GMP-Grade Manufacturing of T Cells Engineered to Express a Defined γδTCR.


:γ9δ2T cells play a critical role in daily cancer immune surveillance by sensing cancer-mediated metabolic changes. However, a major limitation of the therapeutic application of γ9δ2T cells is their diversity and regulation through innate co-receptors. In order to overcome natural obstacles of γ9δ2T cells, we have developed the concept of T cells engineered to express a defined γδT cell receptor (TEGs). This next generation of chimeric antigen receptor engineered T (CAR-T) cells not only allows for targeting of hematological but also of solid tumors and, therefore, overcomes major limitations of many CAR-T and γδT cell strategies. Here, we report on the development of a robust manufacturing procedure of T cells engineered to express the high affinity Vγ9Vδ2T cell receptor (TCR) clone 5 (TEG001). We determined the best concentration of anti-CD3/CD28 activation and expansion beads, optimal virus titer, and cell density for retroviral transduction, and validated a Good Manufacturing Practice (GMP)-grade purification procedure by utilizing the CliniMACS system to deplete non- and poorly-engineered T cells. To the best of our knowledge, we have developed the very first GMP manufacturing procedure in which αβTCR depletion is used as a purification method, thereby delivering untouched clinical grade engineered immune cells. This enrichment method is applicable to any engineered T cell product with a reduced expression of endogenous αβTCRs. We report on release criteria and the stability of TEG001 drug substance and TEG001 drug product. The GMP-grade production procedure is now approved by Dutch authorities and allows TEG001 to be generated in cell numbers sufficient to treat patients within the approved clinical trial NTR6541. NTR6541 will investigate the safety and tolerability of TEG001 in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and relapsed/refractory multiple myeloma.


Front Immunol


Frontiers in immunology


Straetemans T,Kierkels GJJ,Doorn R,Jansen K,Heijhuurs S,Dos Santos JM,van Muyden ADD,Vie H,Clemenceau B,Raymakers R,de Witte M,Sebestyén Z,Kuball J




Has Abstract


2018-05-30 00:00:00








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    abstract::Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications - such as DC-bas...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Datta J,Berk E,Cintolo JA,Xu S,Roses RE,Czerniecki BJ

    更新日期:2015-06-02 00:00:00

  • Isolation of Single-Domain Antibody Fragments That Preferentially Detect Intact (146S) Particles of Foot-and-Mouth Disease Virus for Use in Vaccine Quality Control.

    abstract::Intact (146S) foot-and-mouth disease virus (FMDVs) can dissociate into specific (12S) viral capsid degradation products. FMD vaccines normally consist of inactivated virions. Vaccine quality is dependent on 146S virus particles rather than 12S particles. We earlier isolated two llama single-domain antibody fragments (...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Harmsen MM,Seago J,Perez E,Charleston B,Eblé PL,Dekker A

    更新日期:2017-08-17 00:00:00

  • Anti-CD2 Antibody-Coated Nanoparticles Containing IL-2 Induce NK Cells That Protect Lupus Mice via a TGF-β-Dependent Mechanism.

    abstract::We recently reported that the treatment with nanoparticles (NPs) loaded with tolerogenic cytokines suppressed the manifestations of lupus-like disease induced by the transfer of donor CD4+ T cells from DBA/2 mice into (C57BL/6 × DBA/2)F1 (BDF1) mice. Although the protective effects were ascribed to the induction of ad...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Horwitz DA,Liu A,Bickerton S,Castaldo G,Matarese G,Fahmy TM,La Cava A

    更新日期:2020-12-16 00:00:00

  • CD4+CD8+ T-Lymphocytes in Xenogeneic and Human Graft-versus-Host Disease.

    abstract::Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we de...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Alhaj Hussen K,Michonneau D,Biajoux V,Keita S,Dubouchet L,Nelson E,Setterblad N,Le Buanec H,Bouaziz JD,Guimiot F,Socié G,Canque B

    更新日期:2020-11-24 00:00:00

  • Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock.

