Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas–FasL-Dependent AICD

Künkele, Annette; Johnson, Adam; Rolczynski, Lisa S.; Chang, Cindy A.; Hoglund, Virginia; Kelly-Spratt, Karen S.; Jensen, Michael C.

doi:10.1158/2326-6066.cir-14-0200

Cited by 151 publications

(182 citation statements)

References 39 publications

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“…The main manifestation of viral myocarditis during the first 7 days of viral infection is myocardial infiltration by NK cells and macrophages. Though they are meant to control the early stages of viral infection, infiltrating NK cells release perforin, which damages myocardial cells Lutz et al, 2014;Hsiao et al, 2015;Künkele et al, 2015;Peng et al, 2015). Between 7 and 14 days after the initial onset of the viral infection, most of the infiltrated cells are T-cells, which become CTLs when activated, and are programmed to kill target cells (Chen et al, 2014;Grygorczuk et al, 2015;Shi et al, 2015;Tao et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis

Huang

Wang

et al. 2016

Genet. Mol. Res.

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Section: Discussionmentioning

confidence: 99%

Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis

Huang

Wang

et al. 2016

Genet. Mol. Res.

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“…[28][29][30][31][32] The AICD that CAR T cells exhibited in our experiments was likely There was a total of ten mice in each group except the SP6-CD828Z group, which had five mice. The graphs show the mean tumor size ± SEM for each time point.…”

Section: E) T Cells From Six Different Donors Expressing Eithermentioning

confidence: 92%

“…6,27 The hinge and transmembrane regions of a CAR can potentially be important to the function of T cells expressing the CAR. [27][28][29][30] Activation-induced cell death (AICD) is a process by which T cell activation leads to apoptosis of T cells. [28][29][30][31][32] To investigate how CAR hinge and transmembrane components affect the biology of anti-CD19 CAR T cells, we have conducted experiments with CARs containing hinge and transmembrane regions from either the human CD28 molecule or the human CD8a molecule.…”

Section: Introductionmentioning

confidence: 99%

Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains

et al. 2017

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Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19 target cells and carried out functions including degranulation, cytokine release, and proliferation. We compared CARs with CD28 costimulatory moieties along with hinge and transmembrane domains from either the human CD28 molecule or the human CD8α molecule. Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8α hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8α or CD28 had similar abilities to eliminate established tumors in mice. In anti-CD19 CARs with CD28 costimulatory moieties, lower levels of inflammatory cytokine production and AICD are potential clinical advantages of CD8α hinge and transmembrane domains over CD28 hinge and transmembrane domains.

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“…In support of this, constitutive proliferating CAR T cells showed inferior antitumor effect (18). In addition, repetitive signaling rendered CAR T cells susceptible to activation -induced cell death (AICD) (19).…”

Section: Discussionmentioning

confidence: 99%

Costimulation with anti-cluster of differentiation 3 and anti-cluster of differentiation 28 reduces the activity of mucin 1-stimulated human mononuclear cells

et al. 2015

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Abstract. Cytotoxic T-lymphocyte activation and extension of the cell life span is necessary in order to enable immunotherapy to perform effectively against cancer. In the present study, mucin 1 (MUC1)-stimulated human mononuclear cells (M1SHMCs) were costimulated with bead-attached monoclonal antibodies specific for cluster of differentiation (CD)3 and CD28 receptors. The study was undertaken to determine whether costimulation was capable of enhancing the killing of cancer cells in vitro and of protecting non-obese diabetic severe combined immunodeficient mice from tumor development. Lysis of MCF-7 tumor cells by M1SHMCs was reduced following costimulation with anti-CD3 and anti-CD28. Furthermore, costimulation with anti-CD3 and anti-CD28 eliminated the protective effects of M1SHMCs on MCF-7 breast cancer cell growth in the non-obese diabetic severe combined immunodeficient mice. The present study suggested that costimulation with anti-CD3 and anti-CD28 is not advisable following antigen activation of lymphocytes under the conditions used here. Using a lower anti-CD3/CD28 bead to T-cell ratio may prevent immune suppression, however, further studies are required to support this hypothesis. IntroductionCytotoxic T-lymphocyte (CTL) activation and extension of the cell life span are necessary in order to enable immunotherapy to perform effectively against cancer cells (1). CTLs are activated via the T-cell receptor (TCR; signal one) (2), which induces the proliferation of CTLs. Engagement of a second receptor, cluster of differentiation 28 (CD28; signal two), by ligands on antigen-presenting cells, is required to prevent anergy and the apoptosis of CTLs (3). This results in extension of the CTL lifespan. CTLs may be activated via the CD3 receptor [a component of the TCR (2)] and the CD28 receptor using monoclonal antibodies specific for their respective receptors (4). In order to obtain an adequate number of CTLs for the effective performance of immunotherapy, costimulation with anti-CD3 and anti-CD28 has been utilized (5). Costimulated lymphocytes cells have been demonstrated to exhibit logarithmic growth and inhibit apoptosis via enhanced cytotoxicity for the targeting of tumor cells (6). The present study aimed to determine whether the mucin 1 (MUC1)-stimulated human mononuclear cells (M1SHMCs) of breast cancer patients would demonstrate expanded levels of growth without compromising their ability to kill cancer cells when costimulated with anti-CD3 and anti-CD28. Materials and methods MUC1-variable number tandem repeat 1 (VNTR1) peptide.GSTAPPAHGVTSAPDTRPAP (7) peptide was synthesized by American Peptide Co., Inc., (Sunnyvale, CA, USA) and Novartis International AG (Basel, Switzerland).Anti-CD3/CD28 antibody beads. Anti-CD28 antibodies were obtained from Murine Hybridoma 9.3 (8), which was a gift from Professor John Hansen (University of Washington, Seattle, USA). Dynabeads ® M-450 Tosylactivated (Thermo Fisher Scientific, Inc., Waltham, MA, USA) are superparamagnetic polystyrene beads, which were activated usi...

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Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas–FasL-Dependent AICD

Cited by 151 publications

References 39 publications

Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis

Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis

Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains

Costimulation with anti-cluster of differentiation 3 and anti-cluster of differentiation 28 reduces the activity of mucin 1-stimulated human mononuclear cells

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