Blockade of <scp>PD</scp>‐1 and <scp>CTLA</scp>‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

Hou, Kai; Xu, Xiaohui; Ge, Xin; Jiang, Jiacen; Ouyang, Fan

doi:10.1002/biof.2012

Cited by 3 publications

(3 citation statements)

References 150 publications

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“…The field started considering antibody‐mediated immunotherapies more seriously for solid tumor cancer treatments after the success of checkpoint inhibitor monoclonal antibodies in the clinics against PD‐1, CTLA‐4, and PD‐L1 (ligand of PD‐1). 126 , 127 , 128 , 129 Approaches for targeting intracellular oncoproteins and mutated oncodrivers have been restricted to the development of novel small molecule inhibitors. 130 Some of them are like different EGFR inhibitors.…”

Section: Therapeutic Antibodies In the Clinics And Future Perspectivesmentioning

confidence: 99%

B cell responses and antibody‐based therapeutic perspectives in human cancers

Mandal,

Pradhan

2024

Cancer Reports

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BackgroundImmuno‐oncology has been focused on T cell‐centric approaches until the field recently started appreciating the importance of tumor‐reactive antibody production by tumor‐infiltrating plasma B cells, and the necessity of developing novel therapeutic antibodies for the treatment of different cancers.Recent FindingsB lymphocytes often infiltrate solid tumors and the extent of B cell infiltration normally correlates with stronger T cell responses while generating humoral responses against malignant progression by producing tumor antigens‐reactive antibodies that bind and coat the tumor cells and promote cytotoxic effector mechanisms, reiterating the fact that the adaptive immune system works by coordinated humoral and cellular immune responses. Isotypes, magnitude, and the effector functions of antibodies produced by the B cells within the tumor environment differ among cancer types. Interestingly, apart from binding with specific tumor antigens, antibodies produced by tumor‐infiltrating B cells could bind to some non‐specific receptors, peculiarly expressed by cancer cells. Antibody‐based immunotherapies have revolutionized the modalities of cancer treatment across the world but are still limited against hematological malignancies and a few types of solid tumor cancers with a restricted number of targets, which necessitates the expansion of the field to have newer effective targeted antibody therapeutics.ConclusionHere, we discuss about recent understanding of the protective spontaneous antitumor humoral responses in human cancers, with an emphasis on the advancement and future perspectives of antibody‐based immunotherapies in cancer.

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Section: Therapeutic Antibodies In the Clinics And Future Perspectivesmentioning

confidence: 99%

B cell responses and antibody‐based therapeutic perspectives in human cancers

Mandal,

Pradhan

2024

Cancer Reports

View full text Add to dashboard Cite

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“…It is primarily found on the surface of B lymphocytes, as well as activated CD8+ and CD4+ T lymphocytes. CTLA-4 is involved in regulating T-cell apoptosis, controlling cytokine expression, and suppressing T-cell proliferation, leading to an immunosuppressive effect [ 120 ]. Therefore, molecules capable of targeting PD-1 (Nivolumab and Pembrolizumab), PD-L1 (Atezolizumab, Durvalumab), and CTLA-4 (Nivolumab, Ipilimumab, Tremelimumab-actl), known as immune checkpoint inhibitors, stimulate the immune response against tumor cells [ 119 ].…”

Section: Tumoral Microenvironmentmentioning

confidence: 99%

“…M1 macrophages, activated by lipopolysaccharides or interferon-gamma (IFN-γ), secrete IL-2, which plays a role in the proliferation of effector T lymphocytes, and produce reactive oxygen species and nitric oxide, with tumoricidal roles. However, M2 macrophages, activated by IL4, IL-10, and IL-13, secrete TGF-β, IL-10, and chemokine (C-C motif) ligand (CCL) family members (CCL17, CCL18, CCL22, CCL24), with immunosuppressive effects [ 120 ].…”

Section: Tumoral Microenvironmentmentioning

confidence: 99%

Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments—An Overview

Szilveszter,

Muntean,

Florea

2024

Biomolecules

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Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial–mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages—predominantly with a pro-tumoral role—hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines.

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Discovery of Pyridine-2-Carboxamides Derivatives as Potent and Selective HPK1 Inhibitors for the Treatment of Cancer

Peng,

Ding,

Chen

et al. 2024

J. Med. Chem.

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Hematopoietic progenitor kinase 1 (HPK1) has emerged as an attractive target for immunotherapy due to its critical role in T cell activation and proliferation. The major challenge in developing HPK1 inhibitors lies in balancing kinase selectivity, pharmacokinetic (PK) properties, and therapeutic efficacy. In this study, we report a series of pyridine-2-carboxamide analogues demonstrating strong HPK1 inhibitory activity in enzymatic and cellular assays, along with good kinase selectivity. Among these analogues, compound 19 showed good in vitro HPK1 inhibitory activity, excellent kinase selectivity (>637-fold vs GCK-like kinase and >1022-fold vs LCK), and robust in vivo efficacy in the CT26 (tumor growth inhibition (TGI) = 94.3%, 2/6 CRs) and MC38 murine colorectal cancer models (TGI = 83.3%, 1/6 complete response) when administered in combination with anti-PD-1. Compound 19 also demonstrated adequate in vitro ADME and in vivo PK properties, displaying good oral bioavailability across multiple species (F % = 35−63). These findings summarize our compound's favorable safety and efficacy profiles, justifying its testing in future translational studies.

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Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

Cited by 3 publications

References 150 publications

B cell responses and antibody‐based therapeutic perspectives in human cancers

B cell responses and antibody‐based therapeutic perspectives in human cancers

Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments—An Overview

Discovery of Pyridine-2-Carboxamides Derivatives as Potent and Selective HPK1 Inhibitors for the Treatment of Cancer

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