Immune evasion in renal cell carcinoma: biology, clinical translation, future directions

Abstract

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Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…The richness and activation of BM TMEs regarding cellular subtypes, frequencies, and functional states parallels their favorable clinical response to ICIs [42]. Checkpoint interactions, such as PD-1:PD-L1, CTLA4:B7-1/2, T-cell immunoglobulin and mucin domain-3 (TIM-3):Galectin-9, and lymphocyte activation gene-3 (LAG-3):MHC class II, play an important role in immune evasion of cancers [1]. Drug Administration (FDA) for mRCC include those that block co-inhibitory molecules, such as cytotoxic T-lymphocyte activating protein-4 (CTLA-4), PD-1, and PD-L1, thus facilitating T cell effector function and anti-tumor response [52,53].…”

“…Nivolumab, a human IgG4 monoclonal antibody (mAb) that blocks PD-1, has been approved as a second-line treatment after disease progression during TKI therapy [1,107,108]. Nivolumab demonstrated activity in patients with mRCC when used as a monotherapy in both phase I and phase II clinical trials [107,[109][110][111].…”

“…Improved anti-tumor immunity in the brain may also be mediated by combinations of antiangiogenic agents and ICIs [150,151]. Recently, the FDA approved two ICIs plus TKI combinations for mRCC: pembrolizumab plus axitinib and avelumab plus axitinib as firstline treatment in untreated intermediate and poor-risk subsets [1,16,53,126,133,150,152]. Both combinations were tested against the TKI sunitinib in large, randomized, multi-center trials and demonstrated improved median PFS with a 4-5-to month margin and superior overall ORR [1,122,126,152].…”

“…Recently, the FDA approved two ICIs plus TKI combinations for mRCC: pembrolizumab plus axitinib and avelumab plus axitinib as firstline treatment in untreated intermediate and poor-risk subsets [1,16,53,126,133,150,152]. Both combinations were tested against the TKI sunitinib in large, randomized, multi-center trials and demonstrated improved median PFS with a 4-5-to month margin and superior overall ORR [1,122,126,152]. Promising data from trials confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus lenvatinib as first-line treatment for mRCC [53,153].…”

“…Renal cell carcinomas (RCC) comprise a heterogeneous histologic subtype of malignant neoplasms arising from the nephron, and widely vary with respect to the underlying pathogenesis, genomic/molecular characteristics, and clinical treatment, including the susceptibility to conventional therapeutics [1][2][3][4][5][6][7][8]. Sequential events in the molecular etiopathogenesis of Von Hippel-Lindau (VHL)-inactivated metastatic RCC (mRCC) can be summarized as constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity, fostering global changes in the metabolome, genome, and epigenome in apoptotic, cell cycle regulatory, and mismatch repair pathways, angiogenesis, metabolic adaptations, and immune evasion [1][2][3][4][5]9,10].…”