International Journal of Clinical Case Reports 2024, Vol.14, No.4, 189-201 http://medscipublisher.com/index.php/ijccr 194 4.1 Mechanisms of major immune checkpoints (PD-1, PD-L1, CTLA-4) Immune checkpoints act as critical regulators of the immune response, preventing excessive immune activation. Tumors hijack these pathways to avoid immune destruction, which makes them valuable therapeutic targets. The PD-1 (programmed death-1) receptor is an inhibitory checkpoint found on activated T cells. When PD-1 binds to its ligands, PD-L1 or PD-L2, the T cells become functionally exhausted, limiting their ability to attack cancer cells. Tumors often overexpress PD-L1 to evade immune detection. By blocking PD-1 or PD-L1, ICB therapies re-engage T cells and restore their ability to fight tumors (Rappold et al., 2021). CTLA-4 (cytotoxic T-lymphocyte antigen 4) is another inhibitory checkpoint found on T cells. It competes with CD28, a stimulatory molecule, for binding to B7 molecules on antigen-presenting cells. When CTLA-4 binds B7, it inhibits T-cell activation. Blocking CTLA-4 enhances T-cell activation, amplifying the immune response against tumors. This mechanism is crucial in early immune responses and has been targeted in renal cell carcinoma to boost anti-tumor immunity (Flippot et al., 2018). 4.2 Approved immune checkpoint inhibitors and their clinical trial results Several immune checkpoint inhibitors have been approved for mRCC, showing significant improvements in overall survival and progression-free survival compared to traditional therapies. Nivolumab, a PD-1 inhibitor, was one of the first immune checkpoint inhibitors to show efficacy in renal cell carcinoma. The CheckMate 025 trial demonstrated that nivolumab improved overall survival compared to everolimus in patients with previously treated mRCC (Flippot et al., 2018). This marked a pivotal shift in the management of advanced renal cell carcinoma. Pembrolizumab, another PD-1 inhibitor, has also shown success in combination with the tyrosine kinase inhibitor (TKI) axitinib. The KEYNOTE-426 trial demonstrated that this combination significantly improved both progression-free survival and overall survival in treatment-naive patients with advanced RCC (Bedke et al., 2020). Additionally, the combination of ipilimumab, an anti-CTLA-4 antibody, and nivolumab has proven to be particularly effective in intermediate- and poor-risk patients, as shown in the CheckMate 214 trial. This combination has resulted in significant improvements in overall survival and objective response rates, making it a first-line treatment for certain RCC patients (Flippot et al., 2018). 4.3 Combination therapy strategies: with targeted therapy, radiotherapy, and chemotherapy Combining immune checkpoint blockade with other therapeutic modalities has emerged as a strategy to enhance treatment efficacy. The combination of ICB with tyrosine kinase inhibitors (TKIs) has shown particularly promising results. The CheckMate 9ER trial demonstrated that nivolumab combined with cabozantinib significantly improved progression-free survival and overall survival compared to sunitinib monotherapy in patients with advanced RCC (Massari et al., 2021). These combinations leverage the anti-angiogenic effects of TKIs, which help modulate the tumor microenvironment, making it more susceptible to immune attack (Martínez-Sabadell et al., 2022). Radiotherapy is another modality being explored in combination with immune checkpoint inhibitors. Radiotherapy can induce immunogenic cell death, releasing tumor antigens that enhance the immune response. Clinical trials are ongoing to determine the synergistic effects of radiotherapy with ICB in RCC, though early results suggest potential benefits in enhancing anti-tumor immunity (Bedke et al., 2020). Chemotherapy, traditionally thought to suppress immune responses, has also been shown to synergize with ICB in certain contexts. Preclinical studies have demonstrated that chemotherapy can sensitize tumors to immune checkpoint blockade by enhancing antigen presentation and reducing the immunosuppressive tumor microenvironment. For example, combining 5-fluorouracil (5-FU) with anti-PD-L1 antibodies increased survival and tumor infiltration of cytotoxic T cells in RCC mouse models (Figure 1) (Cui et al., 2017).
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