Preclinical Evaluation of Chimeric Antigen Receptor–Modified T Cells Specific to Epithelial Cell Adhesion Molecule for Treating Colorectal Cancer

Zhang, Binglan; Li, Dan; Gong, Youling; Huang, Yong; Qin, Diyuan; Jiang, Lin; Liang, Xiao; Yang, Xiao; Gou, Hongfeng; Wang, Yongsheng; Wei, Yuquan; Wang, Wei

doi:10.1089/hum.2018.229

Cited by 72 publications

(51 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As TICs/CSCs with unlimited selfrenewal capacity and differentiation potential have been broadly considered to be source to tumor recurrence, metastasis, and therapeutic resistance, it is reasonable to hypothesize that a durable antitumor e cacy would be achieved if speci cally targeting TIC/CSCs by immunotherapeutic modalities, including CAR T-cell therapy. In fact, CAR T cells targeting several biomarkers of TICs/CSCs, including CD133, CD24, Receptor tyrosine kinase-like orphan receptor 1 (ROR1) or the epithelial cell adhesion molecule (EpCAM) have been developed and exhibited the excellent antitumor effects in preclinical models [34][35][36][37][38][39][40]; more importantly, CD133-targeting CAR T cells alone or in combination have demonstrated antitumor activity in treating patients with CD133-postive metastasis malignancies with controllable toxicities in clinical trials [41,42]. Intriguingly, both PTK7 and ROR1 belong to Wnt ligand binding receptors with important roles in the non-canonical Wnt signaling [10].…”

Section: Discussionmentioning

confidence: 99%

PTK7-Targeting CAR T-cells for the Treatment of Lung Cancer and other Malignancies

Jie

Liu

Feng

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. Methods: In this study, we constructed 3 different PTK7-specific CAR (PTK7-CAR1/2/3) each comprising a humanized PTK7-specific single chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus mediated transduction of human activated T cells accordingly, and sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo.Results: T cells transduced with all 3 PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression level of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Conclusion: Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.

show abstract

Section: Discussionmentioning

confidence: 99%

PTK7-Targeting CAR T-cells for the Treatment of Lung Cancer and other Malignancies

Jie

Liu

Feng

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…EpCAM proved to be a suitable target for CARs in a xenograft mouse model. The EpCAM CAR T-cell delayed tumor growth and displayed an excellent safety profile [118]. Deng et al [119] showed that NKG2D CAR T-cells exhibit specific cytotoxicity in human CRC cell lines.…”

Section: Car T-cell Therapy Studies For Crcmentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

Sur

Havași

Căinap

et al. 2020

JCM

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T-cell therapy represents a new genetically engineered method of immunotherapy for cancer. The patient’s T-cells are modified to express a specific receptor that sticks to the tumor antigen. This modified cell is then reintroduced into the patient’s body to fight the resilient cancer cells. After exhibiting positive results in hematological malignancies, this therapy is being proposed for solid tumors like colorectal cancer. The clinical data of CAR T-cell therapy in colorectal cancer is rather scarce. In this review, we summarize the current state of knowledge, challenges, and future perspectives of CAR T-cell therapy in colorectal cancer. A total of 22 articles were included in this review. Eligible studies were selected and reviewed by two researchers from 49 articles found on Pubmed, Web of Science, and clinicaltrials.gov. This therapy, at the moment, provides modest benefits in solid tumors. Not taking into consideration the high manufacturing and retail prices, there are still limitations like increased toxicities, relapses, and unfavorable tumor microenvironment for CAR T-cell therapy in colorectal cancer.

show abstract

“…EpCAM plays an important role in cell signaling, differentiation, migration, and proliferation and, therefore, plays a key role in tumorigenesis and metastasis [ 38 , 39 , 40 , 41 ]. EpCAM is an excellent target for various therapeutic methods, including immunotherapy, because it is expressed uniformly on the whole surface of neoplastic cells [ 41 , 42 ]. The overexpression of EpCAM is associated with a poor prognosis in patients with multiple tumors, and its level can be used as a marker for circulating neoplastic cells (CTC) involved in metastasis [ 42 ].…”

Section: Targets For Car-t Cell Therapymentioning

confidence: 99%

“…EpCAM is an excellent target for various therapeutic methods, including immunotherapy, because it is expressed uniformly on the whole surface of neoplastic cells [ 41 , 42 ]. The overexpression of EpCAM is associated with a poor prognosis in patients with multiple tumors, and its level can be used as a marker for circulating neoplastic cells (CTC) involved in metastasis [ 42 ]. EpCAM is overexpressed in >90% of gastric tumors, and consequently, its use as a therapeutic target is encouraging [ 38 , 43 ].…”

Section: Targets For Car-t Cell Therapymentioning

confidence: 99%

CAR-T Cell Therapy—An Overview of Targets in Gastric Cancer

Bębnowska

Grywalska

Niedźwiedzka-Rystwej

et al. 2020

JCM

View full text Add to dashboard Cite

Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.

show abstract

Preclinical Evaluation of Chimeric Antigen Receptor–Modified T Cells Specific to Epithelial Cell Adhesion Molecule for Treating Colorectal Cancer

Cited by 72 publications

References 40 publications

PTK7-Targeting CAR T-cells for the Treatment of Lung Cancer and other Malignancies

PTK7-Targeting CAR T-cells for the Treatment of Lung Cancer and other Malignancies

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

CAR-T Cell Therapy—An Overview of Targets in Gastric Cancer

Contact Info

Product

Resources

About