Construction of PD1/CD28 Fusion Receptor Enhances Anti-Tumor Ability of c-Met CAR-T in Gastric Cancer

2020 ◽  
Author(s):  
Cong Chen ◽  
Yan-mei Gu ◽  
Zheng-chao Zhang ◽  
Ya-ting Zhang ◽  
Yi-di He ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Car T ◽  
Fusion Receptor

scholarly journals Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer

2021 ◽  
Vol 10 (1) ◽  
pp. 1901434
Author(s):  
Cong Chen ◽  
Yan-Mei Gu ◽  
Fan Zhang ◽  
Zheng-Chao Zhang ◽  
Ya-Ting Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Car T

scholarly journals EGLIF-CAR-T Cells Secreting PD-1 Blocking Antibodies Significantly Mediate the Elimination of Gastric Cancer

2020 ◽  
Vol Volume 12 ◽  
pp. 8893-8902
Author(s):  
Jing-Tao Zhou ◽  
Jiang-Hao Liu ◽  
Ting-Ting Song ◽  
Bo Ma ◽  
Nuermaimait Amidula ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Car T Cells ◽  
Car T ◽  
Blocking Antibodies

scholarly journals Human Hyaluronidase PH20 Potentiates the Antitumor Activities of Mesothelin-Specific CAR-T Cells Against Gastric Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruocong Zhao ◽  
Yuanbin Cui ◽  
Yongfang Zheng ◽  
Shanglin Li ◽  
Jiang Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Cell Infiltration ◽  
Car T Cells ◽  
Car T Cell ◽  
T Cell Infiltration ◽  
Car T

T cell infiltration into tumors is essential for successful immunotherapy against solid tumors. Herein, we found that the expression of hyaluronic acid synthases (HAS) was negatively correlated with patient survival in multiple types of solid tumors including gastric cancer. HA impeded in vitro anti-tumor activities of anti-mesothelin (MSLN) chimeric antigen receptor T cells (CAR-T cells) against gastric cancer cells by restricting CAR-T cell mobility in vitro. We then constructed a secreted form of the human hyaluronidase PH20 (termed sPH20-IgG2) by replacing the PH20 signal peptide with a tPA signal peptide and attached with IgG2 Fc fragments. We found that overexpression of sPH20-IgG2 promoted CAR-T cell transmigration through an HA-containing matrix but did not affect the cytotoxicity or cytokine secretion of the CAR-T cells. In BGC823 and MKN28 gastric cancer cell xenografts, sPH20-IgG2 promoted anti-mesothelin CAR-T cell infiltration into tumors. Furthermore, mice infused with sPH20-IgG2 overexpressing anti-MSLN CAR-T cells had smaller tumors than mice injected with anti-MSLN CAR-T cells. Thus, we demonstrated that sPH20-IgG2 can enhance the antitumor activity of CAR-T cells against solid tumors by promoting CAR-T cell infiltration.

scholarly journals Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo

2017 ◽  
Vol 9 (10) ◽  
pp. 867-878 ◽  
Author(s):  
Yanjing Song ◽  
Chuan Tong ◽  
Yao Wang ◽  
Yunhe Gao ◽  
Hanren Dai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Car T Cells ◽  
Car T

scholarly journals Folate receptor 1 (FOLR1) targeted chimeric antigen receptor (CAR) T cells for the treatment of gastric cancer

PLoS ONE ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. e0198347 ◽  
Author(s):  
Minsung Kim ◽  
Suhkneung Pyo ◽  
Chung Hyo Kang ◽  
Chong Ock Lee ◽  
Heung Kyoung Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Folate Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T

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

2020 ◽  
Vol 9 (6) ◽  
pp. 1894
Author(s):  
Dominika Bębnowska ◽  
Ewelina Grywalska ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Barbara Sosnowska-Pasiarska ◽  
Jolanta Smok-Kalwat ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Folate Receptor ◽  
Growth Factor Receptor ◽  
Genetically Engineered ◽  
Mucin 1 ◽  
Anion Exchanger 1 ◽  
T Cell Therapy ◽  
Neuropilin 1 ◽  
Car T

