TEG001 insert integrity from vector producer cells until medicinal product

Straetemans, Trudy; Janssen, Anke; Jansen, Koen; Doorn, Ruud; Aarts, Tineke; Muyden, A.V.; Simonis, Marieke; Bergboer, Judith G.M.; Witte, Moniek de; Sebestyén, Zsolt; Kuball, Juergen

doi:10.1016/j.jcyt.2020.03.270

Cited by 3 publications

(2 citation statements)

References 59 publications

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“…Within this context we have explored a strategy based on the recent development of purified T cells engineered to express a defined gd T cell receptor (TEGs). [19][20][21][22][23][24][25][26][27][28][29] In this strategy we took advantage of the observation that an anti-human abTCR antibody used for the purification of TEGs does not cross-react with gdTCR chains, and it can thereby differentiate between engineered and non-engineered cells. This anti-human abTCR antibody is routinely used to deplete abTCR T cells from apheresis products using CliniMACS depletion before allogeneic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells

Kierkels

Diest

Hernández-López

et al. 2021

Molecular Therapy - Methods & Clinical Development

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T cell engineering strategies offer cures to patients and have entered clinical practice with chimeric antibody-based receptors; abT cell receptor (abTCR)-based strategies are, however, lagging behind. To allow a more rapid and successful translation to successful concepts also using abTCRs for engineering, incorporating a method for the purification of genetically modified T cells, as well as engineered T cell deletion after transfer into patients, could be beneficial. This would allow increased efficacy, reduced potential side effects, and improved safety of newly to-be-tested lead structures. By characterizing the antigen-binding interface of a good manufacturing process (GMP)-grade anti-abTCR antibody, usually used for depletion of abT cells from stem cell transplantation products, we developed a strategy that allows for the purification of untouched abTCR-engineered immune cells by changing 2 amino acids only in the TCRb chain constant domain of introduced TCR chains. Alternatively, we engineered an antibody that targets an extended mutated interface of 9 amino acids in the TCRb chain constant domain and provides the opportunity to further develop depletion strategies of engineered immune cells.

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Section: Introductionmentioning

confidence: 99%

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells

Kierkels

Diest

Hernández-López

et al. 2021

Molecular Therapy - Methods & Clinical Development

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“…To partially overcome these obstacles, we introduced the concept of TEGs: αβT cells engineered to express a defined γδTCR. TEGs allow the production of αβT cells transduced with highly tumor‐reactive γδTCR from both Vδ2 + 18‐20 and Vδ2 − 21‐23 subsets and thereby engineering strong tumor reactivity against a broad panel of malignancies. Within this context, we previously identified an allo‐HLA‐restricted and CD8α‐dependent Vγ5Vδ1TCR.…”

Section: Introductionmentioning

confidence: 99%

TEG011 persistence averts extramedullary tumor growth without exerting off-target toxicity against healthy tissues in a humanized HLA-A*24:02 transgenic mice

Johanna

Hernández-López

Heijhuurs

et al. 2020

Journal of Leukocyte Biology

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γδT cells play an important role in cancer immunosurveillance and are able to distinguish malignant cells from their healthy counterparts via their γδTCR. This characteristic makes γδT cells an attractive candidate for therapeutic application in cancer immunotherapy. Previously, we have identified a novel CD8α‐dependent tumor‐specific allo‐HLA‐A*24:02‐restricted Vγ5Vδ1TCR with potential therapeutic value when used to engineer αβT cells from HLA‐A*24:02 harboring individuals. αβT cells engineered to express this defined Vγ5Vδ1TCR (TEG011) have been suggested to recognize spatial changes in HLA‐A*24:02 present selectively on tumor cells but not their healthy counterparts. However, in vivo efficacy and toxicity studies of TEG011 are still limited. Therefore, we extend the efficacy and toxicity studies as well as the dynamics of TEG011 in vivo in a humanized HLA‐A*24:02 transgenic NSG (NSG‐A24:02) mouse model to allow the preparation of a first‐in‐men clinical safety package for adoptive transfer of TEG011. Mice treated with TEG011 did not exhibit any graft‐versus‐host disease‐like symptoms and extensive analysis of pathologic changes in NSG‐A24:02 mice did not show any off‐target toxicity of TEG011. However, loss of persistence of TEG011 in tumor‐bearing mice was associated with the outgrowth of extramedullary tumor masses as also observed for mock‐treated mice. In conclusion, TEG011 is well tolerated without harming HLA‐A*24:02+ expressing healthy tissues, and TEG011 persistence seems to be crucial for long‐term tumor control in vivo.

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γδ T cells: a sparkling star for clinical immunotherapy

et al. 2022

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Human γδ T cells are unconventional lymphocytes that function in innate and adaptive immune responses and immunosurveillance. These cells show potent cytotoxicity against tumor cells in a major histocompatibility complex unrestricted manner and have recently gained considerable attention as a sparkling star for clinical immunotherapy. Clinical immunotherapy trials with activated γδ T cells are tolerated well. However, clinical benefits are still unsatisfactory. Therefore, anti-tumor effects need to further increase the cytotoxicity of γδ T cells via several mechanisms, including the novel nitrogen-containing bisphosphonate products, adjuvant use with a bispecific antibody and chimeric antigen receptor, co-immunotherapy with γδ T cells plus immune checkpoint inhibitors, and adoptive immunotherapy with Vδ1 T cells and T cells engineered to express a defined γδ T cell receptor. Here, this article describes the crucial role of γδ T cells in anti-tumor immunity, concludes transduction strategies and summarizes the different development of novel approaches for clinical applications and cancer immunotherapy, which may be effective in overcoming current therapeutic limitations.

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TEG001 insert integrity from vector producer cells until medicinal product

Cited by 3 publications

References 59 publications

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells

TEG011 persistence averts extramedullary tumor growth without exerting off-target toxicity against healthy tissues in a humanized HLA-A*24:02 transgenic mice

γδ T cells: a sparkling star for clinical immunotherapy

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