BRAF and MEK Inhibition Variably Affect GD2-specific Chimeric Antigen Receptor (CAR) T-Cell Function In Vitro

2015 ◽  
Vol 38 (1) ◽  
pp. 12-23 ◽  
Author(s):  
Tessa Gargett ◽  
Cara K. Fraser ◽  
Gianpietro Dotti ◽  
Eric S. Yvon ◽  
Michael P. Brown
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Cell Function ◽  
Antigen Receptor ◽  
Mek Inhibition ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T

scholarly journals HIV-1-Specific Chimeric Antigen Receptor T Cells Fail To Recognize and Eliminate the Follicular Dendritic Cell HIV Reservoir In Vitro

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Matthew T. Ollerton ◽  
Edward A. Berger ◽  
Elizabeth Connick ◽  
Gregory F. Burton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Follicular Dendritic

ABSTRACT The major obstacle to a cure for HIV infection is the persistence of replication-competent viral reservoirs during antiretroviral therapy. HIV-specific chimeric antigen receptor (CAR) T cells have been developed to target latently infected CD4+ T cells that express virus either spontaneously or after intentional latency reversal. Whether HIV-specific CAR-T cells can recognize and eliminate the follicular dendritic cell (FDC) reservoir of HIV-bound immune complexes (ICs) is unknown. We created HIV-specific CAR-T cells using human peripheral blood mononuclear cells (PBMCs) and a CAR construct that enables the expression of CD4 (domains 1 and 2) and the carbohydrate recognition domain of mannose binding lectin (MBL) to target native HIV Env (CD4-MBL CAR). We assessed CAR-T cell cytotoxicity using a carboxyfluorescein succinimidyl ester (CFSE) release assay and evaluated CAR-T cell activation through interferon gamma (IFN-γ) production and CD107a membrane accumulation by flow cytometry. CD4-MBL CAR-T cells displayed potent lytic and functional responses to Env-expressing cell lines and HIV-infected CD4+ T cells but were ineffective at targeting FDC bearing HIV-ICs. CD4-MBL CAR-T cells were unresponsive to cell-free HIV or concentrated, immobilized HIV-ICs in cell-free experiments. Blocking intercellular adhesion molecule-1 (ICAM-1) inhibited the cytolytic response of CD4-MBL CAR-T cells to Env-expressing cell lines and HIV-infected CD4+ T cells, suggesting that factors such as adhesion molecules are necessary for the stabilization of the CAR-Env interaction to elicit a cytotoxic response. Thus, CD4-MBL CAR-T cells are unable to eliminate the FDC-associated HIV reservoir, and alternative strategies to eradicate this reservoir must be sought. IMPORTANCE Efforts to cure HIV infection have focused primarily on the elimination of latently infected CD4+ T cells. Few studies have addressed the unique reservoir of infectious HIV that exists on follicular dendritic cells (FDCs), persists in vivo during antiretroviral therapy, and likely contributes to viral rebound upon cessation of antiretroviral therapy. We assessed the efficacy of a novel HIV-specific chimeric antigen receptor (CAR) T cell to target both HIV-infected CD4+ T cells and the FDC reservoir in vitro. Although CAR-T cells eliminated CD4+ T cells that express HIV, they did not respond to or eliminate FDC bound to HIV. These findings reveal a fundamental limitation to CAR-T cell therapy to eradicate HIV.

Novel media formulations to enhance Chimeric Antigen Receptor (CAR) T-cell potency and anti-tumor cell function for adoptive immunotherapy

Cytotherapy ◽  
2020 ◽  
Vol 22 (5) ◽  
pp. S133
Author(s):  
S. Ghassemi ◽  
F. Martinez-Becerra ◽  
A. Master ◽  
S.A. Richman ◽  
D. Heo ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cell ◽  
Chimeric Antigen Receptor ◽  
Adoptive Immunotherapy ◽  
Cell Function ◽  
Antigen Receptor ◽  
Car T Cell ◽  
Car T

scholarly journals Galunisertib enhances chimeric antigen receptor-modified T cell function

