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


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.


CAR TCR avidity Safeguards T cell engineering 



Antibody-dependent cellular cytotoxicity


Complement-dependent cytotoxicity


CAR-related encephalopathy syndrome


Cytokine-release syndrome


Truncated epidermal growth factor receptor




Herpes simplex virus thymidine kinase


Inhibitory chimeric antigen receptor


Inducible caspase 9


Peptide-major histocompatibility complex


Central memory precursor T cells


Author contribution

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


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.


  1. 1.
    Osgoog (1939) Aplastic anemia treated with daily transfusion and intravenous marrow; case report. Ann Intern Med 13:357. CrossRefGoogle Scholar
  2. 2.
    Passweg JR, Baldomero H, Bader P et al (2016) Hematopoietic stem cell transplantation in Europe 2014: more than 40,000 transplants annually. Bone Marrow Transplant. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Barrett AJ, Battiwalla M (2010) Relapse after allogeneic stem cell transplantation. Expert Rev, HematolCrossRefGoogle Scholar
  4. 4.
    Choi SW, Reddy P (2014) Current and emerging strategies for the prevention of graft-versus-host disease. Nat Rev Clin Oncol 11:536–547. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Remberger M, Mattsson J, Hentschke P et al (2002) The graft-versus-leukaemia effect in haemotopoietic stem cell transplantation using unrelated donors. Bone Marrow Transplant 30:761–768. CrossRefPubMedGoogle Scholar
  6. 6.
    Riddell, Watanabe K, Goodrich J et al (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science (80-) 257:238–241. CrossRefGoogle Scholar
  7. 7.
    Cobbold M, Khan N, Pourgheysari B et al (2005) Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers. J Exp Med. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Knabel M, Franz TJ, Schiemann M et al (2002) Reversible MHC multimer staining for functional isolation of T-cell populations and effective adoptive transfer. Nat Med. CrossRefPubMedGoogle Scholar
  9. 9.
    Neuenhahn M, Albrecht J, Odendahl M et al (2017) Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT. Leukemia. CrossRefPubMedGoogle Scholar
  10. 10.
    Rooney CM, Ng CYC, Loftin S et al (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet. CrossRefPubMedGoogle Scholar
  11. 11.
    Doubrovina E, Oflaz-Sozmen B, Prockop SE et al (2012) Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV + lymphomas after allogeneic hematopoietic cell transplantation. Blood 119:2644–2656. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tzannou I, Leen AM (2015) Preventing stem cell transplantation-associated viral infections using T-cell therapy. Immunotherapy 7:793–810. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kolb HJ, Mittermüller J, Clemm C et al (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465CrossRefPubMedGoogle Scholar
  14. 14.
    Spiess PJ, Yang JC, Rosenberg SA (1987) In vivo antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst 79:1067–1075PubMedGoogle Scholar
  15. 15.
    Topalian SL, Solomon D, Avis FP et al (1988) Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J Clin Oncol. CrossRefPubMedGoogle Scholar
  16. 16.
    Dudley ME, Wunderlich JR, Robbins PF et al (2002) Supplemental online materials to cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–855CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rosenberg SA, Yang JC, Sherry RM et al (2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17:4550–4557. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Besser MJ, Shapira-Frommer R, Treves AJ et al (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res. CrossRefPubMedGoogle Scholar
  19. 19.
    Radvanyi LG, Bernatchez C, Zhang M et al (2012) Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Andersen R, Donia M, Ellebaek E et al (2016) Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated il2 regimen. Clin Cancer Res 22:3734–3745. CrossRefPubMedGoogle Scholar
  21. 21.
    Dudley ME, Gross CA, Langhan MM et al (2010) CD8 + enriched “Young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Johnson LA, Morgan RA, Dudley ME et al (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fujita K, Ikarashi H, Takakuwa K et al (1995) Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res 1(5):501–507PubMedGoogle Scholar
  24. 24.
    Zacharakis N, Chinnasamy H, Black M et al (2018) Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci. CrossRefPubMedGoogle Scholar
  26. 26.
    Pule MA, Savoldo B, Myers GD et al (2008) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14:1264–1270. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Park JH, Geyer MB, Brentjens RJ (2016) CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood 127:3312–3320. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Maude SL, Laetsch TW, Buechner J et al (2018) Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med 378:439–448. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Van Zelm MC, Reisli I, Van Der Burg M et al (2006) An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med. CrossRefPubMedGoogle Scholar
  30. 30.