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Halbgebauer R,Karasu E,Braun CK,Palmer A,Braumüller S,Schultze A,Schäfer F,Bückle S,Eigner A,Wachter U,Radermacher P,Resuello RRG,Tuplano JV,Nilsson Ekdahl K,Nilsson B,Armacki M,Kleger A,Seufferlein T,Kalbitz M,Gebh

    更新日期:2020-08-26 00:00:00

  • Cellular Regulation of the Uterine Microenvironment That Enables Embryo Implantation.

    abstract::Implantation of the fertilized egg into the maternal uterus is a crucial step in pregnancy establishment. Increasing evidence suggests that its success depends on various cell types of the innate immune system and on the fine balance between inflammatory and anti-inflammatory processes. In addition, it has recently be...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Zenclussen AC,Hämmerling GJ

    更新日期:2015-06-17 00:00:00

  • Ubiquitin-Specific Protease 14 Negatively Regulates Toll-Like Receptor 4-Mediated Signaling and Autophagy Induction by Inhibiting Ubiquitination of TAK1-Binding Protein 2 and Beclin 1.

    abstract::Ubiquitin-specific protease 14 (USP14), one of three proteasome-associated deubiquitinating enzymes, has multifunctional roles in cellular context. Here, we report a novel molecular mechanism and function of USP14 in regulating autophagy induction and nuclear factor-kappa B (NF-κB) activation induced by toll-like rece...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Min Y,Lee S,Kim MJ,Chun E,Lee KY

    更新日期:2017-12-15 00:00:00

  • Metabolic reprograming of mononuclear phagocytes in progressive multiple sclerosis.

    abstract:UNLABELLED:Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Accumulation of brain damage in progressive MS is partly the result of mononuclear phagocytes (MPs) attacking myelin sheaths in the CNS. Although there is no cure yet for MS, significant advances have be...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Tannahill GM,Iraci N,Gaude E,Frezza C,Pluchino S

    更新日期:2015-03-11 00:00:00

  • The relationship between CD27 negative and positive B cell populations in human peripheral blood.

    abstract::CD27 expression has been used to distinguish between memory and naive B cells in humans. However, low levels of mutated and isotype-switched CD27-IgD- cells are seen in healthy adults, and these are increased in some autoimmune diseases and in the elderly. Thus CD27 is not a universal marker of memory B cells in human...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Wu YC,Kipling D,Dunn-Walters DK

    更新日期:2011-12-26 00:00:00

  • Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16- Monocytes.

    abstract::Monocytes in humans consist of 3 subsets; CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16- monocytes are significantly elevated and migrate to the sites of injury via the adhesion c...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Lee MKS,Al-Sharea A,Shihata WA,Bertuzzo Veiga C,Cooney OD,Fleetwood AJ,Flynn MC,Claeson E,Palmer CS,Lancaster GI,Henstridge DC,Hamilton JA,Murphy AJ

    更新日期:2019-09-06 00:00:00

  • Nuclear Deformation During Neutrophil Migration at Sites of Inflammation.

    abstract::Cell migration is indispensable for various biological processes including angiogenesis, wound healing, and immunity. In general, there are two different migration modes described, the mesenchymal migration mode and the amoeboid migration mode. Neutrophils rapidly migrate toward the sites of injury, infection, and inf...

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    pub_type: 杂志文章,评审


    authors: Salvermoser M,Begandt D,Alon R,Walzog B

    更新日期:2018-11-16 00:00:00

  • Dynamic Interplay of Innate and Adaptive Immunity During Sterile Retinal Inflammation: Insights From the Transcriptome.

    abstract::The pathogenesis of many retinal degenerations, such as age-related macular degeneration (AMD), is punctuated by an ill-defined network of sterile inflammatory responses. The delineation of innate and adaptive immune milieu among the broad leukocyte infiltrate, and the gene networks, which construct these responses, a...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Natoli R,Mason E,Jiao H,Chuah A,Patel H,Fernando N,Valter K,Wells CA,Provis J,Rutar M

    更新日期:2018-07-18 00:00:00

  • Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients.

    abstract::Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplan...

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    pub_type: 杂志文章


    authors: Alvarez Salazar EK,Cortés-Hernández A,Alemán-Muench GR,Alberú J,Rodríguez-Aguilera JR,Recillas-Targa F,Chagoya de Sánchez V,Cuevas E,Mancilla-Urrea E,Pérez García M,Mondragón-Ramírez G,Vilatobá M,Bostock I,Hernández-Méndez E,

    更新日期:2017-03-03 00:00:00

  • Emerging Concepts about NAIP/NLRC4 Inflammasomes.

    abstract::Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are activated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically a...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Lage SL,Longo C,Branco LM,da Costa TB,Buzzo Cde L,Bortoluci KR

    更新日期:2014-07-02 00:00:00

  • Stem cell transplantation as a dynamical system: are clinical outcomes deterministic?

    abstract::Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However, the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time acco...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Toor AA,Kobulnicky JD,Salman S,Roberts CH,Jameson-Lee M,Meier J,Scalora A,Sheth N,Koparde V,Serrano M,Buck GA,Clark WB,McCarty JM,Chung HM,Manjili MH,Sabo RT,Neale MC

