TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity

Pouw, Nadine; Treffers-Westerlaken, Elike; Mondino, Anna; Lamers, Cor H.J.; Debets, Reno

doi:10.1016/j.molimm.2010.02.022

Cited by 18 publications

(17 citation statements)

References 46 publications

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Section: Introductionmentioning

confidence: 99%

“…Various studies have shown that the T cell phenotype depends on T cell activation and expansion conditions (Duarte et al, 2002;Bondanza et al, 2006;Pouw et al, 2010b). Along this line, retroviral TCR engineering of primary murine T cells has been reported to benefit from T cell activation with a combination of soluble anti-CD3 and CD28 rather than immobilized anti-CD3 and CD28 mAbs in terms of a more favorable T cell differentiation state and better antigen-specific T cell responses (Pouw et al, 2010b).…”

Section: Introductionmentioning

confidence: 99%

“…HUMAN GENE THERAPY METHODS 25:345-357 (December 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/hgtb.2014.051 (Hinrichs et al, 2008;Kaneko et al, 2009;Pouw et al, 2010b;Yang et al, 2013). In fact, short-term exposure of primary murine T cells to both IL15 and IL21 resulted in a significant enrichment of CD62Lhi, CD44lo, CD27int, and CCR7hi T cells (phenotypical definition of naïve T cells), which was paralleled by decreased expression of genes involved in T cell differentiation and increased expression of genes involved in T cell survival (Pouw et al, 2010a).…”

Section: Introductionmentioning

confidence: 99%

“…One of the underlying reasons for these disappointing results might be a low persistence of these gene-modified T cells (Robbins et al, 2004;Huang et al, 2005). Persistence of T cells is associated with the immunogenicity of the transgene (Lamers et al, 2011(Lamers et al, , 2013a, but also with the differentiation state and replicative history of transferred T cells with the longest persistence for those T cells with a more naïve phenotype Hinrichs et al, 2009).Various studies have shown that the T cell phenotype depends on T cell activation and expansion conditions (Duarte et al, 2002;Bondanza et al, 2006;Pouw et al, 2010b). Along this line, retroviral TCR engineering of primary murine T cells has been reported to benefit from T cell activation with a combination of soluble anti-CD3 and CD28 rather than immobilized anti-CD3 and CD28 mAbs in terms of a more favorable T cell differentiation state and better antigen-specific T cell responses (Pouw et al, 2010b).…”

mentioning

confidence: 99%

“…Along this line, retroviral TCR engineering of primary murine T cells has been reported to benefit from T cell activation with a combination of soluble anti-CD3 and CD28 rather than immobilized anti-CD3 and CD28 mAbs in terms of a more favorable T cell differentiation state and better antigen-specific T cell responses (Pouw et al, 2010b). In addition, recent studies demonstrated that common-c cytokines interleukin-2 (IL2), IL7, IL15, and IL21 play important roles in skewing or slowing down T cell differentiation Kaneko et al, 2009;Pouw et al, 2010b;Yang et al, 2013). In fact, short-term exposure of primary murine T cells to both IL15 and IL21 resulted in a significant enrichment of CD62Lhi, CD44lo, CD27int, and CCR7hi T cells (phenotypical definition of naïve T cells), which was paralleled by decreased expression of genes involved in T cell differentiation and increased expression of genes involved in T cell survival (Pouw et al, 2010a).…”

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confidence: 99%

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T Cell Receptor-Engineered T Cells to Treat Solid Tumors: T Cell Processing Toward Optimal T Cell Fitness

