CAR-T cell and Personalized Medicine

  • Marlid Cruz-Ramos
  • Jesús García-FoncillasEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1168)


Adoptive T cell transfer (ACT) is a new era for cancer treatment, involving infusion of autologous lymphocytes. Chimeric antigen receptors (CAR) on the surface of T cells are emerging as a novel therapeutic that is giving other direction to T-cell specificity and precision medicine. T cells are engineered modification to recognize specific target antigen and are co-stimulated with intracellular signal to increase the T cell response. CAR-T cells have impressive involvement in outcome on hematological malignancies; however severe toxicities as cytokine release syndrome or neurotoxicity are a challenge to face. Solid tumors have heterogeneous antigens and tumor microenvironment that hinder CAR-T cell efficacy and increase the risk of on-target/off-tumor. Novel strategies to increase CAR-Ts specificity, safety and efficacy are ongoing in clinical trials to improve clinical outcomes in hematological and solid malignances.


Adaptive immune system Chimeric antigen receptor (CAR) Hematological malignancies Solid tumors Target antigen 


  1. 1.
    Topalian SL, Muul LM, Solomon D, Rosenberg SA (1987) Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. J Immunol Methods 102(1):127–141PubMedCrossRefGoogle Scholar
  2. 2.
    Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12:269–281PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Jackson HJ, Rafiq S, Brentjens RJ (2016) Driving CAR T – cells forward. Nat Rev Clin Oncol 13(6):370–383PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Sadelain M, Brentjens R, Rivière I (2013) The basic principles of chimeric antigen receptor design. Cancer Discov 3:388–398PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR et al (2010) Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16(9):1245–1256PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Pillai M, Burt DJ 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 66(11):1425–1436PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G et al (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121(5):1822–1826PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M (2010) Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI 3 kinase/AKT/Bcl-X L activation and CD8 T cell-mediated tumor eradication. Mol Ther 18(2):413–420PubMedCrossRefGoogle Scholar
  9. 9.
    Park JH, Riviere I, Wang X, Bernal Y, Purdon T, Halton E, Curran KJ, Craig Steven Sauter MS (2015) Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. J Clin Oncol 33:7010–7010CrossRefGoogle Scholar
  10. 10.
    Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al (2013) Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Maude SL, Teachey DT, Rheingold SR, Shaw PA, Aplenc R, Barrett DM, Barker CS, Callahan C, Frey NV, Nazimuddin F, Lacey SF, Zheng Z, Levine B, Melenhorst JJ, SAG L (2016) Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. J Clin Oncol 34:3011–3011CrossRefGoogle Scholar
  13. 13.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA et al (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):517–528PubMedCrossRefGoogle Scholar
  14. 14.
    Lee DW III, Stetler-Stevenson M, Yuan CM et al (2016) Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood 128(22):218CrossRefGoogle Scholar
  15. 15.
    Turtle CJ, Berger C, Sommermeyer D, Budiarto T, Hanafi L-A, Melville K, Pender B, Steevens N, Chaney C, Heimfeld S, Cherian S, Wood BL, Soma L, Chen X, Jensen M, Sta DGM (2015) Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition. J Clin Oncol 33(15_suppl):3006):3006–3006):3006CrossRefGoogle Scholar
  16. 16.
    Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ 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):492–500PubMedCrossRefGoogle Scholar
  17. 17.
    Turtle CJ, Hanafi L, Berger C, Gooley TA, Cherian S, Hudecek M et al (2016) CD19 CAR – T cells of defined CD4 + : CD8 + composition in adult B cell ALL patients. J Clin Invest 1(6):1–16Google Scholar
  18. 18.
    Porter DL, Hwang W, Frey NV, Lacey SF, P a S, Loren AW et al (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7(303):303ra139PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA et al (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. Scholar
  20. 20.
    Garfall AL, Maus MV, Hwang W-T, Lacey SF, Mahnke YD, Melenhorst JJ et al (2015) Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med 373(11):1040–1047PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Fitzgerald JC, Weiss SL, Maude SL, Barrett DM, Lacey SF, Melenhorst JJ et al (2017) Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med 45(2):e124–e131PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K et al (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6(224):224ra25PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K et al (2017) Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129(25):3322–3331PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Maude SL, Barrett DM, Rheingold SR, Aplenc R, Teachey DT, Callahan C et al (2016) Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/refractory acute lymphoblastic leukemia. Blood 128(22):217 LP–217217CrossRefGoogle Scholar
