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

Abstract

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

The Role of Microglia in Brain Metastases: Mechanisms and Strategies

“…Therefore, it is important to study the small molecular inhibitors with intracranial permeability, the specific role of cellular components and their interactions in brain microenvironment. In addition, the combination of systemic therapy and stereotactic radiosurgery, or that of targeted therapy (anti-proliferating, pro-apoptotic, anti-angiogenic inhibitors) and ICIs, or dual ICIs (targeting different immune checkpoints) are potential strategies to treat brain metastases [ 3 , 113 , 114 , 159 , 160 ].…”

Therapeutic options for different metastatic sites arising from renal cell carcinoma: A review

“…The selection of an optimal treatment strategy necessitates a thorough evaluation of multiple factors, including the potential long-term toxicity, projected patient survival, and the presence of competing risks. [123][124][125] Currently, the consensus within the BRM-RCC therapeutic landscape favors neurosurgery or stereotactic radiosurgery (SRS) as the gold standard for single or oligometastases. [120,126] SRS, in particular, has been recognized for its capacity to effectively manage cerebral manifestations of BRM-RCC, achieving diseases control in most cases with fewer complications, thereby enhancing the quality of survival, especially when brain metastases are identified early.…”