Lamers

Steenbergen-Langeveld

Brakel

et al. 2014

Human Gene Therapy Methods

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Therapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T cells specific for carbonic anhydrase IX (CAIX), we observed toxicities that (most likely) indicated in vivo function of CAR T cells as well as low T cell persistence and clinical response rates. The latter observations were confirmed by later clinical trials in other solid tumor types and other gene-modified T cells. To improve the efficacy of T cell therapy, we have redefined in vitro conditions to generate T cells with young phenotype, a key correlate with clinical outcome. For their impact on gene-modified T cell phenotype and function, we have tested various anti-CD3/CD28 mAb-based T cell activation and expansion conditions as well as several cytokines prior to and/or after gene transfer using two different receptors: CAIX CAR and MAGE-C2(ALK)/HLA-A2 TCR. In a total set of 16 healthy donors, we observed that T cell activation with soluble anti-CD3/CD28 mAbs in the presence of both IL15 and IL21 prior to TCR gene transfer resulted in enhanced proportions of gene-modified T cells with a preferred in vitro phenotype and better function. T cells generated according to these processing methods demonstrated enhanced binding of pMHC, and an enhanced proportion of CD8 + , CD27 + , CD62L + , CD45RA + T cells. These new conditions will be translated into a GMP protocol in preparation of a clinical adoptive therapy trial to treat patients with MAGE-C2-positive tumors. IntroductionT he use of receptor gene therapy, in which a patient's own T cells are gene-modified with either a tumor-specific chimeric antigen receptor (CAR) or a T cell receptor (TCR), has broadened the clinical applicability of adoptive therapy with antigen-specific T cells to treat tumors. Initial trials using gene-modified T cells to treat various tumor types did not show antitumor responses in a substantial number of patients (Kershaw et al., 2006;Morgan et al., 2006;Till et al., 2008;Johnson et al., 2009; Lamers et al., 2013a,b). Despite that some recent trials using either a CD19 CAR to treat B cell leukemias (Kalos et al., 2011;Davila et al., 2014;Lee et al., 2014;Maude et al., 2014) or an NY-ESO TCR to treat melanoma and synovial carcinoma (Robbins et al., 2011) showed significant clinical activities, the majority of the studies performed so far fail to demonstrate substantial antitumor effects (Gilham et al., 2012;Kunert et al., 2013). One of the underlying reasons for these disappointing results might be a low persistence of these gene-modified T cells (Robbins et al., 2004;Huang et al., 2005). Persistence of T cells is associated with the immunogenicity of the transgene (Lamers et al., 2011(Lamers et al., , 2013a, but also with the differentiation state and replicative history of transferred T cells with the longest persistence for those T cells with a...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

T Cell Receptor-Engineered T Cells to Treat Solid Tumors: T Cell Processing Toward Optimal T Cell Fitness

Lamers

Steenbergen-Langeveld

Brakel

et al. 2014

Human Gene Therapy Methods

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View full text Add to dashboard Cite

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Adoptive Cell Therapy for the Treatment of Metastatic Melanoma

Chacon

Hwu

Radvanyi

2011

Targeted Therapeutics in Melanoma

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Chimeric Antigen Receptors for T-Cell Based Therapy

Cheadle

Sheard

Hombach

et al. 2012

Antibody Engineering

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The Chimeric Antigen Receptor (CAR) consists of an antibody-derived targeting domain fused with T-cell signaling domains that, when expressed by a T-cell, endows the T-cell with antigen specificity determined by the targeting domain of the CAR. CARs can potentially redirect the effector functions of a T-cell towards any protein and nonprotein target expressed on the cell surface as long as an antibody or similar targeting domain is available. This strategy thereby avoids the requirement of antigen processing and presentation by the target cell and is applicable to nonclassical T-cell targets like carbohydrates. This circumvention of HLA-restriction means that the CAR T-cell approach can be used as a generic tool broadening the potential of applicability of adoptive T-cell therapy. Proof-of-principle studies focusing upon the investigation of the potency of CAR T-cells have primarily focused upon the genetic modification of human and mouse T-cells for therapy. This chapter focuses upon methods to modify T-cells from both species to generate CAR T-cells for functional testing.

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TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity

Cited by 18 publications

References 46 publications

T Cell Receptor-Engineered T Cells to Treat Solid Tumors: T Cell Processing Toward Optimal T Cell Fitness

T Cell Receptor-Engineered T Cells to Treat Solid Tumors: T Cell Processing Toward Optimal T Cell Fitness

Adoptive Cell Therapy for the Treatment of Metastatic Melanoma

Chimeric Antigen Receptors for T-Cell Based Therapy

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