Revolutionizing Kidney Cancer with Immunotherapy

Avishek Roy

Scientific Liaison Manager
4baseCare

Kidney cancer is the third urological and sixth most diagnosed cancer in men and eight in women. The prognosis of kidney cancer is poor because 30% of patients are metastatic at diagnosis and almost 30% of the remaining will develop metastases during the follow-ups. There are two main types of kidney cancer including renal cell carcinoma (RCC) and renal pelvis carcinoma. RCC is the most prevalent accounting for 90 % of all kidney cancers. RCC arises from the proximal renal tubular epithelium and involves several different cell types, such as clear cells, granular cells, and spindle cells. The most common subtypes are clear cell (cc) RCC, accounting for 70–75% of RCC and it is characterized by dysregulation of the von Hippel Lindau/hypoxia-inducible factor pathway (VHL/HIF pathway). Metastatic or advance RCC (mRCC) is resistant to conventional therapies such as chemotherapy, radiotherapy and surgery.

The development of systemic therapy for RCC to date can be divided into 4 phases: cytokine, cytokine, molecularly targeted (2005-2014) and ICIs era (2015 to now). Interleukin‑2 (IL‑2) is a standard-of-care treatment for young healthy patients with kidney cancer. The 5-year overall survival rate with RCC was found to improve after the approval of cytokine therapy and first tyrosine kinase inhibitor (TKI). During the TKI and ICIs era, the mortality rate decreased by 9% and by 7%, respectively. Overall, the mortality rate has decreased by 17% since 1992.

Precision Oncology in RCC
In the era of precision oncology, single-cell technologies like RNA sequencing can be used to study the intra-tumor heterogeneity of RCC and helps to characterization of cell population of kidney cancer which led to the development of personalized or precision medicines of an individual patient and reduce the adverse events.

Role of CGP and NGS in RCC
Introduction of molecular profiling approaches such as The Cancer Genome Atlas (TCGA), TRAcking Cancer Evolution through therapy (TRACERx), next generation sequencing (NGS) and genome-wide association studies (GWAS) improve understanding of the RCC biology and molecular markers of RCC, especially advance or metastasis RCC. It marked a new milestone in improving patient outcomes by identifying predisposing genetic variants, uncovered tumor heterogeneous characterization and help in a better understanding of the molecular mechanisms involved in RCC to turn the treatment towards precision medicines. RCC patients do not always respond to conventional therapy and develop therapeutic resistance which causes mortality. Study of comprehensive genome profile (CGP) has led to the development of more effective therapies such as immune checkpoint inhibitors (ICIs) for the treatment of such kidney cancer.

Revolutionizing kidney cancer treatment with immunotherapy
In kidney cancer, tumors can exploit immune-inhibitory signals (immune checkpoints) to evade the immune system which has led to the development of novel immunotherapeutic agents. Advancement in immunotherapy revolutionized the treatment of kidney cancer with ICIs and improved the overall prognosis of patients.

Immune checkpoints inhibitors (ICIs)
In the era of precision oncology, the discovery of ICIs, cytokines and molecularly targeted therapies including vascular endothelial growth factor–directed agents (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have become the latest addition to the RCC. The advent of ICIs such as anti-cytotoxic T-lymphocyte antigen-4 (CTLA4) and anti-programmed death 1 (PD-1) with its ligands alone or in combination with antiangiogenics (VEGF pathway inhibitors) can be used to treat the resistant cases of RCC via targeting CTLA-4 and PD-1 pathways. Single use of nivolumab or combined with ipilimumab or VEGFR TKIs are now established as part of the standard of care for metastasis or advanced RCC. Nivolumab produced improved overall survival (OS) and fewer serious adverse events than everolimus. ICIs can inhibit T-cell responses and can mediate measurable tumour shrinkage in kidney cancer. The FDA approved nivolumab as second line and its combination with ipilimumab (in 2018) as first line treatment for RCC. Nivolumab also approved by the FDA for treating mRCC patients for whom previous therapy has failed. Other ICIs, including the anti-PD-1 pembrolizumab and the anti-programmed death-ligand 1 (anit-PD-L1) atezolizumab are still under development. ICIs can also be used with cancer vaccine.

Important molecular markers of RCC
The most common predictive and prognostic molecular markers of kidney cancer include mutations and epigenetic inactivation of von Hippel-Lindau (VHL) gene, Vascular Endothelial Growth Factor (VEGF) and Carbonic anhydrase IX (CIAX). These molecular markers help in the characterization of tumor type, its progression and treat metastasis in RCC. The inactivation of VHL gene protein product results in aberrant stabilization of hypoxia-inducible factor (HIF), which drives the transcription of numerous genes involved in tumor formation. PBRM1, SETD2, BAP1, and KDM5C genes are located near the VHL gene indicating their roles in oncogenesis of ccRCC of kidney cancer. BAP1 and SETD2 mutations are associated with worse outcomes while PBRM1 with angiogenic gene expression. TC PD-L1 is used as a predictive biomarker for mccRCC. These molecular markers may helpful for the development of personalized treatment with novel therapeutic agnets.