4-1BB Targeting Immunotherapy: Mechanism, Antibodies, and Chimeric Antigen Receptor T

Shen, Xiu-Da; Zhang, Rusong; Yang, Yanhua; Hua, Yingqi; Lü, Peng

doi:10.1089/cbr.2023.0022

Cited by 4 publications

(3 citation statements)

References 105 publications

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“…Additionally, incorporating 4-1BB as a costimulatory domain in chimeric antigen receptor T (CAR-T) cells enhances T cell proliferation and survival while mitigating T cell exhaustion ( Pichler et al, 2023 ). With ligand binding by 4-1BB, the nuclear factor-kappa B signaling pathway is activated, which results in transcription of corresponding genes such as interleukin-2 and interferon-γ, as well as the induction of T cell proliferation and antiapoptotic signals ( Shen et al, 2023 ). GTP controls the function of Rac1, a guanine nucleotide-binding protein, leading to the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5).…”

Section: Discussionmentioning

confidence: 99%

Identification of an inflammatory response-related gene prognostic signature and immune microenvironment for cervical cancer

Wu,

Zhuang,

Liang

et al. 2024

Front. Mol. Biosci.

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Background: Cervical cancer (CC) is the fourth most common cancer among women worldwide. As part of the brisk cross-talk between the host and the tumor, prognosis can be affected through inflammatory responses or the tumor microenvironment. However, further exploration of the inflammatory response-related genes that have prognostic value, microenvironment infiltration, and chemotherapeutic therapies in CC is needed.Methods: The clinical data and mRNA expression profiles of CC patients were downloaded from a public database for this study. In the TCGA cohort, a multigene prognostic signature was constructed by least absolute shrinkage and selection operator (LASSO) and Cox analyses. CC patients from the GEO cohort were used for validation. K‒M analysis was used to compare overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors of OS. The immune cell infiltration and immune-related functional score were calculated by single-sample gene set enrichment analysis (GSEA). Immunohistochemistry was utilized to validate the protein expression of prognostic genes in CC tissues.Results: A genetic signature model associated with the inflammatory response was built by LASSO Cox regression analysis. Patients in the high-risk group had a significantly lower OS rate. The predictive ability of the prognostic genes was evaluated by means of receiver operating characteristic (ROC) curve analysis. The risk score was confirmed to be an independent predictor of OS by univariate and multivariate Cox analyses. The immune status differed between the high-risk and low-risk groups, and the cancer-related pathways were enriched in the high-risk group according to functional analysis. The risk score was significantly related to tumor stage and immune infiltration type. The expression levels of five prognostic genes (LCK, GCH1, TNFRSF9, ITGA5, and SLC7A1) were positively related to sensitivity to antitumor drugs. Additionally, the expression of prognostic genes was significantly different between CC tissues and myoma patient cervix (non-tumorous) tissues in the separate sample cohort.Conclusion: A model consisting of 5 inflammation-related genes can be used to predict prognosis and influence immune status in CC patients. Furthermore, the inhibition or enhancement of these genes may become a novel alternative therapy.

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Section: Discussionmentioning

confidence: 99%

Identification of an inflammatory response-related gene prognostic signature and immune microenvironment for cervical cancer

Wu,

Zhuang,

Liang

et al. 2024

Front. Mol. Biosci.

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“…The MSLN CAR construct is a fully human second-generation vector, including the following components in-frame from the 5' end to the 3' end: anti-MSLN single-chain variable fragment (scFv), the hinge and transmembrane domain of the CD8α molecule, 4-1BB co-stimulatory domain ( 17 ), and the CD3 zeta intracellular signaling domain ( Figure 1A ). The CD19 CAR was prepared as the control group, and had the same structure, except for anti-CD19 scFv.…”

