)(7)(8). In addition, monoclonal antibodies, such as bevacizumab, pembrolizumab, ipilimumab and nivolumab, have yielded positive results (9)(10)(11). Cabozantinib is one of several approved treatment options, which has been studied specifically in the subgroup of patients with bone metastases, based on data from the METEOR trial (12).…”