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.

scholarly journals Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor

2020 ◽  
Vol 8 (2) ◽  
pp. e000756
Author(s):  
Boning Zhang ◽  
John Victor Napoleon ◽  
Xin Liu ◽  
Qian Luo ◽  
Madduri Srinivasarao ◽  
...  
Keyword(s):  
T Cell ◽  
Ligand Binding ◽  
Folate Receptor ◽  
Cell Activity ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Car T Cell ◽  
Car T ◽  
Fusion Receptor

BackgroundMost adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.MethodsWe describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface. Because the ligand-binding domain is designed to bind a ligand not normally present in humans, any drug conjugated to this ligand will bind and endocytose selectively into the ACT.ResultsIn two embodiments of our strategy, we fuse the chronically endocytosing domain of human folate receptor alpha to either a murine scFv that binds fluorescein or human FK506 binding protein that binds FK506, thereby creating a fusion receptor composed of largely human components. We then create the ligand-targeted drug by conjugating any desired drug to either fluorescein or FK506, thereby generating a ligand-drug conjugate with ~10-9 M affinity for its fusion receptor. Using these tools, we demonstrate that CAR T cell activities can be sensitively tuned down or turned off in vitro as well as tightly controlled following their reinfusion into tumor-bearing mice.ConclusionsWe suggest this ‘chimeric endocytosing receptor’ can be exploited to manipulate not only CAR T cells but other ACTs following their reinfusion into patients. With efforts to develop ACTs to treat diseases including diabetes, heart failure, osteoarthritis, cancer and sickle cell anemia accelerating, we argue an ability to manipulate ACT activities postinfusion will be important.

scholarly journals c-Met-Specific Chimeric Antigen Receptor T Cells Demonstrate Anti-Tumor Effect in c-Met Positive Gastric Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5738
Author(s):  
Chung Hyo Kang ◽  
Yeongrin Kim ◽  
Da Yeon Lee ◽  
Sang Un Choi ◽  
Heung Kyoung Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Jurkat Cells ◽  
Car T Cells ◽  
Car T

Chimeric antigen receptor (CAR) technology has been highlighted in recent years as a new therapeutic approach for cancer treatment. Although the impressive efficacy of CAR-based T cell adoptive immunotherapy has been observed in hematologic cancers, limited effect has been reported on solid tumors. Approximately 20% of gastric cancer (GC) patients exhibit a high expression of c-Met. We have generated an anti c-Met CAR construct that is composed of a single-chain variable fragment (scFv) of c-Met antibody and signaling domains consisting of CD28 and CD3ζ. To test the CAR construct, we used two cell lines: the Jurkat and KHYG-1 cell lines. These are convenient cell lines, compared to primary T cells, to culture and to test CAR constructs. We transduced CAR constructs into Jurkat cells by electroporation. c-Met CAR Jurkat cells secreted interleukin-2 (IL-2) only when incubated with c-Met positive GC cells. To confirm the lytic function of CAR, the CAR construct was transduced into KHYG-1, a NK/T cell line, using lentiviral particles. c-Met CAR KHYG-1 showed cytotoxic effect on c-Met positive GC cells, while c-Met negative GC cell lines were not eradicated by c-Met CAR KHYG-1. Based on these data, we created c-Met CAR T cells from primary T cells, which showed high IL-2 and IFN-γ secretion when incubated with the c-Met positive cancer cell line. In an in vivo xenograft assay with NSG bearing MKN-45, a c-Met positive GC cell line, c-Met CAR T cells effectively inhibited the tumor growth of MKN-45. Our results show that the c-Met CAR T cell therapy can be effective on GC.

Sign in / Sign up

Export Citation Format

Share Document