Advertisement

Resistance to Chimeric Antigen Receptor T-Cell Therapy

  • Ana C. XavierEmail author
  • Luciano J. Costa
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 21)

Abstract

Chimeric antigen receptor (CAR) T-cells are a form of adoptive immunotherapy constituted of autologous T-cells engineered with a receptors that is able to target tumor antigens. Treatment with CAR19 cells leads to rapid response in a significant proportion of patients with relapsed or refractory aggressive B-cell lymphomas. However, relapses post CAR-T cell therapy are common. In this chapter, we will discuss what is currently known about mechanisms of resistance to CAR-T cell therapy in B-cell lymphomas or leukemias.

Keywords

Lymphoma Large B-cell Diffuse; immunotherapy Adoptive; drug resistance Neoplasm 

Abbreviations

ALL

Acute Lymphoblastic Leukemia

AML

Acute Myeloid Leukemia

Axi-cel

Axicabtagene Ciloleucel

CAN

Copy-number Alteration

CAR

Chimeric Antigen Receptor

CARB

CAR-transduced B-cell leukemia

CR

Complete Response

CRS

Cytokine Release Syndrome

DLBCL

Diffuse Large B-Cell Lymphoma

Liso-cel

Lisocabtagene Maraleucel

LOH

Loss Of Heterozygosity

MCL

Mantle Cell Lymphoma

OS

Overall Survival

PFS

Progression-Free Survival

PMBCL

Primary Mediastinal B-Cell Lymphoma

PR

Partial Response

r/r

Relapsed/refractory

RR

Response Rate

SCT

Stem Cell Transplant

TCR

T-Cell Receptor

tFL

DLBCL arising from Follicular Lymphoma

Tisa-cel

Tisagenlecleucel

WES

Whole-genome sequencing

Notes

Acknowledgements

The authors would like to thank Erin Morris, RN in her assistance in the preparation of this manuscript.

Disclosure of Conflict of Interest

L.J.M has received research support from Celgene, Janssen, Amgen, and GlaxoSmithKline; honorarium from Celgene, Amgen, Karyopharm, GlaxoSmithKline, and Kite; and speaker fees from Amgen and Sanofi. A.C.X has no conflict of interest to disclose.

References

  1. 1.
    Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9(9):1183–97.CrossRefGoogle Scholar
  2. 2.
    Strati P, Neelapu SS. Chimeric antigen receptor-engineered T cell therapy in lymphoma. Curr Oncol Rep. 2019;21(5):38.CrossRefGoogle Scholar
  3. 3.
    Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.CrossRefGoogle Scholar
  4. 4.
    Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31–42.CrossRefGoogle Scholar
  5. 5.
    Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116.CrossRefGoogle Scholar
  6. 6.
    Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56.CrossRefGoogle Scholar
  7. 7.
    Abramson JS, Gordon LI, Palomba ML, Lunning MA, Arnason JE, Forero-Torres A, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36(15_suppl):7505.CrossRefGoogle Scholar
  8. 8.
    Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, et al. Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood. 2016;127(24):2980–90.CrossRefGoogle Scholar
  9. 9.
    Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122(25):4129–39.CrossRefGoogle Scholar
  10. 10.
    Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med. 2017;23(2):242–9.CrossRefGoogle Scholar
  11. 11.
    Rivers J, Annesley C, Summers C, Finney O, Pulsipher M, Wayne A, et al. Early response data for pediatric patients wiht non-Hodgkin lymphoma treated with CD19 chimeric antigen receptor (CAR) T-cells. Br J Haematol. 2018;182(Suppl. 1). (23):Abstract 29Google Scholar
  12. 12.
    Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–95.CrossRefGoogle Scholar
  13. 13.
    Fischer J, Paret C, El Malki K, Alt F, Wingerter A, Neu MA, et al. CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis. J Immunother. 2017;40(5):187–95.CrossRefGoogle Scholar
  14. 14.
    van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F, et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120(4):1265–74.CrossRefGoogle Scholar
  15. 15.
    Braig F, Brandt A, Goebeler M, Tony HP, Kurze AK, Nollau P, et al. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017;129(1):100–4.CrossRefGoogle Scholar
  16. 16.
    Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127(20):2406–10.CrossRefGoogle Scholar
  17. 17.
    Yang Y, Kohler ME, Chien CD, Sauter CT, Jacoby E, Yan C, et al. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci Transl Med. 2017;9(417):eaag1209.CrossRefGoogle Scholar
  18. 18.
    Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581–90.CrossRefGoogle Scholar
  19. 19.
    Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24(10):1499–503.CrossRefGoogle Scholar
  20. 20.
    Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20–8.CrossRefGoogle Scholar
  21. 21.
    Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129(8):1039–41.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of PediatricsUniversity of Alabama at Birmingham, Children’s Hospital of AlabamaBirminghamUSA
  2. 2.Division of Hematology/Oncology, Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations