Skip to main content

Advertisement

SpringerLink
Log in

CAR T Cells for Solid Tumors

  • Cellular Therapies: Preclinical and Clinical (EM Horwitz, Section Editor)
  • Published:
Current Stem Cell Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

In this manuscript, we review the current state of chimeric antigen receptor (CAR) T cells, their successes and shortcomings in targeting solid tumors. These engineered receptors have evolved from an over reaching concept to a clinical product that has revolutionized cancer therapy.

Recent Findings

Unlike earlier generations of expanded tumor-infiltrating lymphocytes, CAR T cells are not limited to an MHC-restricted response. Armed with multiple costimulatory domains in one frame, CAR T cells carry unparalleled activation potential. CAR T cells for relapsed leukemia have had an enormous impact on the field of cancer immunology and have become a beacon of hope for some difficult to treat patients. Unfortunately, CAR T cells have to date not shown similar efficacy for solid tumors.

Summary

Here, we delve into specifics within solid tumor microenvironments that are responsible for dampening CAR T cell efficacy. Each of these elements constitutes a front where future opportunity lies. We encourage our readers to explore this field, which is in its infancy, and take steps to move it forward.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev. 2016;30:157–67.

    Article  CAS  PubMed  Google Scholar 

  2. •• Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86:10024–8. This study provides first proof of concept for non MHC restrcited T cell cytotoxicity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dudley ME, Gross CA, Somerville RP, Hong Y, Schaub NP, Rosati SF, et al. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol. 2013;31:2152–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Johnson LA, June CH. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 2017;27:38–58.

    Article  CAS  PubMed  Google Scholar 

  6. Hughes MS, Yu YY, Dudley ME, Zheng Z, Robbins PF, Li Y, et al. Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. Hum Gene Ther. 2005;16:457–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. •• Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126–9. This study is one of earliest engineered T cell work in combat with cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eshhar Z, Bach N, Fitzer-Attas CJ, Gross G, Lustgarten J, Waks T, et al. The T-body approach: potential for cancer immunotherapy. Springer Semin Immunopathol. 1996;18:199–209.

    Article  CAS  PubMed  Google Scholar 

  9. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14:1264–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Krebs S, Chow KK, Yi Z, Rodriguez-Cruz T, Hegde M, Gerken C, et al. T cells redirected to interleukin-13Rα2 with interleukin-13 mutein—chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1. Cytotherapy. 2014;16:1121–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sentman CL, Meehan KR. NKG2D CARs as cell therapy for cancer. Cancer J. 2014;20:156–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. VanSeggelen H, Hammill JA, Dvorkin-Gheva A, Tantalo DG, Kwiecien JM, Denisova GF, et al. T cells engineered with chimeric antigen receptors targeting NKG2D ligands display lethal toxicity in mice. Mol Ther. 2015;23:1600–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang X, Xiao Q, Wang Z, Feng WL. CAR-T therapy for leukemia: progress and challenges.. Transl Res. 2017;182:135–44.

  14. Bridgeman JS, Hawkins RE, Hombach AA, Abken H, Gilham DE. Building better chimeric antigen receptors for adoptive T cell therapy. Curr Gene Ther. 2010;10:77–90.

    Article  CAS  PubMed  Google Scholar 

  15. Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121:1165–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118:6050–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol. 2004;172:104–13.

    Article  CAS  PubMed  Google Scholar 

  18. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Barrett DM, Singh N, Porter DL, Grupp SA, June CH. Chimeric antigen receptor therapy for cancer. Annu Rev Med. 2014;65:333–47.

    Article  CAS  PubMed  Google Scholar 

  20. Wang Z, Sokolovska A, Seymour R, Sundberg JP, Hogenesch H. SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells. PLoS One. 2012;7:e31809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Imai C, Mihara K, Andreansky M, Nicholson IC, Pui C-HH, Geiger TL, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004;18:676–84.

