Advertisement

CAR-T Cells for Cancer Treatment: Current Design and Next Frontiers

  • Virgínia Picanço-CastroEmail author
  • Kamilla Swiech
  • Kelen Cristina Ribeiro Malmegrim
  • Dimas Tadeu Covas
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 2086)

Abstract

Immunotherapy has been growing in the past decade as a therapeutic alternative for cancer treatment. In this chapter, we deal with CAR-T cells, genetically engineered autologous T cells to express a chimeric receptor specific for an antigen expressed on tumor cell surface. While this type of personalized therapy is revolutionizing cancer treatment, especially B cell malignancies, it has some challenging limitations. Here, we discuss the basic immunological and technological aspects of CAR-T cell therapy, the limitations that have compromised its efficacy and safety, and the current proposed strategies to overcome these limitations, thereby allowing for greater therapeutic application of CAR-T cells.

Key words

CAR-T cells Chimeric antigen receptor Immunotherapy T cells 

Notes

Acknowledgements

This work was financially supported by FAPESP (2012/23228-4, 2016/08374- 5, 2017/09491-8), CTC Center for Cell-based Therapies (FAPESP 2013/08135-2) and National Institute of Science and Technology in Stem Cell and Cell Therapy (CNPq 573754-2008-0 and FAPESP 2008/578773). The authors also acknowledge financial support from Secretaria Executiva do Ministério da Saúde (SE/MS), Departamento de Economia da Saúde, Investimentos e Desenvolvimento (DESID/SE), Programa Nacional de Apoio à Atenção Oncológica (PRONON) Process 25000.189625/2016-16.

