Advertisement

BioDrugs

, Volume 33, Issue 6, pp 647–659 | Cite as

CAR-T Engineering: Optimizing Signal Transduction and Effector Mechanisms

  • Emiliano Roselli
  • Jeremy S. Frieling
  • Konrad Thorner
  • María C. Ramello
  • Conor C. Lynch
  • Daniel Abate-DagaEmail author
Review Article

Abstract

The adoptive transfer of genetically engineered T cells expressing a chimeric antigen receptor (CAR) has shown remarkable results against B cell malignancies. This immunotherapeutic approach has advanced and expanded rapidly from preclinical models to the recent approval of CAR-T cells to treat lymphomas and leukemia by the Food and Drug Administration (FDA). Ongoing research efforts are focused on employing CAR-T cells as a therapy for other cancers, and enhancing their efficacy and safety by optimizing their design. Here we summarize modifications in the intracellular domain of the CAR that gave rise to first-, second-, third- and next-generation CAR-T cells, together with the impact that these different designs have on CAR-T cell biology and function. Further, we describe how the structure of the antigen-sensing ectodomain can be enhanced, leading to superior CAR-T cell signaling and/or function. Finally we discuss how tissue-specific factors may impact the clinical efficacy of CAR-T cells for bone and the central nervous system, as examples of specific indications that may require further CAR signaling optimization to perform in such inhospitable microenvironments.

Notes

Acknowledgements

We would like to thank Gondor S. for assistance with figure design.

Compliance with Ethical Standards

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Emiliano Roselli, Jeremy S. Frieling, Konrad Thorner, and Conor C. Lynch declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. María Cecilia Ramello is listed as co-inventor in a provisional patent application filed by Moffitt Cancer Center. Daniel Abate-Daga is a member of Anixa Biosciences’ scientific advisory board and is listed as inventor or co-inventor in CAR-related provisional patent applications filed by Moffitt Cancer Center.