    Article  CAS  PubMed  Google Scholar 

  22. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. •• Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17. This study highlights the most succesful anti CD19 CAR trial avialable clinically until today.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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;21:581–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–90.

    Article  CAS  PubMed  Google Scholar 

  26. Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhong X-SS, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther. 2010;18:413–20.

    Article  CAS  PubMed  Google Scholar 

  28. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009;106:3360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hollyman D, Stefanski J, Przybylowski M, Bartido S, Borquez-Ojeda O, Taylor C, et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J Immunother. 2009;32:169–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hurton LV, Singh H, Najjar AM, Switzer KC, Mi T, Maiti S, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A. 2016;113:E7788–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Barrett DM, Singh N, Liu X, Jiang S, June CH, Grupp SA, et al. Relation of clinical culture method to T-cell memory status and efficacy in xenograft models of adoptive immunotherapy. Cytotherapy. 2014;16:619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu Y, Zhang M, Ramos CA, Durett A, Liu E, Dakhova O, et al. 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. 2014;123:3750–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maus MV, Thomas AK, Leonard DG, Allman D, Addya K, Schlienger K, et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nat Biotechnol. 2002;20:143–8.

    Article  CAS  PubMed  Google Scholar 

  35. Scholler J, Brady TL, Binder-Scholl G, Hwang W-TT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4:132ra53.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang GP, Levine BL, Binder GK, Berry CC, Malani N, McGarrity G, et al. Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther. 2009;17:844–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hackett PB, Largaespada DA, Cooper LJ. A transposon and transposase system for human application. Mol Ther. 2010;18:674–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kebriaei P, Huls H, Jena B, Munsell M, Jackson R, Lee DA, et al. Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. Hum Gene Ther. 2012;23:444–50.

    Article  CAS  PubMed  Google Scholar 

  39. Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res. 2014;2:112–20.

    Article  CAS  PubMed  Google Scholar 

  40. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013;10:267–76.

    Article  CAS  PubMed  Google Scholar 

  41. Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.

    Article  CAS  PubMed  Google Scholar 

  44. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112:2261–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116:4099–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18:843–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fousek K, Ahmed N. The evolution of T-cell therapies for solid malignancies. Clin Cancer Res. 2015;21:3384–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H. Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Science China Life … [Internet]. 2016; Available from: http://link.springer.com/article/10.1007/s11427-016-5023-8

  52. Wilkie S, Picco G, Foster J, Davies DM. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. The Journal of … [Internet]. 2008; Available from: http://www.jimmunol.org/content/180/7/4901.short

  53. Johnson LA, Scholler J, Ohkuri T. Rational development and characterization of humanized anti–EGFR variant III chimeric antigen receptor T cells for glioblastoma. Science translational … [Internet]. 2015; Available from: http://stm.sciencemag.org/content/7/275/275ra22.short

  54. Gargett T, Brown MP. 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. 2014;5:235.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Marin V, Cribioli E, Philip B, Tettamanti S, Pizzitola I, Biondi A, et al. Comparison of different suicide-gene strategies for the safety improvement of genetically manipulated T cells. Hum Gene Ther Methods. 2012;23:376–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira AC, et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J Clin Immunol. 2012;32:1059–70.

    Article  CAS  PubMed  Google Scholar 

  57. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol. 2013;31:71–5.

    Article  CAS  PubMed  Google Scholar 

  58. Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10:53.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M, et al. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell. 2016;164:780–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, et al. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res. 2014;20:972–84.

    Article  CAS  PubMed  Google Scholar 

  61. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077–85.

  62. Craddock JA, Lu A, Bear A, Pule M. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. Journal of … [Internet]. 2010; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998197/

  63. Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res. 2014;74:5195–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Slaney CY, von Scheidt B, Davenport AJ, Beavis PA, Westwood JA, Mardiana S, Tscharke DC, Ellis S, Prince HM, Trapani JA, Johnstone RW, Smyth MJ, Teng MW, Ali A, Yu Z, Rosenberg SA, Restifo NP, Neeson P, Darcy PK, Kershaw MH. Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting. Clin Cancer Res. 2017;23(10):2478–490.

