Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Abstract

Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

Treatment of Refractory Metastatic Renal Cell Carcinoma

“…Non-clear cell renal cell carcinoma (nccRCC) represents a heterogenous group of malignancies, making up 25% of all renal cell carcinoma cases [ 55 ]. Management of refractory metastatic nccRCC is a challenge given the variety in histology amongst these malignancies, with limited prospective data to guide treatment decisions in the refractory setting.…”

The Dilemma of HSV-1 Oncolytic Virus Delivery: The Method Choice and Hurdles

“…However, its therapeutic efficacy in most cold tumors and PD-L1-negative solid tumors remains limited. Therefore, alternative therapeutic strategies are urgently required [ 141 ]. HSV-1 oncolytic virus, as an excellent gene vector, can not only effectively lyse tumor cells but also improve the TME by carrying various cytokines, which bodes well for tumor immunotherapy.…”

PANK1 associates with cancer metabolism and immune infiltration in clear cell renal cell carcinoma: a retrospective prognostic study based on the TCGA database

“…In the present study, we found that PANK1 knockdown regulated mitochondrial bioenergetics and redox status, which is a critical mechanism underlying PANK1-mediated effects on ccRCC. Tumor-associated immune cells and immune checkpoint inhibition play important roles in the carcinogenesis and treatment of ccRCC (41). PANK1 has been shown to be correlated with the infiltration status of several types of immune cells.…”