Skip to main content

Advertisement

SpringerLink
Log in

Adverse Effects Associated with Clinical Applications of CAR Engineered T Cells

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Cancer has been ranked as the second leading cause of death in the United States. To reduce cancer mortality, immunotherapy is gaining momentum among other therapeutic modalities, due to its impressive results in clinical trials. The genetically engineered T cells expressing chimeric antigen receptors (CARs) are emerging as a new approach in cancer immunotherapy, with the most successful outcomes in the refractory/relapse hematologic malignancies. However, the widespread clinical applications are limited by adverse effects some of which are life-threatening. Strategies to reduce the chance of side effects as well as close monitoring, rapid diagnosis and proper treatment of side effects are necessary to take the most advantages of this valuable therapy. Here we review the reported toxicities associated with CAR engineered T cells, the strategies to ameliorate the toxicity, and further techniques and designs leading to a safer CAR T-cell therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bonifant CL, Jackson HJ, Brentjens RJ et al (2016) Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 3:16011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Byrd JC, Furman RR, Coutre SE et al (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369:32–42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Caratelli S, Sconocchia T, Arriga R et al (2017) FCgamma chimeric receptor-engineered T cells: methodology, advantages, limitations, and clinical relevance. Front Immunol 8:457

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 75:3505–3518

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Casucci M, Bondanza A (2011) Suicide gene therapy to increase the safety of chimeric antigen receptor-redirected T lymphocytes. J Cancer 2:378–382

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Curran KJ, Pegram HJ, Brentjens RJ (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med 14:405–415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dai H, Wang Y, Lu X et al (2016) Chimeric antigen receptors modified T-cells for cancer therapy. J Natl Cancer Inst 108:djv439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davila ML, Sadelain M (2016) Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol 104:6–17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davila ML, Riviere I, Wang X et al (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • DeFrancesco L (2017) CAR-T’s forge ahead, despite Juno deaths. Nat Biotechnol 35:6–7

    Article  PubMed  CAS  Google Scholar 

  • Di Stasi A, De Angelis B, Rooney CM et al (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113:6392–6402

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fitzgerald JC, Weiss SL, Maude SL et al (2017) Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med 45:e124–e131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gargett T, Brown MP (2014) The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol 5:235

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ghosh A, Smith M, James SE et al (2017) Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med 23:242–249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 USA 86:10024–10028

    Article  PubMed  CAS  Google Scholar 

  • Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41:2502–2512

    Article  PubMed  CAS  Google Scholar 

  • Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32:23–63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jones BS, Lamb LS, Goldman F et al (2014) Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol 5:254

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lee DW, Gardner R, Porter DL et al (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • MacLeod DT, Antony J, Martin AJ et al (2017) Integration of a CD19 CAR into the TCR Alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol Ther 25:949–961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Magee MS, Snook AE (2014) Challenges to chimeric antigen receptor (CAR)-T cell therapy for cancer. Discov Med 18:265–271

    PubMed  Google Scholar 

  • Marin V, Cribioli E, Philip B et al (2012) Comparison of different suicide-gene strategies for the safety improvement of genetically manipulated T cells. Hum Gene Ther Methods 23:376–386

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maude SL, Barrett D, Teachey DT et al (2014) Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20:119–122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maus MV, Levine BL (2016) Chimeric antigen receptor T-cell therapy for the community oncologist. Oncologist 21:608–617

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maus MV, Haas AR, Beatty GL et al (2013) T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 1:26–31

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maus MV, Grupp SA, Porter DL et al (2014) Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123:2625–2635

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Namuduri M, Brentjens RJ (2016) Medical management of side effects related to CAR T cell therapy in hematologic malignancies. Expert Rev Hematol 9:511–513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Rodgers DT, Mazagova M, Hampton EN et al (2016) Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci USA 113:E459–E468

    Article  PubMed  CAS  Google Scholar 

  • Ruella M, Kenderian SS, Shestova O et al (2017) Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia 31:246–248

    Article  PubMed  CAS  Google Scholar 

  • Saha B, Jyothi PS et al (2010) Gene modulation and immunoregulatory roles of interferon gamma. Cytokine 50:1–14

    Article  PubMed  CAS  Google Scholar 

  • Tasian SK, Gardner RA (2015) CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Ther Adv Hematol 6:228–241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Teachey DT, Rheingold SR, Maude SL et al (2013) Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121:5154–5157

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Terakura S, Yamamoto TN, Gardner RA et al (2012) Generation of CD19-chimeric antigen receptor modified CD8 + T cells derived from virus-specific central memory T cells. Blood 119:72–82

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tiu RV, Mountantonakis SE, Dunbar AJ et al (2007) Tumor lysis syndrome. Semin Thromb Hemost 33:397–407

    Article  PubMed  Google Scholar 

  • Venkiteshwaran A (2009) Tocilizumab MAbs 1:432–438

    Article  PubMed  Google Scholar 

  • Wang X, Chang WC, Wong CW et al (2011) A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118:1255–1263

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang ML, Rule S, Martin P et al (2013) Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wu CY, Roybal KT, Puchner EM et al (2015) Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:aab4077

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu XJ, Tang YM (2014) Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells. Cancer Lett 343:172–178

    Article  PubMed  CAS  Google Scholar 

  • Zhao Y, Moon E, Carpenito C et al (2010) Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res 70:9053–9061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Funds from Kids Walk for Kids with Cancer NYC, Katie Find a Cure Foundation, the Robert Steel Foundation, and NIH/NCI Cancer Center Support Grant P30 CA008748.

Author information

Authors and Affiliations

  1. 475 Main Street, New York, NY, 10044, USA

    Zohreh Sadat Badieyan

  2. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 170, New York, NY, 10065, USA

    Sayed Shahabuddin Hoseini

Authors
  1. Zohreh Sadat Badieyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sayed Shahabuddin Hoseini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sayed Shahabuddin Hoseini.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Badieyan, Z.S., Hoseini, S.S. Adverse Effects Associated with Clinical Applications of CAR Engineered T Cells. Arch. Immunol. Ther. Exp. 66, 283–288 (2018). https://doi.org/10.1007/s00005-018-0507-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-018-0507-9

Keywords

Search

Navigation