Nivolumab and Ipilimumab Acting as Tormentors of Advanced Tumors by Unleashing Immune Cells and Associated Collateral Damage

Abstract

Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and CTLA4, play a pivotal role in modulating immune responses. Blocking these checkpoints unleashes anticancer activity, and the synergy observed when combining multiple checkpoint inhibitors underscores their potential for enhanced efficacy. Nivolumab and ipilimumab harness the host's immune system to target cancer cells, presenting a powerful approach to prevent tumor development. Despite their efficacy, immune checkpoint inhibitors are accompanied by a distinct set of adverse effects, particularly immune-related adverse effects affecting various organs. Understanding these challenges is crucial for optimizing treatment strategies and ensuring patient well-being. Ongoing clinical trials are actively exploring the combination of checkpoint inhibitory therapies, aiming to decipher their synergistic effects and efficacy against diverse cancer types. This review discusses the mechanisms, adverse effects, and various clinical trials involving nivolumab and ipilimumab across different cancers, emphasizing their transformative impact on cancer treatment.

Keywords: CTLA-4; PDL-1; advanced melanoma; immune subtypes; ipilimumab; molecular pathways; nivolumab; potentially malignant tumors; translational genomics.

Figure 1

This figure illustrates the mechanisms and clinical implications of ipilimumab and nivolumab in cancer therapy. Ipilimumab inhibits CTLA-4, enhancing T cell activation, while nivolumab blocks PD-1/PD-L1 interaction, enabling activated T cells to target tumor cells. Combination therapy improves PFS and OS, enhancing T cell activation, IFN-γ cytotoxic activity, and NK cell activation, despite potential irAEs and toxicities.

Figure 2

Signaling pathways inhibited by ipilimumab and nivolumab. Ipilimumab inhibits the CTLA-4 receptor on T cells, preventing its interaction with CD80/CD86 on antigen-presenting cells (APCs). Additionally, it disrupts the association between CTLA-4 and the LCK protein kinase, impacting downstream signaling events crucial for T cell activation. The interference with RTK activation domain phosphorylation and disruption of associations with CD3ζ, CD3e, and CD274 further contribute to its influence on T cell activation. Moreover, ipilimumab inhibits the association of CTLA-4 with PTPN11, a tyrosine protein phosphatase involved in key cellular processes. Nivolumab operates on multiple fronts to counteract immune evasion mechanisms in cancer. Interleukin-gamma (IFN-gamma) typically induces the expression of programmed death ligand 1 (PD-L1) on the surface of tumor cells, allowing them to evade immune surveillance. Nivolumab inhibits this immune escape strategy by blocking the PD-1 receptor on T cells, preventing its interaction with PD-L1 and PD-L2 on tumor cells. The inhibition of PD-1 signaling enhances NK cell cytotoxicity and promotes their antitumor functions. Additionally, nivolumab’s ability to boost T cell responses contributes to an environment less conducive to the suppressive effects of MDSCs. This blockade not only disrupts the communication between cancer cells and immune cells but also inhibits the activation of immune checkpoint pathways, boosting T cell activity against cancer cells. While not directly targeting the indoleamine 2,3-dioxygenase (IDO) enzyme, known for its role in immune tolerance, nivolumab indirectly impacts it by enhancing T cell responses, contributing to a comprehensive strategy to unleash the immune system against cancer.

Figure 3

Reasons for side effects associated with nivolumab and ipilimumab combination therapy.