Immunotherapy in Renal Cell Carcinoma

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Background

Renal cell carcinoma (RCC) accounts for 90-95% of all kidney malignancies. If detected early and managed surgically, the 5-year overall survival rate for RCC patients is ~90%. However, one-third of these treated patients will develop disease recurrence or metastases. Patients diagnosed with advanced-stage, metastatic disease have a very poor prognosis, with a 5-year survival rate of < 10%. There remains an unclear and unmet clinical need for the development of effective interventional therapies for RCC patients, particularly for those individuals with advanced-stage disease.

Cytokine-based immunotherapies were developed as standard-of-care treatments for RCC patients in the 1990s. However, only a minority of patients derived durable clinical benefit. With the advent of refined molecular profiling of RCC, the field witnessed the rapid evolution of targeted therapeutic approaches yielding improved response rates in the early 2000s, with more recent advances (since 2013) including the application of immune checkpoint inhibitors (ICI) to enhance and sustain anti-tumor immune cell function in association with extended progression-free and overall survival in treated RCC patients.

Monoclonal antibodies specifically binding to, and antagonizing the function of, programmed cell death protein-1 (PD-1) as well as other immune checkpoints have proven promising in revitalizing anti-tumor effector T-cell responses in RCC patients, with Nivolumab improving overall survival rates in advanced-stage ccRCC patients. However, further research is clearly warranted based on intrinsic/acquired resistance to treatment and immune-related adverse events (irAEs) that have limited the number of patients receiving durable benefits from these cutting-edge interventions.

In this regard, it is essential that emerging approaches integrate a firm understanding of likely impact on the tumor microenvironment (TME), which includes components such as immune cells, stromal cells, vascular cells, extracellular matrix molecules, etc. This knowledge is essential to provide a foundational understanding of the molecular mechanisms (and thereby relevant biomarkers) underlying tumor progression based on the support of tumor growth, proliferation and metastasis. Biomarkers (at baseline and on-treatment) associated with patient response to immunotherapy are also expected to improve patient diagnoses and therapeutic management, while coordinately serving as monitoring tools to assess patient response to treatment in real-time. As an example, recent studies have investigated how immune-related genes (IRGs) may be used as biomarkers to establish a RCC patient's immune characteristics and therefore, to potentially improve early diagnosis.

Immunotherapy is arguably the most exciting field for the development of effective therapeutic approaches in the cancer setting. This Research Topic therefore aims to provide an open discussion focused on RCC immunobiology and the genesis of novel immunotherapies for the more effective treatment of RCC. Topics of interest include:

-Local (TME) and systemic anti-RCC impact of immune checkpoint inhibitors and alternate forms of immunotherapy
-irAEs associated with immunotherapeutic intervention in the setting of RCC
-Immune-related cells, genes and protein (biomarkers) in the RCC patients that are predictive of
patient prognosis and response to immunotherapy
-Combination immunotherapies demonstrating improved response rates and providing novel insights in immunologic mechanism(s) of action

Please note: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are considered as out of scope for this section and will not be considered for inclusion in this Research Topic.

Keywords: immunotherapy, renal cell carcinoma, metastatic, immune checkpoints, prognostic, clear cell renal cell carcinoma, inhibitors, tumor microenvironment

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