  25. 25.
    Rossig C, Pule M, Altvater B, Saiagh S, Wright G, Ghorashian S et al (2017) Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia. Leukemia 31(5):1087–1095PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Competitive transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T cells for B-cell leukemia/lymphoma – full text view – [Internet].
  27. 27.
    Genetically engineered lymphocyte therapy in treating patients with lymphoma that is resistant or refractory to chemotherapy – full text view – [Internet].
  28. 28.
    Treatment of relapsed and/or chemotherapy refractory B-cell malignancy by tandem CAR T cells targeting CD19 and CD20 – full text view – [Internet].
  29. 29.
    Anti-CD22 chimeric receptor T cells in pediatric and young adults with recurrent or refractory CD22-expressing B cell malignancies – full text view – [Internet].
  30. 30.
    Administration of T lymphocytes for Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (CART CD30) – full text view – [Internet]. [citado 20 de abril de 2018].
  31. 31.
    Treatment of relapsed and/or chemotherapy refractory CD33 positive acute myeloid leukemia by CART-33 – full text view – [Internet]. [citado 20 de abril de 2018].
  32. 32.
    Genetically modified T-cell immunotherapy in treating patients with relapsed/refractory acute myeloid leukemia and persistent/recurrent Blastic Plasmacytoid dendritic cell neoplasm – full text view – [Internet].
  33. 33.
    Treatment of chemotherapy refractory multiple myeloma by CART-138 – full text view – [Internet].
  34. 34.
    Autologous ROR1R-CAR-T cells for chronic lymphocytic leukemia (CLL) – full text view – [Internet].
  35. 35.
    Kappa-CD28 T lymphocytes, chronic lymphocytic leukemia, B-cell lymphoma or multiple myeloma, CHARKALL – full text view – [Internet].
  36. 36.
    Safety study of anti LewisY chimeric antigen receptor in myeloma, acute myeloid leukemia or myelodysplastic syndrome – full text view – [Internet].
  37. 37.
    Study of T cells targeting B-cell maturation antigen for previously treated multiple myeloma – full text view – [Internet].
  38. 38.
    D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M (2018) CAR-T cells: the long and winding road to solid tumors review-article. Cell Death Dis 9:282PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Fiorentino A, De BP, Chiesa S, Balducci M, Fusco V (2013) Elderly patients with glioblastoma: the treatment challenge. Expert Rev Neurother 13:1099–1105PubMedCrossRefGoogle Scholar
  40. 40.
    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (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(4):843–851PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C 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(15):1688–1696PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hassan R, Bera T, Mesothelin PI (2004) A new target for immunotherapy. Clin Cancer Res 10:3937–3942PubMedCrossRefGoogle Scholar
  43. 43.
    Morello A, Sadelain M, Adusumilli PS (2016) Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov 6:133–146PubMedCrossRefGoogle Scholar
  44. 44.
    Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X et al (2013) T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 1(1):26–31PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD et al (2011) Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118(23):6050–6056PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    A phase I trial of t cells expressing an anti-GD2 chimeric antigen receptor in children and young adults with GD2+ solid tumors – full text view – [Internet].
  47. 47.
    Haffner MC, Kronberger IE, Ross JS, Sheehan CE, Zitt M, Mühlmann G et al (2009) Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers. Hum Pathol 40(12):1754–1761PubMedCrossRefGoogle Scholar
  48. 48.
    Slovin SF, Wang X, Borquez-Ojeda O, Stefanski J, Olszewska M, Taylor C et al (2012) Targeting castration resistant prostate Cancer (CRPC) with autologous PSMA-directed chimeric antigen receptor T cells. Mol Ther 20:S33Google Scholar
  49. 49.
    Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo ASY et al (2016) Phase I trial of anti-PSMA designer CAR-T cells in prostate Cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate 76(14):1257–1270PubMedCrossRefGoogle Scholar
  50. 50.
    Autologous T cells redirected to EGFRVIII-with a chimeric antigen receptor in patients with EGFRVIII+ glioblastoma – full text view –
  51. 51.
    CAR T cell receptor immunotherapy targeting EGFRvIII for patients with malignant gliomas expressing EGFRvIII – full text view – [Internet].