Section: Methodsmentioning

confidence: 99%

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice

Zhou,

Yang,

et al. 2024

J Gastrointest Oncol

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Background Liver metastasis is the major cause of colorectal cancer related death. Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T-cell therapy has been illustrated effective and safe through regional delivery of breast cancer, ovarian cancer and malignant mesothelioma tumors. Herein, we investigated the safety, efficacy, and immune microenvironment of regional delivery of MSLN (CAR) T-cell in the treatment of colorectal carcinoma liver metastases (CRLM). Methods Second-generation MSLN CAR T-cells were administered by portal vein (PV) or caudal vein (CV, systemic administration) delivery in an orthotopic MSLN + CRLM nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/γc −/− (NSG) mouse model. A total of 20 mice were randomly divided into control group, non-transduced T cell (NT)-CV group, NT-PV group, MSLN CAR T-cell CV (MSLN-CV) group, and MSLN CAR T-cell PV (MSLN-PV) group, with each group containing four mice to examine the safety and efficacy. The bioluminescence intensity (BLI) of tumor burden, tumor tissue macroscopic and microscopic observation were used to evaluate treatment efficacy. The safety was examined by body weight, survival time, and vital organ damage of mice. CAR T-cell infiltration and cytokine concentration were analyzed by flow cytometry, and immunostaining. The change of immune microenvironment between regional delivery and systemic delivery was investigated on an immune reconstructed CRLM patient-derived xenograft (PDX) model. Additionally, T cell subsets and immunosuppressive markers were examined. Results PV administration of 1×10 7 /100 μL MSLN CAR T-cells in 20 NSG mice was well tolerated, and no overt toxicity was observed. The tumor burden in the PV group was obviously alleviated. The BLI was (0.73±0.52)×10 9 in PV group and (1.97±0.11)×10 9 in CV group (P<0.05), CD8 + granzyme B (GB) + T cell percentage (MSLN-CV 4.42%±0.47% vs. MSLN-PV 13.5%±4.67%, P<0.01) and cytokine concentration were obviously increased in the MSLN-PV group. In the immune reconstituted CRLM PDX model, intratumor (IT) delivery of MSLN CAR T-cells exhibited much more infiltration of CD4 + and CD8 + T cells accompanied with elevated expression levels of PD-1, LAG-3, and TIM-3. Conclusions Regional delivery of MSLN-targeted CAR T-cell therapy has encouraging results in the orthotopic CRLM NSG mouse model and PDX model, and converts the tumor microenvironment from cold to hot. This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

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“…DAP10, a major adaptor protein and the exclusive signaling intermediate of NKG2D in human NK cells, is known to enhance the cytotoxic ability of CAR-NK cells against certain tumor cells [22]. DAP12, an important adaptor molecule that is associated with multiple activating receptors, is also utilized in CAR-NK cells to improve their anti-tumor potential [22,23].…”

Section: Intracellular Signaling Domainsmentioning

confidence: 99%

CAR-NK Cell Therapy: A Transformative Approach to Overcoming Oncological Challenges

Li,

Wang,

Zhang

et al. 2024

Preprint

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The use of chimeric antigen receptor (CAR) in natural killer (NK) cells for cancer therapy is gaining momentum, marking a significant shift in cancer treatment. This review aims to explore the potential of CAR-NK cell therapy in cancer immunotherapy, providing a fresh perspective. It discusses the innovative approaches in CAR-NK cell design and engineering, particularly targeting refractory or recurrent cancers. By comparing CAR-NK cells with traditional therapies, the review highlights their unique ability to tackle tumor heterogeneity and immune system suppression. Additionally, it explains how novel cytokines and receptors can enhance CAR-NK cell efficacy, specificity, and functionality. The review underscores the advantages of CAR-NK cells, including reduced toxicity, lower cost, and broader accessibility compared to CAR-T cells, along with their potential in treating both blood cancers and solid tumors.

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4-1BB Targeting Immunotherapy: Mechanism, Antibodies, and Chimeric Antigen Receptor T

Cited by 4 publications

References 105 publications

Identification of an inflammatory response-related gene prognostic signature and immune microenvironment for cervical cancer

Identification of an inflammatory response-related gene prognostic signature and immune microenvironment for cervical cancer

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice

CAR-NK Cell Therapy: A Transformative Approach to Overcoming Oncological Challenges

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