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T cell engineering for adoptive T cell therapy: safety and receptor avidity

  • Focussed Research Review
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Abstract

Since the first bone marrow transplantation, adoptive T cell therapy (ACT) has developed over the last 80 years to a highly efficient and specific therapy for infections and cancer. Genetic engineering of T cells with antigen-specific receptors now provides the possibility of generating highly defined and efficacious T cell products. The high sensitivity of engineered T cells towards their targets, however, also bears the risk of severe off-target toxicities. Therefore, different safety strategies for engineered T cells have been developed that enable removal of the transferred cells in case of adverse events, control of T cell activity or improvement of target selectivity. Receptor avidity is a crucial component in the balance between safety and efficacy of T cell products. In clinical trials, T cells equipped with high avidity T cell receptor (TCR)/chimeric antigen receptor (CAR) have been mostly used so far because of their faster and better response to antigen recognition. However, over-activation can trigger T cell exhaustion/death as well as side effects due to excessive cytokine production. Low avidity T cells, on the other hand, are less susceptible to over-activation and could possess better selectivity in case of tumor antigens shared with healthy tissues, but complete tumor eradication may not be guaranteed. In this review we describe how ‘optimal’ TCR/CAR affinity can increase the safety/efficacy balance of engineered T cells, and discuss simultaneous or sequential infusion of high and low avidity receptors as further options for efficacious but safe T cell therapy.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

CDC:

Complement-dependent cytotoxicity

CRES:

CAR-related encephalopathy syndrome

CRS:

Cytokine-release syndrome

EGFRt:

Truncated epidermal growth factor receptor

GvT:

Graft-versus-tumor

HSV-TK:

Herpes simplex virus thymidine kinase

iCAR:

Inhibitory chimeric antigen receptor

iCasp9:

Inducible caspase 9

pMHC:

Peptide-major histocompatibility complex

TCMp:

Central memory precursor T cells

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Funding

This work was supported by the Deutsche Forschungsgemeinschaft (SFB1321/TP17)

Author information

Authors and Affiliations

  1. Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Trogerstr. 30, 81675, Munich, Germany

    Elvira D’Ippolito, Kilian Schober, Magdalena Nauerth & Dirk H. Busch

  2. German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany

    Dirk H. Busch

  3. Focus Group ‘‘Clinical Cell Processing and Purification”, Institute for Advanced Study, Technische Universität München (TUM), Munich, Germany

    Dirk H. Busch

Authors
  1. Elvira D’Ippolito
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  2. Kilian Schober
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  3. Magdalena Nauerth
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  4. Dirk H. Busch
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Contributions

All authors contributed to the writing and to the revisions of the manuscript. They all approved the final version.

Corresponding author

Correspondence to Dirk H. Busch.

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D’Ippolito, E., Schober, K., Nauerth, M. et al. T cell engineering for adoptive T cell therapy: safety and receptor avidity. Cancer Immunol Immunother 68, 1701–1712 (2019). https://doi.org/10.1007/s00262-019-02395-9

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  • DOI: https://doi.org/10.1007/s00262-019-02395-9

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