References

  1. 1.
    Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.  https://doi.org/10.1056/NEJMoa1215134.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    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(16):1507–17.  https://doi.org/10.1056/NEJMoa1407222.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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(9967):517–28.  https://doi.org/10.1016/S0140-6736(14)61403-3.CrossRefPubMedGoogle Scholar
  4. 4.
    Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.  https://doi.org/10.1126/scitranslmed.aac5415.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.  https://doi.org/10.1056/NEJMoa1709866.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    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.  https://doi.org/10.1038/nm.4441.CrossRefPubMedGoogle Scholar
  7. 7.
    Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun. 1987;149(3):960–8.CrossRefGoogle Scholar
  8. 8.
    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. 1989;86:10024–8.CrossRefGoogle Scholar
  9. 9.
    Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–37.  https://doi.org/10.1056/NEJMoa1817226.CrossRefPubMedGoogle Scholar
  10. 10.
    Vormittag P, Gunn R, Ghorashian S, Veraitch FS. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol. 2018;53:164–81.  https://doi.org/10.1016/j.copbio.2018.01.025.CrossRefPubMedGoogle Scholar
  11. 11.
    June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361–5.  https://doi.org/10.1126/science.aar6711.CrossRefPubMedGoogle Scholar
  12. 12.
    Kohl U, Arsenieva S, Holzinger A, Abken H. CAR T cells in trials: recent achievements and challenges that remain in the production of modified T cells for clinical applications. Hum Gene Ther. 2018;29(5):559–68.  https://doi.org/10.1089/hum.2017.254.CrossRefPubMedGoogle Scholar
  13. 13.
    Marchingo JM, Kan A, Sutherland RM, Duffy KR, Wellard CJ, Belz GT, et al. T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion. Science. 2014;346(6213):1123–7.  https://doi.org/10.1126/science.1260044.CrossRefPubMedGoogle Scholar
  14. 14.
    Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181:1653–9.CrossRefGoogle Scholar
  15. 15.
    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 Investig. 2011;121(5):1822–6.  https://doi.org/10.1172/JCI46110.CrossRefPubMedGoogle Scholar
  16. 16.
    Golumba-Nagy V, Kuehle J, Hombach AA, Abken H. CD28-zeta CAR T cells resist TGF-beta repression through IL-2 signaling, which can be mimicked by an engineered IL-7 autocrine loop. Mol Ther. 2018;26(9):2218–30.  https://doi.org/10.1016/j.ymthe.2018.07.005.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Loskog A, Giandomenico V, Rossig C, Pule M, Dotti G, Brenner MK. Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia. 2006;20(10):1819–28.  https://doi.org/10.1038/sj.leu.2404366.CrossRefPubMedGoogle Scholar
  18. 18.
    Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2):380–90.  https://doi.org/10.1016/j.immuni.2016.01.021.CrossRefPubMedGoogle Scholar
  19. 19.
    Priceman SJ, Gerdts EA, Tilakawardane D, Kennewick KT, Murad JP, Park AK, et al. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA + metastatic prostate cancer. Oncoimmunology. 2018;7(2):e1380764.  https://doi.org/10.1080/2162402X.2017.1380764.CrossRefPubMedGoogle Scholar
  20. 20.
    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.  https://doi.org/10.1038/nm.3838.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, et al. Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep. 2017;21(1):17–26.  https://doi.org/10.1016/j.celrep.2017.09.015.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li G, Boucher JC, Kotani H, Park K, Zhang Y, Shrestha B, et al. 4-1BB enhancement of CAR T function requires NF-kappaB and TRAFs. JCI Insight. 2018.  https://doi.org/10.1172/jci.insight.121322.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mamonkin M, Mukherjee M, Srinivasan M, Sharma S, Gomes-Silva D, Mo F, et al. Reversible transgene expression reduces fratricide and permits 4-1BB costimulation of CAR T cells directed to T-cell malignancies. Cancer Immunol Res. 2018;6(1):47–58.  https://doi.org/10.1158/2326-6066.CIR-17-0126.CrossRefPubMedGoogle Scholar
  24. 24.
    Salter AI, Ivey RG, Kennedy JJ, Voillet V, Rajan A, Alderman EJ, et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal. 2018.  https://doi.org/10.1126/scisignal.aat6753.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ramello MC, Benzaid I, Kuenzi BM, Lienlaf-Moreno M, Kandell WM, Santiago DN, et al. An immunoproteomic approach to characterize the CAR interactome and signalosome. Sci Signal. 2019.  https://doi.org/10.1126/scisignal.aap9777.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hombach AA, Heiders J, Foppe M, Chmielewski M, Abken H. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4(+) T cells. Oncoimmunology. 2012;1(4):458–66.CrossRefGoogle Scholar
