Current Status of Immunotherapy for Localized and Locally Advanced Renal Cell Carcinoma

Abstract

Systemic therapy strategies in the setting of localized and locally advanced renal cell carcinoma (RCC) have continued to evolve in two directions: as adjuvant therapy (to reduce risk of recurrence or progression in high risk localized groups), or as neoadjuvant therapy as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. In the realm of adjuvant therapy, the results of phase III randomized clinical trials have been mixed and contradictory; nonetheless based on the findings of the landmark S-TRAC study, the tyrosine kinase inhibitor Sunitinib has been approved as an adjuvant agent in the United States. In the realm of neoadjuvant therapy, presurgical tumor reduction has been demonstrated in a number of phase II studies utilizing targeted molecular agents. The advent of immunomodulation through checkpoint inhibition as first line therapy for metastatic RCC represents an exciting horizon for adjuvant and neoadjuvant strategies. This article reviews the current status and future prospects of adjuvant and neoadjuvant immunotherapy in localized and locally advanced RCC.

Identification of an immune-related risk signature for predicting prognosis in clear cell renal cell carcinoma

“…However, many AGING RCC patients do not have targetable mutations. The emergence of immune checkpoint targets, such as programmed death-1 (PD-1) and programmed deathligand-1 (PD-L1) provides another therapeutic strategy for metastatic RCC [7], perhaps more compelling than targeted therapy agents [8], which emphasizes the importance of the tumor immune status on the outcome of RCC patients. Indeed, various components of the tumor immune microenvironment have been shown to be essential during cancer initiation and progression [9].…”

RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome

“…Moreover, the RUNX genes are themselves regulated by HIFs, raising the possibility that they are both downstream targets, and act to potentiate the oncogenic signal (43). Molecular characterisation of RCC subtypes revealed that increased immune cell infiltration gene expression signatures associated with the poorest performing patients specifically in ccRCC (4,44,45) and immune checkpoint inhibitors are currently in clinical trial for advanced disease (8,9). In this regard it is interesting that our study reveals a positive correlation between RUNX and local inflammatory cell infiltration.…”

“…Early stage non-metastatic RCC can be treated by partial or radical nephrectomy, however early stage disease is often asymptomatic resulting in patients more commonly presenting with advanced disease which has a much poorer prognosis (6). Standard of care for high risk, advanced metastatic or recurrent RCC involves targeted tyrosine kinase inhibitors (TKI) primarily against the VEGF and mTOR pathways, which have modest improvement over previous cytokine therapies (7,8). Recently, combinatorial use of TKI with immune checkpoint inhibitors against programmed cell death complex (PD1 and PDL1) have shown promising results in stage III clinical trials (9).…”

ATLAS trial of adjuvant axitinib in patients with renal cell carcinoma: subgroup analyses with focus on axitinib dosing and racial groups

“… 9 There are numerous ongoing/unreported adjuvant or neo-adjuvant trials in RCC involving single immuno-oncology agents or combinations, including atezolizumab, nivolumab alone and with ipilimumab, pembrolizumab, durvalumab and tremelimumab. 18 Final efficacy and safety data from these trials are not yet available. Sunitinib is currently the only agent for adjuvant treatment of RCC approved by the US Food and Drug Administration, 4 but has not been approved by any other regulatory authority.…”