    Hay KA (2018) Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy. Br J Haematol 183:364–374. CrossRefPubMedGoogle Scholar
  31. 31.
    Gauthier J, Turtle CJ (2018) Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med 66:50–52. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang Z, Han W (2018) Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gust J, Hay KA, Hanafi LA et al (2017) Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Neelapu SS, Tummala S, Kebriaei P et al (2018) Chimeric antigen receptor T-cell therapy-assessment and management of toxicities. Nat Rev Clin Oncol 15:47–62CrossRefPubMedGoogle Scholar
  35. 35.
    Rupp LJ, Schumann K, Roybal KT et al (2017) CRISPR/Cas9-mediated PD-1 disruption enhances anti-Tumor efficacy of human chimeric antigen receptor T cells. Sci Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Peng W, Ye Y, Rabinovich BA et al (2010) Transduction of tumor-specific T cells with CXCR36 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Adachi K, Kano Y, Nagai T et al (2018) IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. CrossRefPubMedGoogle Scholar
  38. 38.
    Wartewig T, Kurgyis Z, Keppler S et al (2017) PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552:121–125. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Morgan RA, Yang JC, Kitano M et al (2010) Case report of a serious adverse event following the administration of t cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18:843–851. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lamers CHJ, Sleijfer S, Van Steenbergen S et al (2013) Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Thistlethwaite FC, Gilham DE, Guest RD et al (2017) The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immunother. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zhong S, Malecek K, Johnson LA et al (2013) T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proc Natl Acad Sci 110:6973–6978. CrossRefPubMedGoogle Scholar
  43. 43.
    Robbins PF, Morgan RA, Feldman SA et al (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Morgan RA, Chinnasamy N, Abate-Daga D et al (2013) Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Cameron BJ, Dukes J, Harper JV et al (2013) Identification of a titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tiberghien P, Ferrand C, Lioure B et al (2001) Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood. CrossRefPubMedGoogle Scholar
  47. 47.
    Ciceri F, Bonini C, Teresa M et al (2009) Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol 10:489–500. CrossRefPubMedGoogle Scholar
  48. 48.
    Berger C, Flowers ME, Warren EH, Riddell SR (2006) Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bonini C, Ferrari G, Verzeletti S et al (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724CrossRefPubMedGoogle Scholar
  50. 50.
    Lee WYW, Zhang T, Lau CPY et al (2013) Immortalized human fetal bone marrow-derived mesenchymal stromalcell expressing suicide gene for anti-tumor therapy in vitro andin vivo. Cytotherapy. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Di Stasi A, Tey S-K, Dotti G et al (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wang X, Chang WC, Wong CLW et al (2011) A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Paszkiewicz PJ, Fräßle SP, Srivastava S et al (2016) Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 126:4262–4272. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wu C-Y, Roybal KT, Puchner EM et al (2015) Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science (80-). CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cartellieri M, Feldmann A, Koristka S et al (2016) Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J 6:e458. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Fedorov VD, Themeli M, Sadelain M (2013) PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med 5:215ra172. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Eyquem J, Mansilla-Soto J, Giavridis T et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Roth TL, Puig-Saus C, Yu R et al (2018) Reprogramming human T cell function and specificity with non-viral genome targeting. Nature. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Schober K, Müller T, Gökmen F et al (2019) Orthotopic replacement of T-cell receptor α- and β-chains with preservation of near-physiological T-cell function. Nat Biomed Eng. CrossRefPubMedGoogle Scholar
  60. 60.
    Kloss CC, Condomines M, Cartellieri M et al (2013) Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol 31:71–75. CrossRefPubMedGoogle Scholar
  61. 61.
    Lanitis E, Poussin M, Klattenhoff AW et al (2013) Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol Res. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kim MY, Yu KR, Kenderian SS et al (2018) Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Liu X, Jiang S, Fang C et al (2015) Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Caruso HG, Hurton LV, Najjar A et al (2015) Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Park S, Shevlin E, Vedvyas Y et al (2017) Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Drent E, Themeli M, Poels R et al (2017) A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther 25:1946–1958. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ahmed N, Brawley VS, Hegde M et al (2015) Human epidermal growth factor receptor 2 (HER2)—specific chimeric antigen receptor—modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Norelli M, Camisa B, Barbiera G et al (2018) Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 24:739–748. CrossRefPubMedGoogle Scholar