  52. 52.
    Her2 chimeric antigen receptor expressing T cells in advanced sarcoma – full text view – [Internet].
  53. 53.
    T Cells expressing HER2-specific chimeric antigen receptors (CAR) For patients with glioblastoma – full text view – [Internet].
  54. 54.
    CMV-specific cytotoxic T lymphocytes expressing CAR targeting HER2 in patients with GBM – full text view – [Internet].
  55. 55.
    Autologous redirected RNA Meso-CIR T cells – full text view – [Internet].
  56. 56.
    Pilot study of autologous T-cells in patients with metastatic pancreatic cancer – full text view – [Internet].
  57. 57.
    CAR T Cell receptor immunotherapy targeting mesothelin for patients with metastatic cancer – full text view – [Internet].
  58. 58.
    3rd generation GD-2 chimeric antigen receptor and iCaspase suicide safety switch, neuroblastoma, grain – full text view – [Internet].
  59. 59.
    Adoptive transfer of autologous T cells targeted to prostate specific membrane antigen (PSMA) for the treatment of castrate metastatic prostate Cancer (CMPC) – full text view – [Internet].
  60. 60.
    Trial of anti-PSMA designer T cells in advanced prostate cancer after non-myeloablative conditioning – full text view – [Internet].
  61. 61.
    CAR T cells in treating patients with malignant gliomas overexpressing EGFR – full text view – [Internet].
  62. 62.
    Re-directed T cells for the treatment (FAP)-positive malignant pleural mesothelioma – full text view – [Internet].
  63. 63.
    Phase I/II study of anti-Mucin1 (MUC1) CAR T cells for patients with MUC1+ advanced refractory solid tumor – full text view – [Internet].
  64. 64.
    Engineered neuroblastoma cellular immunotherapy (EnciT)-01 – full text view – [Internet].
  65. 65.
    Anti-GPC3 CAR T for treating patients with advanced HCC – full text view – [Internet].
  66. 66.
    Genetically modified T-cells in treating patients with recurrent or refractory malignant glioma – full text view – [Internet].
  67. 67.
    Wang Z, Wu Z, Liu Y, Han W (2017) New development in CAR-T cell therapy. J Hematol Oncol 10:53Google Scholar
  68. 68.
    Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA et al (2016) Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest 126(8):3036–3052PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    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(215):215ra172PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Diaconu I, Ballard B, Zhang M, Chen Y, West J, Dotti G et al (2017) Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol Ther 25(3):580–592PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    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 5:235PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR et al (2016) Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci 113(4):E459–E468PubMedCrossRefGoogle Scholar
  73. 73.
    Sentman CL, Meehan KR (2014) NKG2D CARs as cell therapy for Cancer. Cancer J 20(2):156–159PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Zhang T, Barber A, Sentman CL (2007) Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways. Cancer Res 67(22):11029–11036PubMedCrossRefGoogle Scholar
  75. 75.
    Chmielewski M, Abken H (2015) TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther 15(8):1145–1154PubMedCrossRefGoogle Scholar
  76. 76.
    Chinnasamy D, Yu Z, Theoret MR, Zhao Y, Shrimali RK, Morgan RA et al (2010) Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J Clin Invest 120(11):3953–3968PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC (2018) CAR T cell immunotherapy for human cancer. Science 359(6382):1361–1365PubMedCrossRefGoogle Scholar
  78. 78.
    Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355(10):1018–1028PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N et al (2016) Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. CD-16-0040Google Scholar
  80. 80.
    Milone MC (2018) BVG. The pharmacology of T cell therapies. Mol Ther Methods Clin Dev 8:210–221PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M et al (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124(2):188–195PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ et al (2018) Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 378(5):449–459PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Gust J, Hay KA, Hanafi L-A, Li D, Myerson D, Gonzalez-Cuyar LF et al (2017) Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 7(12):1404–1419PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Annesley CE, Summers C, Ceppi F, Gardner RA (2018) The evolution and future of CAR T cells for B-cell acute lymphoblastic leukemia. Clin Pharmacol Ther 103(4):591–598PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Translational Oncology Division, Oncohealth InstituteIIS-Fundación Jimenez Diaz-UAMMadridSpain

Personalised recommendations