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Cancer Immunology, Immunotherapy

, Volume 68, Issue 10, pp 1701–1712 | Cite as

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

  • Elvira D’Ippolito
  • Kilian Schober
  • Magdalena Nauerth
  • Dirk H. BuschEmail author
Focussed Research Review

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.

Keywords

CAR TCR avidity Safeguards T cell engineering 

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

Notes

Author contribution

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

Funding

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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute for Medical Microbiology, Immunology and HygieneTechnische Universität München (TUM)MunichGermany
  2. 2.German Center for Infection Research (DZIF)MunichGermany
  3. 3.Focus Group ‘‘Clinical Cell Processing and Purification”, Institute for Advanced StudyTechnische Universität München (TUM)MunichGermany

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