Monotherapy or combination therapy with immune checkpoint inhibitors: comparing additive effects and differential mechanisms in antitumor response

Abstract

Cancer is a public health issue in Brazil and worldwide, with estimates of 18 million new cases emerging globally in 2018 and over 600,000 new cases in Brazil in 2020. The mortality related to the disease is alarming, with 9.6 million cancer-related deaths in 2018. Immune system cells, particularly CD8 T lymphocytes, play a crucial role in defending against tumors. However, mechanisms of immune evasion, such as decreased expression of class I MHC on tumor cells and the action of immune checkpoints like CTLA-4 and PD-1, hinder the effectiveness of the immune response. CTLA-4 inhibits lymphocyte activation, while PD-1, upon interacting with its ligands, limits the function of lymphocytes, favoring tumor survival. Checkpoint blockade immunotherapy, with drugs such as Ipilimumab (anti-CTLA-4) and Nivolumab (anti-PD-1), has shown promising results, increasing survival and response in cancer patients. The combination of these therapies shows better outcomes than monotherapy, demonstrating greater efficacy and activation of effector T cells. However, there are concerns about adverse effects and the understanding of the underlying molecular mechanisms. Combined therapy induces a distinct gene expression profile and immune response, suggesting synergistic actions. Despite encouraging results, the need for further research to fully comprehend this synergy and optimize therapy remains evident, aiming to improve clinical application and treatment standards for cancer.