PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells

Wei, Xinru; Lai, Yunxin; Li, Jin; Qin, Le; Xu, Yi; Zhao, Ruocong; Li, Baiheng; Lin, Shudong; Wang, Suna; Wu, Qianni; Liang, Qiubin; Peng, Muyun; Yu, Fenglei; Li, Yangqiu; Zhang, Xuchao; Wu, Yi‐Long; Liu, Pentao; Pei, Duanqing; Yao, Yao; P, Li

doi:10.1080/2162402x.2017.1284722

Cited by 97 publications

(83 citation statements)

References 53 publications

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“…253,254 MUC1 and PSCA CAR-T cells showed independent and synergistic antitumor efficacy in a patient-derived xenograft model of NSCLC. 255 The First People's Hospital in Hefei, China is completing a Phase I/ II study of MUC1-CAR T cells for patients with MUC1+ advanced refractory NSCLC (NCT02587689). The same group is also completing a similar study using MUC1-CAR-pNK cells, placing the CAR construct in placental derived NK cells in advanced refractory NSCLC patients (NCT02839954).…”

Section: Ctla-4 Antibodymentioning

confidence: 99%

Making cold malignant pleural effusions hot: driving novel immunotherapies

et al. 2019

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Malignant pleural effusions, arising from either primary mesotheliomas or secondary malignancies, heralds advanced disease and poor prognosis. Current treatments, including therapeutic thoracentesis and tube thoracostomy, are largely palliative. The immunosuppressive environment within the pleural cavity includes myeloid derived suppressor cells, T-regulatory cells, and dysfunctional T cells. The advent of effective immunotherapy with checkpoint inhibitors and adoptive cell therapies for lung cancer and other malignancies suggests a renewed examination of local and systemic therapies for this malady. Prior strategies reporting remarkable success, including instillation of the cytokine interleukin-2, perhaps coupled with checkpoint inhibitors, should be further evaluated in the modern era.

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Section: Ctla-4 Antibodymentioning

confidence: 99%

Making cold malignant pleural effusions hot: driving novel immunotherapies

et al. 2019

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“…xenografts (PDX). We rst con rmed the anti-tumor activity of dPD1z T cells in a non-small cell lung cancer (NSCLC) PDX (P1) ( Figure S2A-B) [44]. Remarkably, tumors in the dPD1z T-cell group stopped growth after twice infusions of dPD1z T cells, whereas tumors in the CAR19z T-cell group grew robustly ( Figure 2C-D).…”

Section: Dpd1z T and Carpd-l1z T Cells Inhibited The Growth Of Multipmentioning

confidence: 82%

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

Qin

Zhao

Chen

et al. 2020

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Background: Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1. Methods: Here, we designed a dominant-negative form of PD-1 , dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain. Results: dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1 + tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells. Conclusions: In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.

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“…26 Eighteen days after tumor inoculation, we i.v infused 5 × 10 6 M28z or M28z10 T cells or an equivalent number of GFP T cells into these mice, and the CAR-T cell percentage was normalized with untransduced T cells. Tumor volume was measured every 3 days after infusion, and mice were sacrificed on day 38 (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively. T cells expressing M28z10 or G28z10 showed enhanced and prolonged effector function against MSLN+ lung cancer or GPC3+ hepatocellular carcinoma cell lines in culture and secreted elevated levels of cytokines, including IL-2, IFN-γ, granzyme B, and GM-CSF. In addition, M28z10 CAR-T cells showed greater anti-tumor activity than those expressing M28z in both A549 cell line xenografts and human lung cancer patient-derived xenografts (PDX). Similarly, G28z10 exhibited higher efficacy in causing tumor regression than did G28z in hepatocellular carcinoma PDX. Therefore, our results show that DAP10 signaling contributes to the function of CAR-T cells in both lung cancer and hepatocellular carcinoma and can enhance the efficacy of CAR-T cells.

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PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells

Cited by 97 publications

References 53 publications

Making cold malignant pleural effusions hot: driving novel immunotherapies

Making cold malignant pleural effusions hot: driving novel immunotherapies

Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

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