Engineering T-Cell Specificity Genetically to Generate Anti-melanoma Reactivity

Weizman, Eviatar; Cohen, Cyrille J.

doi:10.1007/7651_2015_297

Cited by 3 publications

(3 citation statements)

References 17 publications

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“…For virus production, transfection of 2 × 10 6 293GP cells with 9 µg DNA of MSGV1-based retroviral construct and 4.5 µg envelop plasmid (VSV-G) was performed using JetPrime transfection reagent (Polyplus, France) ( 43 – 45 ). Retroviral supernatant was collected 36 h after the DNA transfection.…”

Section: Methodsmentioning

confidence: 99%

“…Freshly isolated human PBLs were stimulated for 48 h in the presence of 50 ng/ml OKT3 (eBioscience, San Diego, CA, USA) before transduction. Following stimulation, lymphocytes were transduced with retroviral vectors by transfer to non-treated tissue culture dishes (Nunc, Rochester, NY, USA) that had been precoated with RetroNectin (Takara, Japan) and retroviral vectors as previously described ( 43 ).…”

Section: Methodsmentioning

confidence: 99%

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Targeting Multiple Tumors Using T-Cells Engineered to Express a Natural Cytotoxicity Receptor 2-Based Chimeric Receptor

et al. 2017

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Recent developments in cancer treatment are demonstrating the increasing and powerful potential of immunotherapeutic strategies. In this regard, the adoptive transfer of tumor-specific T-lymphocytes approaches can lead to tumor regression in cancer patients. More recently, the use of T-cells genetically engineered to express cancer-specific receptors such as the anti-CD19 chimeric antigen receptor (CAR) continues to show promise for the treatment of hematological malignancies. Still, there is a crucial need to develop efficient CAR-T cell approaches for the treatment of solid tumors. It has been shown that other lymphocytes such as natural killer (NK) cells can demonstrate potent antitumor function—nonetheless, their use in immunotherapy is rather limited due to difficulties in expanding these cells to therapeutically relevant numbers and to suppression by endogenous inhibitory mechanisms. Cancer recognition by NK cells is partly mediated by molecules termed natural cytotoxicity receptors (NCRs). In the present study, we hypothesize that it is possible to endow T-cells with an NK recognition pattern, providing them with a mean to recognize tumor cells, in a non-MHC restricted way. To test this, we genetically modified human T-cells with different chimeric receptors based on the human NCR2 molecule and then assessed their antitumor activity in vitro and in vivo. Our results show that expression in primary lymphocytes of an NCR2-derived CAR, termed s4428z, confers T-cells with the ability to specifically recognize heterogeneous tumors and to mediate tumor cytotoxicity in a mouse model. This study demonstrates the benefit of combining tumor recognition capability of NK cells with T cell effectiveness to improve cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Targeting Multiple Tumors Using T-Cells Engineered to Express a Natural Cytotoxicity Receptor 2-Based Chimeric Receptor

et al. 2017

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“…The implementation of high-throughput technologies led to the identification of a large series of mutations, which appeared to be involved in the development, maintenance and progression of malignant melanoma (MM), but might also serve as suitable targets for T-cell-based immunotherapies, due to the creation of neo-antigens [1][2][3]. Despite that tumor-associated antigens (TAA) can be recognized by CD8+ cytotoxic T lymphocytes (CTL) in the context of HLA class I antigens, T-cell-based immunotherapies of melanoma might exhibit a lower efficacy than expected [4], and patients often develop resistances to these treatments [5].…”

Section: Introductionmentioning

confidence: 99%

Distinct Molecular Mechanisms of Altered HLA Class II Expression in Malignant Melanoma

Meyer

Handke

Müeller

et al. 2021

Cancers

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Background: The human leukocyte antigen (HLA) class II molecules are constitutively expressed in some melanoma, but the underlying molecular mechanisms have not yet been characterized. Methods: The expression of HLA class II antigen processing machinery (APM) components was determined in melanoma samples by qPCR, Western blot, flow cytometry and immunohistochemistry. Immunohistochemical and TCGA datasets were used for correlation of HLA class II expression to tumor grading, T-cell infiltration and patients’ survival. Results: The heterogeneous HLA class II expression in melanoma samples allowed us to characterize four distinct phenotypes. Phenotype I totally lacks constitutive HLA class II surface expression, which is inducible by interferon-gamma (IFN-γ); phenotype II expresses low basal surface HLA class II that is further upregulated by IFN-γ; phenotype III lacks constitutive and IFN-γ controlled HLA class II expression, but could be induced by epigenetic drugs; and in phenotype IV, lack of HLA class II expression is not recovered by any drug tested. High levels of HLA class II APM component expression were associated with an increased intra-tumoral CD4+ T-cell density and increased patients’ survival. Conclusions: The heterogeneous basal expression of HLA class II antigens and/or APM components in melanoma cells is caused by distinct molecular mechanisms and has clinical relevance.

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