  65. Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology. 2015;4:e994446.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Koneru M, O’Cearbhaill R, Pendharkar S, Spriggs DR, Brentjens RJ. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med. 2015;13:102.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee C-CRC, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210:1125–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schönfeld K, Koch J, Dotti G, Heslop HE, Gottschalk S, Wels WS, Baker ML, Ahmed N. TanCAR: A novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids. 2013;2:e105

  69. Zhang Y, Ertl HC. Starved and asphyxiated: How can CD8(+) T cells within a tumor microenvironment prevent tumor progression. Front Immunol. 2016;7:32. doi:10.3389/fimmu.2016.00032. eCollection 2016.

  70. Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood. 2015;125(25):3905–16.

  71. Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 2015;64:817–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sakaguchi S, Miyara M, Costantino CM. FOXP3+ regulatory T cells in the human immune system. … Reviews Immunology [Internet]. 2010; Available from: http://www.nature.com/nri/journal/v10/n7/abs/nri2785.html

  73. Yao X, Ahmadzadeh M, Lu Y-CC, Liewehr DJ, Dudley ME, Liu F, et al. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012;119:5688–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Katz SC, Point GR, Cunetta M, Thorn M, Guha P, Espat NJ, et al. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther. 2016;23:142–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP, Gattinoni L. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest. 2013;123(10):4479–88.

  76. Newick K, O’Brien S, Sun J, Kapoor V, Maceyko S, Lo A, et al. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase a localization. Cancer Immunol Res. 2016;4:541–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer. 2013;13:788–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Oh SA, Li MO. TGF-β: guardian of T cell function. J Immunol. 2013;191(8):3973–9.

  79. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7:1118–22.

    Article  CAS  PubMed  Google Scholar 

  80. Thomas DA, Massagué J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369–80.

    Article  CAS  PubMed  Google Scholar 

  81. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126:3130–44.

    Article  PubMed  PubMed Central  Google Scholar 

  82. John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19:5636–46.

    Article  CAS  PubMed  Google Scholar 

  83. Moon E, Ranganathan R, Eruslanov E, Kim S, Newick K, O’Brien S, et al. Blockade of programmed death 1 augments the ability of human T cells engineered to target ny-eso-1 to control tumor growth after adoptive transfer. Clin Cancer Res highwire. 2016;22:436–47.

    Article  CAS  Google Scholar 

  84. Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 2016;76:1578–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mahvi DA, Meyers JV, Tatar AJ. CTLA-4 blockade plus adoptive T cell transfer promotes optimal melanoma immunity in mice. Journal of … [Internet]. 2015; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321765/

  86. Müller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010;10:645–56.

    Article  PubMed  Google Scholar 

  87. Newick K, O’Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med. 2017;68:139–52.

    Article  CAS  PubMed  Google Scholar 

  88. Riese MJ, Wang LC, Moon EK, Joshi RP, Ranganathan A, June CH, Koretzky GA, Albelda SM. Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res. 2013;73(12):3566–77.

Download references

Author information

Authors and Affiliations

  1. Division of Oncology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Babak Moghimi & David Barrett

Authors
  1. Babak Moghimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Barrett.

Ethics declarations

Conflict of Interest

Babak Moghimi declares that he has no conflicts of interest.

David Barrett reports that The University of Pennsylvania and Novartis have entered into a clinical trial partnership for chimeric antigen receptors. He is a faculty at the University of Pennsylvania but received no financial support and is in compliance with the University’s conflict of interest policies.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Cellular Therapies: Preclinical and Clinical

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moghimi, B., Barrett, D. CAR T Cells for Solid Tumors. Curr Stem Cell Rep 3, 269–278 (2017). https://doi.org/10.1007/s40778-017-0101-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40778-017-0101-9

Keywords

Search

Navigation