Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models

Zhang, Qing; Zhang, Haixu; Ding, Jiage; Liu, Hongyan; Li, Huizhong; Li, Hailong; Lu, Mengmeng; Miao, Yangna; Li, Liantao; Zheng, Junnian

doi:10.1155/2018/4263520

Cited by 103 publications

(74 citation statements)

References 49 publications

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“…Synergistic effects of regorafenib and EpCAM CAR NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR NK-92 cells specifically recognized EpCAM-positive colorectal cancer cells, released cytokines including IFN-γ, perforin, and granzyme B, and showed cytotoxic activity in vitro (47). These results encouraged the launch of a clinical trial with CAR T cells recognizing EpCAM positive cells in CRC as well as hematological malignancies (NCT03013712).…”

Section: Car T Cells Targeting Crcmentioning

confidence: 94%

Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

2020

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The chimeric antigen receptor (CAR) is an artificial molecule engineered to induce cytolytic T cell reactions in tumors. Generally, this molecule combines an extracellular single-chain variable fragment (scFv) able to recognize tumor-associated epitopes together with the intracellular signaling domains that are required for T cell activation. When expressed by T cells, the CAR enables the recognition and subsequent destruction of cancer cells expressing the complementary antigen on their surface. Although the clinical application for CAR T cells is currently limited to some hematological malignancies, researchers are trying to develop CAR T cell-based therapies for the treatment of solid tumors. However, while in the case of CD19, or other targets restricted to the hematopoietic compartment, the toxicity is limited and manageable, the scarcity of specific antigens expressed by solid tumors and not by healthy cells from vital organs makes the clinical development of CAR T cells in this context particularly challenging. Here we summarize relevant research and clinical trials conducted to redirect CAR T cells to surface antigens in solid tumors and cancer stem cells with a focus on colorectal cancer and glioblastoma. Finally, we will discuss current knowledge of altered glycosylation of CSCs and cancer cells and how these novel epitopes may help to target CAR T cell-based immunotherapy in the future.

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Section: Car T Cells Targeting Crcmentioning

confidence: 94%

Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

2020

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“…Based on the results of CAR-T cell therapy in hematological malignancies, CAR-NK cell therapy has also shown efficacy in the treatment of solid tumors.NK-92 cells can be modified to express CAR protein against various cancer targets, including CD20 against lymphoma and leukemia, CD19 against chronic lymphocytic leukemia (CLL), and neuroblastoma GD2, and EpCAM for breast cancer [93] One study showed that EpCAM-specific CAR-NK-92 cells exhibited antitumor effects in vitro through cytotoxicity and release of cytokines, including IFN-γ, perforin, and granzyme B. The antitumor effects of CAR-NK-92 cells in a colorectal cancer (CRC) mouse model could be enhanced by combination with regorafenib [94].…”

Section: Nkg2d Receptor and Nkg2dl Are Critical Targets For Cancer Immentioning

confidence: 99%

Natural killer group 2D receptor and its ligands in cancer immune escape

et al. 2019

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The immune system plays important roles in tumor development. According to the immune-editing theory, immune escape is the key to tumor survival, and exploring the mechanisms of tumor immune escape can provide a new basis for the treatment of tumors. In this review, we describe the mechanisms of natural killer group 2D (NKG2D) receptor and NKG2D ligand (NKG2DL) in tumor immune responses. Natural killer (NK) cells are important cytotoxic cells in the immune system, and the activated NKG2D receptor on the NK cell surface can bind to NKG2DL expressed in tumor cells, enabling NK cells to activate and kill tumor cells. However, tumors can escape the immune clearance mediated by NKG2D receptor/NKG2DL through various mechanisms. The expression of NKG2D receptor on NK cells can be regulated by cells, molecules, and hypoxia in the tumor microenvironment. Tumor cells regulate the expression of NKG2DL at the level of transcription, translation, and post-translation and thereby escape recognition by NK cells. In particular, viruses and hormones have special mechanisms to affect the expression of NKG2D receptor and NKG2DL. Therefore, NKG2D\NKG2DL may have applications as targets for more effective antitumor therapy.

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“…This point is key to ensure the safety of these off the shelf approaches based on cell lines, as is the case for NK-92 derived cell products. Importantly, recent reports showed that CAR-expressing NK-92 cells can be used in combination with drugs like bortezomib [ 90 ] or regorafenib [ 91 ] or in combination with oncolytic virus [ 92 ] to improve responses in solid tumor models. These results led to several clinical trials using CAR-expressing NK-92 cells for patients with CD33 + AML (acute myeloid leukemia, Identifier: NCT02944162), CD19 + ( Identifier: NCT02892695) or CD7 + ( Identifier: NCT02742727) leukemia/lymphoma and Her2 + glioblastoma ( Identifier: NCT03383978).…”

Section: Alternatives To Primary T Cellsmentioning

confidence: 99%

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

Chicaybam

Bonamino

Invitti

et al. 2020

Cancers

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Gene therapy is now surpassing 30 years of clinical experience and in that time a variety of approaches has been applied for the treatment of a wide range of pathologies. While the promise of gene therapy was over-stated in the 1990’s, the following decades were met with polar extremes between demonstrable success and devastating setbacks. Currently, the field of gene therapy is enjoying the rewards of overcoming the hurdles that come with turning new ideas into safe and reliable treatments, including for cancer. Among these modalities, the modification of T cells with chimeric antigen receptors (CAR-T cells) has met with clear success and holds great promise for the future treatment of cancer. We detail a series of considerations for the improvement of the CAR-T cell approach, including the design of the CAR, routes of gene transfer, introduction of CARs in natural killer and other cell types, combining the CAR approach with checkpoint blockade or oncolytic viruses, improving pre-clinical models as well as means for reducing cost and, thus, making this technology more widely available. While CAR-T cells serve as a prime example of translating novel ideas into effective treatments, certainly the lessons learned will serve to accelerate the current and future development of gene therapy drugs.

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Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models

Cited by 103 publications

References 49 publications

Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

Natural killer group 2D receptor and its ligands in cancer immune escape

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

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