    更新日期:2014-12-03 00:00:00

  • FcαRI Dynamics Are Regulated by GSK-3 and PKCζ During Cytokine Mediated Inside-Out Signaling.

    abstract::IgA binding to FcαRI (CD89) is rapidly enhanced by cytokine induced inside-out signaling. Dephosphorylation of serine 263 in the intracellular tail of FcαRI by PP2A and PI3K activation are instrumental in this process. To further investigate these signaling pathways, we targeted downstream kinases of PI3K. Our experim...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Ten Broeke T,Honing H,Brandsma AM,Jacobino S,Bakema JE,Kanters D,van der Linden JAM,Bracke M,Koenderman L,Leusen JHW

    更新日期:2019-01-31 00:00:00

  • Epstein Barr Virus Interleukin 10 Suppresses Anti-inflammatory Phenotype in Human Monocytes.

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    pub_type: 杂志文章


    authors: Jog NR,Chakravarty EF,Guthridge JM,James JA

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  • Human Milk Blocks DC-SIGN-Pathogen Interaction via MUC1.

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Koning N,Kessen SF,Van Der Voorn JP,Appelmelk BJ,Jeurink PV,Knippels LM,Garssen J,Van Kooyk Y

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: West NR

    更新日期:2019-05-15 00:00:00

  • Oral Administration of Acrylamide Worsens the Inflammatory Responses in the Airways of Asthmatic Mice Through Agitation of Oxidative Stress in the Lungs.

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Hajimohammadi B,Athari SM,Abdollahi M,Vahedi G,Athari SS

    更新日期:2020-10-09 00:00:00

  • Metabolic Reprogramming in CD8+ T Cells During Acute Viral Infections.

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Gupta SS,Wang J,Chen M

    更新日期:2020-05-22 00:00:00

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Wang L,Wang R,Xu C,Zhou H

    更新日期:2020-05-13 00:00:00

  • Potential Involvement of Platelet-Derived Microparticles and Microparticles Forming Immune Complexes during Monocyte Activation in Patients with Systemic Lupus Erythematosus.

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    pub_type: 临床试验,杂志文章


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    更新日期:2018-03-01 00:00:00

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Tarique M,Naz H,Saini C,Suhail M,Shankar H,Khanna N,Sharma A

    更新日期:2020-08-06 00:00:00

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Tang CL,Yu XH,Li Y,Zhang RH,Xie J,Liu ZM

    更新日期:2019-06-26 00:00:00

  • Remote Activation of a Latent Epitope in an Autoantigen Decoded With Simulated B-Factors.

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Pang YP,Casal Moura M,Thompson GE,Nelson DR,Hummel AM,Jenne DE,Emerling D,Volkmuth W,Robinson WH,Specks U

    更新日期:2019-10-25 00:00:00

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Prabhu VM,Singh AK,Padwal V,Nagar V,Patil P,Patel V

    更新日期:2019-12-06 00:00:00

  • Overcoming Target Driven Fratricide for T Cell Therapy.

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    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Breman E,Demoulin B,Agaugué S,Mauën S,Michaux A,Springuel L,Houssa J,Huberty F,Jacques-Hespel C,Marchand C,Marijsse J,Nguyen T,Ramelot N,Violle B,Daro D,De Waele P,Gilham DE,Steenwinckel V

    更新日期:2018-12-12 00:00:00

  • Del-1, an Endogenous Inhibitor of TGF-β Activation, Attenuates Fibrosis.

    abstract::Uncontrolled activation of transforming growth factor (TGF)-β results in a wide range of pathologic conditions. Therapeutic interventions to regulate TGF-β signaling during fibrosis have been developed but the effectiveness is still limited. Here, we show that developmental endothelial locus-1 (Del-1) ameliorates fibr...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Kim DY,Lee SH,Fu Y,Jing F,Kim WY,Hong SB,Song JA,Choe H,Ryu HJ,Kim M,Lim D,Kim MS,Yun CO,Lee T,Hyun H,Choi EY

    更新日期:2020-02-07 00:00:00

  • MicroRNA-Mediated Control of Inflammation and Tolerance in Pregnancy.

    abstract::Gestational age-dependent immune intolerance at the maternal-fetal interface might be a contributing factor to placental pathology and adverse pregnancy outcomes. Although the intrauterine setting is highly choreographed and considered to be a protective environment for the fetus, unscheduled inflammation might overwh...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Kamity R,Sharma S,Hanna N

    更新日期:2019-04-05 00:00:00