2020 ◽  
Author(s):  
Zhixiong Wang ◽  
Qian Liu ◽  
Na Risu ◽  
Jiayu Fu ◽  
Yan Zou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Cell Function ◽  
Antigen Receptor ◽  
Target Cells ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T cell therapy still faces the challenge of immunosuppression when treating solid tumors. TGF-β is one of the critical factors in the tumor microenvironment to help tumors escape surveillance by the immune system. Here we tried using the combination of a small molecule inhibitor of TGF-β receptor I, Galunisertib, and CAR T cells to explore whether Galunisertib could enhance CAR T cell function against solid tumor cells. In vitro experiments showed Galunisertib could significantly enhance the specific cytotoxicity of both CD133- and HER2-specific CAR T cells. However, Galunisertib had no direct killing effect on target cells. Galunisertib significantly increased the cytokine secretion of CAR T cells and T cells that do not express CAR (Nontransfected T cells). Galunisertib did not affect the proliferation of T cells, the antigen expression on target cells and CD69 on CAR T cells. We found that TGF-β was secreted by T cells themselves upon activation, and Galunisertib could reduce TGF-β signaling in CAR T cells. Our findings can provide the basis for further preclinical and clinical studies of the combination of Galunisertib and CAR T cells in the treatment of solid tumors.

scholarly journals Photoswitchable CAR-T Cell Function In Vitro and In Vivo via a Cleavable Mediator

2020 ◽  
Author(s):  
Bo Zhang ◽  
Yan Wang ◽  
Shenlong Huang ◽  
Jiaqi Sun ◽  
Min Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T

Abstract A037: A novel pharmacologic “ON/OFF” switch to modulate CAR-T-cell function in vitro and in vivo

2019 ◽  
Author(s):  
Katrin Mestermann ◽  
Rydzek Julian ◽  
Frenz Silke ◽  
Einsele Hermann ◽  
Michael Hudecek
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T

scholarly journals Go-Rex: A Novel in Vitro System for the Assessment of CAR T Cell Function

2016 ◽  
Vol 22 (3) ◽  
pp. S425
Author(s):  
Pradip Bajgain ◽  
Usanarat Anurathapan ◽  
Ayumi Watanabe ◽  
John Wilson ◽  
Sujita Sukumaran ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
In Vitro System ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T

Chimeric antigen receptor T cells immunotherapy: challenges and opportunities in hematological malignancies

Immunotherapy ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1341-1357
Author(s):  
Nashwa El-Khazragy ◽  
Sherief Ghozy ◽  
Passant Emad ◽  
Mariam Mourad ◽  
Diaaeldeen Razza ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Hematological Malignancies ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Challenges And Opportunities

Taking advantage of the cellular immune system is the mainstay of the adoptive cell therapy, to induce recognition and destruction of cancer cells. The impressive demonstration of this principle is chimeric antigen receptor-modified T (CAR-T)-cell therapy, which had a major impact on treating relapsed and refractory hematological malignancies. Despite the great results of the CAR-T-cell therapy, many tumors are still able to avoid immune detection and further elimination, as well as the possible associated adverse events. Herein, we highlighted the recent advances in CAR-T-cell therapy, discussing their applications beneficial functions and side effects in hematological malignancies, illustrating the underlying challenges and opportunities. Furthermore, we provide an overview to overcome different obstacles using potential manufacture and treatment strategies.

scholarly journals Cancer stem cell-targeted chimeric antigen receptor (CAR)-T cell therapy: Challenges and prospects

2020 ◽  
Author(s):  
Javad Masoumi ◽  
Abdollah Jafarzadeh ◽  
Jalal Abdolalizadeh ◽  
Haroon Khan ◽  
Jeandet Philippe ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Stem Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions

2021 ◽  
Vol 7 (2) ◽  
pp. 156
Author(s):  
Will Garner ◽  
Palash Samanta ◽  
Ghady Haidar
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Fungal Infections ◽  
Antigen Receptor ◽  
Invasive Fungal Infections ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

Studies describing invasive fungal infections (IFIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. Although post-CAR-T-cell IFIs appear to be uncommon, they are associated with significant morbidity and mortality. Specific risk factors for IFIs in CAR-T-cell recipients have not been fully characterized and are often extrapolated from variables contributing to IFIs in patients with other hematologic malignancies or those undergoing hematopoietic cell transplant. Optimal prophylaxis strategies, including the use of yeast versus mold-active azoles, also remain ill-defined. Further research should investigate key risk factors for IFIs and establish an evidence-based approach to antifungal prophylaxis in these patients in order to improve clinical outcomes.

scholarly journals Augmenting anti-CD19 and anti-CD22 CAR T-cell function using PD-1-CD28 checkpoint fusion proteins

2021 ◽  
Vol 11 (6) ◽  
Author(s):  
Franziska Blaeschke ◽  
Dana Stenger ◽  
Antonia Apfelbeck ◽  
Bruno L. Cadilha ◽  
Mohamed-Reda Benmebarek ◽  
...  
Keyword(s):  
T Cell ◽  
Fusion Proteins ◽  
Cell Function ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T
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