CD27 enhances the killing effect of CAR T cells targeting trophoblast cell surface antigen 2 in the treatment of solid tumors

Chen, Huanpeng; Wei, Fengjiao; Yin, Meng; Zhao, Qingyu; Z, Liu; Yu, Bolan; Huang, Zhaofeng

doi:10.1007/s00262-020-02838-8

Cited by 37 publications

(28 citation statements)

References 50 publications

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“…Trop-2 on tumor cells promotes their proliferation and is related to poor prognosis and short overall survival. CD27-based Trop-2 CAR-T cells presented a potent cytotoxic activity, expressed higher levels of IL7-Rα, lower PD-1, and produced more proinflammatory cytokines compared to the CAR-T build of the other tested domains [ 201 ]. Moreover, targeting Trop-2 is a promising approach, as the molecule is expressed on many cancer types including TNBC, while in healthy human cells it can be detected only on trophoblast, prostate stem cells, and liver oval cells.…”

Section: Strategies To Overcome Immunotherapy Resistance Of Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.

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Section: Strategies To Overcome Immunotherapy Resistance Of Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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“…Trop-2 has already been tested as a target for precise medicine. Currently, chimeric antigen receptor (CAR) T cell therapy is tested in solid tumors using in vivo models with promising results [ 20 ]. Moreover, the antibody drug conjugate (ADC) Sacituzumab Govitecan-hziy, which contains a humanized anti-Trop-2 monoclonal antibody and the topoisomerase I inhibitor drug SN-38 [ 21 , 22 ], was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) [ 23 ] based on the results of the randomized phase III ASCENT study.…”

Section: Introductionmentioning

confidence: 99%

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

Erber

Spoerl

Mamilos

et al. 2021

IJMS

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Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed.

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“…S3). In addition, CAR T cells targeting Trop2 failed to eliminate tumours in previous studies of gastric cancer (Zhao et al, 2019) and triple-negative breast cancer (Chen et al, 2021), which was probably related to the a nity of scFv for the CAR structure. Our 2F11-scFv bound to Trop2 with high a nity (Kd=0.17 nM), which can be one of the reasons for the thorough tumour clearance.…”

Section: Discussionmentioning

confidence: 91%

“…As reported, knockdown or knockout of Trop2 on the cell surface signi cantly inhibits the proliferation of tumour cells(Zhang et al, 2018). Since Trop2 is indispensable in the proliferation and migration of tumour cells, it may be a potential and attractive target for epithelial carcinomas(Cubas et al, 2009), and Trop2-speci c chimeric antigen T cells may offer a new therapeutic approach for pancreatic cancer.Despite the e cacy of Trop2 CAR T cells in gastric cancer(Zhao et al, 2019) and triple-negative breast cancer(Chen et al, 2021) in vitro and in vivo, the e cacy in pancreatic cancer has not been reported thus far. Herein, we employed the human scFv phage library to isolate a human single-chain fragment variable that speci cally recognizes EMD of Trop2.…”

mentioning

confidence: 99%

CAR T Cells Equipped With a Fully Human scFv Targeting Trop2 Can Be Used to Treat Pancreatic Cancer

Zhu

Jia

Tan

et al. 2021

Preprint

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Purpose: Chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical success in treating haematologic malignancies but has not been effective against solid tumours thus far. Trop2 is a tumour-related antigen broadly overexpressed on a variety of tumours and has been reported as a promising target for pancreatic cancers. Our study aimed to determine whether CAR T cells designed with a fully human Trop2-specific single-chain fragment variable (scFv) can be used in the treatment of Trop2-positive pancreatic tumours.Methods: We designed Trop2-targeted chimeric antigen receptor engineered T cells with a novel human anti-Trop2 scFv (2F11) and then investigated the cytotoxicity, degranulation, and cytokine secretion profiles of the anti-Trop2 CAR T cells when they were exposed to Trop2+ cancer cells in vitro. We also studied the antitumour efficacy and toxicity of Trop2-specific CAR T cells in vivo using a BxPC-3 pancreatic xenograft model.Results: Trop2-targeted CAR T cells designed with 2F11 effectively killed Trop2-positive pancreatic cancer cells and produced high levels of cytotoxic cytokines in vitro. In addition, Trop2-targeted CAR T cells, which persistently circulate in vivo and efficiently infiltrate into tumour tissues, significantly blocked and even eliminated BxPC-3 pancreatic xenograft tumour growth without obvious deleterious effects observed after intravenous injection into NSG mice. Moreover, disease-free survival was efficiently prolonged.Conclusion: These results show that Trop2-targeted CAR T cells equipped with a fully human anti-Trop2 scFv could be a potential treatment strategy for pancreatic cancer and could be useful for clinical evaluation.

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CD27 enhances the killing effect of CAR T cells targeting trophoblast cell surface antigen 2 in the treatment of solid tumors

Cited by 37 publications

References 50 publications

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

CAR T Cells Equipped With a Fully Human scFv Targeting Trop2 Can Be Used to Treat Pancreatic Cancer

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