  69. 69.
    Giavridis T, Van Der Stegen SJC, Eyquem J et al (2018) CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade letter. Nat Med. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Wunderlich M, Chou FS, Link KA et al (2010) AML xenograft efficiency is significantly improved in NOD/SCID-IL2RG mice constitutively expressing human SCF, GM-CSF and IL-3. Leukemia 24:1785–1788. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Corr M, Slanetz AE, Boyd LF et al (1994) T cell receptor-MHC class I peptide interactions: affinity, kinetics, and specificity. Science 265:946–949CrossRefPubMedGoogle Scholar
  72. 72.
    Nauerth M, Weissbrich B, Knall R et al (2013) TCR-ligand koff rate correlates with the protective capacity of antigen-specific CD8 + T Cells for adoptive transfer. Sci Transl Med 5:192ra87. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Hebeisen M, Schmidt J, Guillaume P et al (2015) Identification of rare high-avidity, tumor-reactive CD8 + T cells by monomeric TCR-ligand off-rates measurements on living cells. Cancer Res 75:1983–1991. CrossRefPubMedGoogle Scholar
  74. 74.
    Allard M, Couturaud B, Carretero-Iglesia L et al (2017) TCR-ligand dissociation rate is a robust and stable biomarker of CD8 + T cell potency. JCI Insight. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Busch DH, Pamer EG (1999) T cell affinity maturation by selective expansion during infection. J Exp Med 189:701–710. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Savage PA, Boniface JJ, Davis MM (1999) A Kinetic Basis For T Cell Receptor Repertoire Selection during an Immune Response primes a specific CD4 ϩ T helper response primarily di- rected toward an immunodominant epitope restricted by the I-E k MHC molecule (Schwartz, 1985). McHeyzer Immun 10:485–492CrossRefGoogle Scholar
  77. 77.
    Zehn D, Lee SY, Bevan MJ (2009) Complete but curtailed T-cell response to very low-affinity antigen. Nature 458:211–214. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Kalergis AH, Boucheron N, Doucey MA et al (2001) Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nat Immunol 2:229–234. CrossRefPubMedGoogle Scholar
  79. 79.
    Lever M, Maini PK, van der Merwe PA, Dushek O (2014) Phenotypic models of T cell activation. Nat Rev Immunol 14:619–629. CrossRefPubMedGoogle Scholar
  80. 80.
    Sabatino JJ, Huang J, Zhu C, Evavold BD (2011) High prevalence of low affinity peptide–MHC II tetramer–negative effectors during polyclonal CD4+ T cell responses. J Exp Med 208:81–90. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Martinez RJ, Evavold BD (2015) Lower affinity T cells are critical components and active participants of the immune response. Front Immunol 6:1–10. CrossRefGoogle Scholar
  82. 82.
    Kim C, Williams MA (2010) Nature and nurture: t-cell receptor-dependent and T-cell receptor-independent differentiation cues in the selection of the memory T-cell pool. Immunology 131:310–317. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Cho YL, Flossdorf M, Kretschmer L et al (2017) TCR signal quality modulates fate decisions of single CD4 + T cells in a probabilistic manner. Cell Rep 20:806–818. CrossRefPubMedGoogle Scholar
  84. 84.
    Knudson KM, Goplen NP, Cunningham CA et al (2013) Low-affinity T cells are programmed to maintain normal primary responses but are impaired in their recall to low-affinity ligands. Cell Rep 4:554–565. CrossRefPubMedGoogle Scholar
  85. 85.
    Caserta S, Kleczkowska J, Mondino A, Zamoyska R (2010) Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J Immunol 185:6545–6554. CrossRefPubMedGoogle Scholar
  86. 86.
    Utzschneider DT, Alfei F, Roelli P et al (2016) High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. J Exp Med 213:1819–1834. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Schober K, Buchholz VR, Busch DH (2018) TCR repertoire evolution during maintenance of CMV-specific T-cell populations. Immunol Rev 283:113–128. CrossRefPubMedGoogle Scholar
  88. 88.
    Irving M, Zoete V, Hebeisen M et al (2012) Interplay between T cell receptor binding kinetics and the level of cognate peptide presented by major histocompatibility complexes governs CD8 + T cell responsiveness. J Biol Chem 287:23068–23078. CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Chmielewski M, Hombach A, Heuser C et al (2004) T cell activation by antibody-like immunoreceptors: increase in affinity of the single-chain fragment domain above threshold does not increase T cell activation against antigen-positive target cells but decreases selectivity. J Immunol 173:7647–7653. CrossRefPubMedGoogle Scholar
  90. 90.
    Watanabe K, Terakura S, Martens AC et al (2015) Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8 + T cells. J Immunol 194:911–920. CrossRefPubMedGoogle Scholar
  91. 91.
    Busch DH, Fräßle SP, Sommermeyer D et al (2016) Role of memory T cell subsets for adoptive immunotherapy. Semin Immunol 28:28–34. CrossRefPubMedPubMedCentralGoogle Scholar

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

Personalised recommendations