Antitumor responses in gastric cancer by targeting B7H3 via chimeric antigen receptor T cells

Sun, Feilong; Yu, Xiaomei; Ju, Ruixue; Wang, Zhanzhao; Wang, Yuhui

doi:10.1186/s12935-022-02471-8

Cited by 18 publications

(12 citation statements)

References 33 publications

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“…CAR T cells aimed at intercellular adhesion molecule 1 effectively inhibited disease progression ( 78 ). B7H3-specific CAR T cells with a humanized antigen recognition structural domain could effectively kill gastric cancer cells while targeting cancer stem cells to improve immune therapy efficacy, which was considered a potential strategy to treat gastric cancer ( 79 ). Optimized CAR T cells identify antigens specific to a patient’s particular gastric tumors, avoiding the killing of non-tumor cells caused by radiation and chemotherapy and providing more effective treatment for gastric cancer.…”

Section: Car T-cell Therapy For Digestive System Tumorsmentioning

confidence: 99%

Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers

et al. 2022

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Bile duct, pancreatic, and gastric cancers are deadly digestive system tumors with high malignancy and poor patient prognosis. The efficiencies of conventional surgical treatment, radiation therapy, and chemotherapy are limited. In contrast, chimeric antigen receptor (CAR) T-cell therapy represents a landmark therapeutic approach to antitumor immunity with great efficacy in treating several hematological malignancies. CAR T-cell therapy involves genetically engineering the expression of specific antibodies based on the patient’s T-cell surface and amplifying these antibodies to identify and target tumor-associated antigens. CAR T-cell therapy can effectively inhibit disease progression and improve the survival of patients with bile duct, pancreatic, and gastric cancers. The effectiveness of CAR T cells in tumor therapy can be validated using xenograft models, providing a scientific testing platform. In this study, we have reviewed the progress in CAR T-cell production and its development, focusing on the current status and optimization strategies for engineered CAR T cells in the bile duct, pancreatic, and gastric cancers.

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Section: Car T-cell Therapy For Digestive System Tumorsmentioning

confidence: 99%

Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers

et al. 2022

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“…Our results on successful use of CD276.V-CAR T in CD276 high RMS tumors are in line with the results obtained with other CAR constructs targeting CD276 in preclinical studies against several types of tumors: 276.8αHD/TM.28CSD.BBCSD.3ζ against glioblastoma (80); 276.MG.8αHD/TM.BBCSD.3ζ against medulloblastoma (70), neuroblastoma (70, 81), osteosarcoma (70), and Ewing sarcoma (70); 276.8H9S3.3.8α.28TM.BBCSD.3ζ against gastric cancer (82); and 276.8αHD.28TM.28CSD.3ζ and 276.8αHD/TM.BBCSD.3ζ against esophagus squamous cell carcinoma (83). All these CAR constructs generally allowed T cells to increase cytokine release in vitro , to prolong survival, and to persist in vivo .…”

Section: Discussionmentioning

confidence: 95%

CAR T cells recognizing CD276 and Dual-CAR T cells against CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models

Timpanaro,

Piccand,

Dzhumashev

et al. 2023

Preprint

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Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New treatments are urgently needed, especially systemic therapies. Chimeric Antigen Receptor T cells (CAR Ts) are very effective against hematological malignancies, but their efficacy against solid tumors needs to be improved. CD276 is a target upregulated in RMS and detected at low levels in normal tissues. FGFR4 is a very specific target for RMS. Here, we optimized CAR Ts for these two targets, alone or in combination, and tested their anti-tumor activity in vitro and in vivo. Methods: Four different single-domain antibodies were used to select the most specific FGFR4-CAR construct. RMS cell killing and cytokine production by CD276- and FGFR4-CAR Ts expressing CD8α or CD28 HD/TM domains in combination with 4-1BB and/or CD28 co-stimulatory domains were tested in vitro. The most effective CD276- and FGFR4-CAR Ts were used to generate Dual-CAR Ts. Tumor killing was evaluated in vivo in three orthotopic RMS mouse models. Results: CD276.V-CAR Ts (276.MG.CD28HD/TM.CD28CSD.3z) showed the strongest killing of RMS cells, and the highest release of IFN-γ and Granzyme B in vitro. FGFR4.V-CAR Ts (F8-FR4.CD28HD/TM.CD28CSD.3z) showed the most specific killing. CD276-CAR Ts successfully eradicated RD- and Rh4-derived RMS tumors in vivo, achieving complete remission in 3/5 and 5/5 mice, respectively. In CD276low JR-tumors, however, they achieved complete remission in only 1/5 mice. FGFR4 CAR Ts instead delayed of Rh4 tumor growth. Dual-CAR Ts promoted Rh4-tumors clearance in 5/5 mice. Conclusions: CD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killing in vitro and eradication of CD276high RMS tumors in vivo. CD276low tumors escaped the therapy showing a correlation of antigen density and effectiveness. FGFR4-CAR Ts showed specific killing in vitro but could only delay RMS growth in vivo. Our results show that combined expression of CD276-CAR with other CAR does not reduce its benefit. Introducing immunotherapy with CD276-CAR Ts in RMS seems to be feasible and promising, although CAR constructs design and target combinations have to be further improved to eradicate tumors with low target expression.

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“…Therefore, a detailed analysis of the tissue distribution of “halo cells” and their correlation with other key molecules in glioblastoma would be important and is now feasible. For instance, Sun et al [ 35 ] demonstrated a positive correlation between CD276 and stemness markers (CD133/PROM1, NGFR, TYH1, SOX2), and Johnston et al pointed out the correlation with immune modulators (i.e., IFNGR1, IFNGR2, TNFRSF1A and TNFSRF1B) and self-renewal genes, including VAX2, SOX21 and CITED1 [ 34 ]. CD276 has also been shown to be involved in the epithelial–mesenchymal transition [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

An Open-Source AI Framework for the Analysis of Single Cells in Whole-Slide Images with a Note on CD276 in Glioblastoma

Alzoubi

Bao

Zhang

et al. 2022

Cancers

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Routine examination of entire histological slides at cellular resolution poses a significant if not insurmountable challenge to human observers. However, high-resolution data such as the cellular distribution of proteins in tissues, e.g., those obtained following immunochemical staining, are highly desirable. Our present study extends the applicability of the PathoFusion framework to the cellular level. We illustrate our approach using the detection of CD276 immunoreactive cells in glioblastoma as an example. Following automatic identification by means of PathoFusion’s bifocal convolutional neural network (BCNN) model, individual cells are automatically profiled and counted. Only discriminable cells selected through data filtering and thresholding were segmented for cell-level analysis. Subsequently, we converted the detection signals into the corresponding heatmaps visualizing the distribution of the detected cells in entire whole-slide images of adjacent H&E-stained sections using the Discrete Wavelet Transform (DWT). Our results demonstrate that PathoFusion is capable of autonomously detecting and counting individual immunochemically labelled cells with a high prediction performance of 0.992 AUC and 97.7% accuracy. The data can be used for whole-slide cross-modality analyses, e.g., relationships between immunochemical signals and anaplastic histological features. PathoFusion has the potential to be applied to additional problems that seek to correlate heterogeneous data streams and to serve as a clinically applicable, weakly supervised system for histological image analyses in (neuro)pathology.

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Antitumor responses in gastric cancer by targeting B7H3 via chimeric antigen receptor T cells

Cited by 18 publications

References 33 publications

Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers

Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers

CAR T cells recognizing CD276 and Dual-CAR T cells against CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models

An Open-Source AI Framework for the Analysis of Single Cells in Whole-Slide Images with a Note on CD276 in Glioblastoma

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