The use of immune checkpoint inhibitors (ICIs) has become the most important achievement in oncology in the last decade. From a more holistic viewpoint, it is a powerful clinical strategy.

Cancer cells are transformed from normal cells, and through altering the tumor immune milieu, the balance between transformed cells and immunity is gradually disrupted. The immune system is cancer's primary defensive strategy, and immunotherapy aims to use the immune system to regulate the balance between malignant cells and the immune system. ICI therapies ( target the immune system to elicit T-cell anti-tumor responses in order to combat immunosuppressive diseases.

CTLA-4 (cytotoxic T lymphocyte-associated molecule-4), PD-1 (programmed cell death receptor 1:, and PD-1 ligand-1 (programmed cell death ligand-1, PD-L1) are the most well-studied immune checkpoints. ICIs that target CTLA-4 and PD-1/PD-L1 have become the standard for cancer immunotherapy management. Ipilimumab, nivolumab, pembrolizumab, and atezolizumab are only a few of the ICIs that have been developed to target CTLA-4, PD-1, and PD-L1. These ICIs are being utilized to treat roughly 50 different forms of cancer as single treatments or in combination with other chemotherapeutic agents.

Although immunotherapy has revolutionized the treatment of multiple advanced cancers, the overall state of its clinical use remains unsatisfactory, with only a small percentage of patients showing meaningful responses to these treatments. Challenges to improving the efficacy of ICI include low response rates, primary or acquired drug resistance, and immune-related adverse events.

Improving clinical outcomes requires figuring out how to boost response rates and overcome resistance to different ICI classes. Despite this, ICI therapy is still a viable cancer therapeutic option.

Discover new territories
A recent review published in the Journal of Hematology & Oncology provides a comprehensive analysis of phase I and phase II clinical trials applying new investigational molecules and ICI pathways within the last 3 years.

Marin-Acevedo and colleagues evaluated raw results from ongoing and completed studies from 2018 to 2020 in their review. Phase III and post-phase III clinical trials, immunostimulants, cellular immunotherapies, vaccines, viruses, studies involving pediatrics, and CTLA-4, PD-1, and/or PD-L1 were all excluded from the study. The review looked at 36 phase I, 9 phase I/II, and 7 phase II clinical trials in total. Based on whether the pathway manipulation had a direct or indirect influence on T-cell effects, the molecules evaluated in those trials were categorized into suppressive immune checkpoints and suppressive targets other than immune checkpoints.

Immune checkpoint targets that have been explored include:
* Lymphocyte activation gene-3 (LAG-3, CD223): A molecule expressed by activated T cells, B cells, natural killer (NK) cells, and dendritic (DC) cells, which interacts with the class II major histocompatibility complex (MHC).
* T cell immunoglobulin-3 (TIM-3): An immune checkpoint that promotes immune tolerance that is expressed by a variety of cells including effector T cells, regulatory T cells (Tregs), B cells, NK cells, DCs, macrophages, and neoplastic cells.
* B7-H3 and B7-H4: Members of the B7 ligand superfamily, which interact with the CD28 receptor family to regulate stimulatory or inhibitory immune signaling.
* PVRIG/PVRL2: Poliovirus receptor-associated immunoglobulin structural domain containing protein (PVRIG), a novel protein and a member of the immunoglobulin receptor superfamily.

Suppressive targets under investigation include:
* CEACAM1, CEACAM5, CEACAM6: Carcinoembryonic antigen-associated cell adhesion molecules (CEACAMs) are a family of proteins that promote different physiological effects, including immune regulation, tissue formation, and angiogenesis.
* CCL2/CCR2: The chemokine CCL2 and its major receptor CCR2 play a role in cancer development, including the recruitment of immunosuppressive cells that promote angiogenesis, tumor growth, proliferation, and metastasis.
* Leukemia inhibitory factor (LIF): An essential peptide in embryo formation that promotes an immunosuppressive microenvironment and protects the embryo from the mother's immune system.
* CD47/SIRPα: Almost all normal tissues express CD47 (, a biomarker of self-recognition, which triggers anti-phagocytic signals once binding to the signal-regulated protein alpha (SIRPα), a transmembrane protein located on the surface of macrophages.

There is significant promise for the development of ICI regimes and new combination regimens or optimization of existing regimens, which are predicted to revolutionize tumor immunotherapy once again, with multiple therapeutic options currently in clinical and preclinical development.

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