References

  1. 1.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264CrossRefGoogle Scholar
  2. 2.
    Mathis S, Vallat JM, Magy L (2016) Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy. Immunotherapy 8:165–178CrossRefGoogle Scholar
  3. 3.
    Kershaw MH, Westwood JA, Slaney CY et al (2014) Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunology. 3:e16CrossRefGoogle Scholar
  4. 4.
    Batlevi CL, Matsuki E, Brentjens RJ et al (2015) Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 13:1–17Google Scholar
  5. 5.
    Maus MV, Grupp SA, Porter DL et al (2014) Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123:2625–2635CrossRefGoogle Scholar
  6. 6.
    Milone MC, Fish JD, Carpenito C et al (2009) Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17:1453–1464CrossRefGoogle Scholar
  7. 7.
    Long AH, Haso WM, Shern JF et al (2015) 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21:581–590CrossRefGoogle Scholar
  8. 8.
    Kalos M, Levine BL, Porter DL et al (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73CrossRefGoogle Scholar
  9. 9.
    Fesnak A, Lin CY, Siegel DL et al (2016) CAR-T Cell Therapies From the Transfusion Medicine Perspective. Transfus Med Rev 30(3):139–145CrossRefGoogle Scholar
  10. 10.
    Bryn T, Yaqub S, Mahic M et al (2008) LPS-activated monocytes suppress T-cell immune responses and induce FOXP3+ T cells through a COX-2-PGE2-dependent mechanism. Int Immunol 20(2):235–245CrossRefGoogle Scholar
  11. 11.
    Dehghani M, Sharifpour S, Amirghofran Z et al (2012) Prognostic significance of T cell subsets in peripheral blood of B cell non-Hodgkin’s lymphoma patients. Med Oncol 29:2364–2371CrossRefGoogle Scholar
  12. 12.
    Golubovskaya V, Wu L (2016) Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancer 8(3):E36CrossRefGoogle Scholar
  13. 13.
    Gattinoni L, Klebanoff CA, Restifo NP (2012) Paths to stemness: Building the ultimate antitumour T cell. Nat Rev Cancer 12(10):671–684CrossRefGoogle Scholar
  14. 14.
    Xu Y, Zhang M, Ramos CA (2014) Closely related T-memory stem cells correlate with in vivo expansion of CAR CD19-T cells and are preserved by IL-7 and IL-15. Blood 123(24):3750–3759CrossRefGoogle Scholar
  15. 15.
    Turtle CJ, Hanafi LA, Berger C (2016) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 126(6):2123–2138CrossRefGoogle Scholar
  16. 16.
    Sommermeyer D, Hudecek M, Kosasih PL et al (2016) Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30(2):492–500CrossRefGoogle Scholar
  17. 17.
    Grupp SA, Kalos M, Barret D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518CrossRefGoogle Scholar
  18. 18.
    Sun Z, Wang S, Zhao RC (2014) The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol 7:14CrossRefGoogle Scholar
  19. 19.
    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 18:843–851CrossRefGoogle Scholar
  20. 20.
    Maude SL, Barrett D, Teachey DT et al (2014) Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20:119–122CrossRefGoogle Scholar
  21. 21.
  22. 22.
    Nassereddine S, Rafei H, Elbahesh E et al (2017) Acute graft versus host disease: a comprehensive review. Anticancer Res 37(4):1547–1555CrossRefGoogle Scholar
  23. 23.
    Poirot L, Philip B, Schiffer-Mannioui C et al (2015) Multiplex genome-edited T-cell manufacturing platform for ‘off-the-shelf’ adoptive T-cell immunotherapies. Cancer Res 75(18):3853–3864CrossRefGoogle Scholar
  24. 24.
    Graham C, Yallop D, Jozwik A (2017) Preliminary results of UCART19, an allogeneic Anti-CD19 CAR T-cell product, in a first-in-human trial (CALM) in adult patients with CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia. Blood 130:887Google Scholar
  25. 25.
    Davila ML, Riviere I, Wang X (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6(224):224ra25CrossRefGoogle Scholar
  26. 26.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517–528CrossRefGoogle Scholar
  27. 27.
    Barlow B, Barlow A, Freyer C (2018) CAR-T cells: driving a new era of oncology immunotherapy. US Pharm 43(11):15–22Google Scholar
  28. 28.
    Brudno JN, Kochenderfer JN (2016) Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127(26):3321–3330CrossRefGoogle Scholar
  29. 29.
    Neelapu SS, Tummala S, Kebriaei P (2018) Chimeric antigen receptor T-cell therapy-assessment and management of toxicities. Nat Rev Clin Oncol 15(1):47–62CrossRefGoogle Scholar
  30. 30.
    Viaud S, Ma JSY, Hardy IR (2018) Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory. Proc Natl Acad Sci 115(46):E10898–E10906CrossRefGoogle Scholar
  31. 31.
    Lee YG, Marks I, Srinivasarao M et al (2019) Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors. Cancer Res 79(2):387–396CrossRefGoogle Scholar
  32. 32.
    Zhang E, Xu H (2017) A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy. J Hematol Oncol 10(1):1CrossRefGoogle Scholar
  33. 33.
    Yeku OO, Purdon T, Spriggs DR et al (2018) Interleukin-12 armored chimeric antigen receptor (CAR) T cells for heterogeneous antigen-expressing ovarian cancer. J Clin Oncol 36(5):12CrossRefGoogle Scholar
  34. 34.
    Hegde M, Mukherjee M, Grada Z (2016) Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest 126(8):3036–3052CrossRefGoogle Scholar
  35. 35.
    Cho JH, Collins JJ, Wong WW (2018) Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173(6):1426–1438CrossRefGoogle Scholar
  36. 36.
    Moon EK, Carpenito C, Sun J et al (2011) Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res 17(14):4719–4730CrossRefGoogle Scholar
  37. 37.
    Caruana I, Savoldo B, Hoyo V et al (2015) Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 21(5):524–529CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Virgínia Picanço-Castro
    • 1
    Email author
  • Kamilla Swiech
    • 2
  • Kelen Cristina Ribeiro Malmegrim
    • 2
  • Dimas Tadeu Covas
    • 1
    • 3
  1. 1.Center for Cell-Based Therapy CTC, Regional Blood Center of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  2. 2.School of Pharmaceutical Sciences of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  3. 3.Ribeirão Preto Medical SchoolUniversity of São PauloSão PauloBrazil

Personalised recommendations