  27. 27.
    Guedan S, Chen X, Madar A, Carpenito C, McGettigan SE, Frigault MJ, et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood. 2014;124(7):1070–80.  https://doi.org/10.1182/blood-2013-10-535245.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Song DG, Ye Q, Poussin M, Harms GM, Figini M, Powell DJ Jr. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood. 2012;119(3):696–706.  https://doi.org/10.1182/blood-2011-03-344275.CrossRefPubMedGoogle Scholar
  29. 29.
    Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. 2012;119(17):3940–50.  https://doi.org/10.1182/blood-2011-10-387969.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhong XS, 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(2):413–20.  https://doi.org/10.1038/mt.2009.210.CrossRefPubMedGoogle Scholar
  31. 31.
    Guedan S, Posey AD Jr, Shaw C, Wing A, Da T, Patel PR, et al. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight. 2018.  https://doi.org/10.1172/jci.insight.96976.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ramos CA, Rouce R, Robertson CS, Reyna A, Narala N, Vyas G, et al. In vivo fate and activity of second- versus third-generation CD19-specific CAR-T cells in B cell non-Hodgkin’s lymphomas. Mol Ther. 2018;26(12):2727–37.  https://doi.org/10.1016/j.ymthe.2018.09.009.CrossRefPubMedGoogle Scholar
  33. 33.
    Abate-Daga D, Lagisetty KH, Tran E, Zheng Z, Gattinoni L, Yu Z, et al. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum Gene Ther. 2014;25(12):1003–12.  https://doi.org/10.1089/hum.2013.209.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med. 2019;25(1):82–8.  https://doi.org/10.1038/s41591-018-0290-5.CrossRefPubMedGoogle Scholar
  35. 35.
    Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, Saso K, et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med. 2018;24(3):352–9.  https://doi.org/10.1038/nm.4478.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mestermann K, Giavridis T, Weber J, Rydzek J, Frenz S, Nerreter T, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019.  https://doi.org/10.1126/scitranslmed.aau5907.CrossRefPubMedGoogle Scholar
  37. 37.
    Weber EW, Lynn RC, Sotillo E, Lattin J, Xu P, Mackall CL. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv. 2019;3(5):711–7.  https://doi.org/10.1182/bloodadvances.2018028720.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ramello MC, Haura EB, Abate-Daga D. CAR-T cells and combination therapies: what’s next in the immunotherapy revolution? Pharmacol Res. 2018;129:194–203.  https://doi.org/10.1016/j.phrs.2017.11.035.CrossRefPubMedGoogle Scholar
  39. 39.
    Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9.  https://doi.org/10.1200/JCO.2014.56.2025.CrossRefPubMedGoogle Scholar
  40. 40.
    Kochenderfer JN, Feldman SA, Zhao Y, Xu H, Black MA, Morgan RA, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009;32(7):689–702.  https://doi.org/10.1097/CJI.0b013e3181ac6138.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    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(95):95ra73.  https://doi.org/10.1126/scitranslmed.3002842.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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(20):4099–102.  https://doi.org/10.1182/blood-2010-04-281931.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Drent E, Themeli M, Poels R, de Jong-Korlaar R, Yuan H, de Bruijn J, et al. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther. 2017;25(8):1946–58.  https://doi.org/10.1016/j.ymthe.2017.04.024.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75(17):3596–607.  https://doi.org/10.1158/0008-5472.CAN-15-0159.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;1(1):26–31.  https://doi.org/10.1158/2326-6066.CIR-13-0006.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lamers CH, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood. 2011;117(1):72–82.  https://doi.org/10.1182/blood-2010-07-294520.CrossRefPubMedGoogle Scholar
  47. 47.
    Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. 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. 2010;16(9):1245–56.  https://doi.org/10.1016/j.bbmt.2010.03.014.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sommermeyer D, Hill T, Shamah SM, Salter AI, Chen Y, Mohler KM, et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia. 2017;31(10):2191–9.  https://doi.org/10.1038/leu.2017.57.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Guedan S, Calderon H, Posey AD Jr, Maus MV. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev. 2019;12:145–56.  https://doi.org/10.1016/j.omtm.2018.12.009.CrossRefPubMedGoogle Scholar
  50. 50.
    Kahlon KS, Brown C, Cooper LJ, Raubitschek A, Forman SJ, Jensen MC. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 2004;64(24):9160–6.  https://doi.org/10.1158/0008-5472.CAN-04-0454.CrossRefPubMedGoogle Scholar
  51. 51.
    Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, et al. Bioactivity and safety of IL13Ralpha2-redirected chimeric antigen receptor CD8 + T cells in patients with recurrent glioblastoma. Clin Cancer Res. 2015;21(18):4062–72.  https://doi.org/10.1158/1078-0432.CCR-15-0428.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–9.  https://doi.org/10.1056/NEJMoa1610497.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Krebs S, Chow KK, Yi Z, Rodriguez-Cruz T, Hegde M, Gerken C, et al. T cells redirected to interleukin-13Ralpha2 with interleukin-13 mutein–chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Ralpha1. Cytotherapy. 2014;16(8):1121–31.  https://doi.org/10.1016/j.jcyt.2014.02.012.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kong S, Sengupta S, Tyler B, Bais AJ, Ma Q, Doucette S, et al. Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. Clin Cancer Res. 2012;18(21):5949–60.  https://doi.org/10.1158/1078-0432.CCR-12-0319.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Krenciute G, Krebs S, Torres D, Wu MF, Liu H, Dotti G, et al. Characterization and functional analysis of scFv-based chimeric antigen receptors to redirect T cells to IL13Ralpha2-positive glioma. Mol Ther. 2016;24(2):354–63.  https://doi.org/10.1038/mt.2015.199.CrossRefPubMedGoogle Scholar
  56. 56.
    Shaffer DR, Savoldo B, Yi Z, Chow KK, Kakarla S, Spencer DM, et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood. 2011;117(16):4304–14.  https://doi.org/10.1182/blood-2010-04-278218.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Siegler E, Li S, Kim YJ, Wang P. Designed ankyrin repeat proteins as Her2 targeting domains in chimeric antigen receptor-engineered T cells. Hum Gene Ther. 2017;28(9):726–36.  https://doi.org/10.1089/hum.2017.021.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hammill JA, VanSeggelen H, Helsen CW, Denisova GF, Evelegh C, Tantalo DG, et al. Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J Immunother Cancer. 2015;3:55.  https://doi.org/10.1186/s40425-015-0099-4.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Pameijer CR, Navanjo A, Meechoovet B, Wagner JR, Aguilar B, Wright CL, et al. Conversion of a tumor-binding peptide identified by phage display to a functional chimeric T cell antigen receptor. Cancer Gene Ther. 2007;14(1):91–7.  https://doi.org/10.1038/sj.cgt.7700993.CrossRefPubMedGoogle Scholar
  60. 60.
    Cortez-Retamozo V, Lauwereys M, Hassanzadeh GhG, Gobert M, Conrath K, Muyldermans S, et al. Efficient tumor targeting by single-domain antibody fragments of camels. Int J Cancer. 2002;98(3):456–62.CrossRefGoogle Scholar
  61. 61.
    De Munter S, Ingels J, Goetgeluk G, Bonte S, Pille M, Weening K, et al. Nanobody based dual specific CARs. Int J Mol Sci. 2018.  https://doi.org/10.3390/ijms19020403.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Sharifzadeh Z, Rahbarizadeh F, Shokrgozar MA, Ahmadvand D, Mahboudi F, Jamnani FR, et al. Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents. Cancer Lett. 2013;334(2):237–44.  https://doi.org/10.1016/j.canlet.2012.08.010.CrossRefPubMedGoogle Scholar
  63. 63.
    Xie YJ, Dougan M, Jailkhani N, Ingram J, Fang T, Kummer L, et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci USA. 2019;116(16):7624–31.  https://doi.org/10.1073/pnas.1817147116.CrossRefPubMedGoogle Scholar
  64. 64.
    Hudecek M, Sommermeyer D, Kosasih PL, Silva-Benedict A, Liu L, Rader C, et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res. 2015;3(2):125–35.  https://doi.org/10.1158/2326-6066.CIR-14-0127.CrossRefPubMedGoogle Scholar
  65. 65.
    Watanabe N, Bajgain P, Sukumaran S, Ansari S, Heslop HE, Rooney CM, et al. Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology. 2016;5(12):e1253656.  https://doi.org/10.1080/2162402X.2016.1253656.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Jonnalagadda M, Mardiros A, Urak R, Wang X, Hoffman LJ, Bernanke A, et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther. 2015;23(4):757–68.  https://doi.org/10.1038/mt.2014.208.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, et al. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol. 2008;180(7):4901–9.  https://doi.org/10.4049/jimmunol.180.7.4901.CrossRefPubMedGoogle Scholar
  68. 68.
    Guest RD, Hawkins RE, Kirillova N, Cheadle EJ, Arnold J, O’Neill A, et al. The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J Immunother. 2005;28(3):203–11.CrossRefGoogle Scholar
  69. 69.
    Qin L, Lai Y, Zhao R, Wei X, Weng J, Lai P, et al. Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells. J Hematol Oncol. 2017;10(1):68.  https://doi.org/10.1186/s13045-017-0437-8.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Alabanza L, Pegues M, Geldres C, Shi V, Wiltzius JJW, Sievers SA, et al. Function of novel Anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol Ther. 2017;25(11):2452–65.  https://doi.org/10.1016/j.ymthe.2017.07.013.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76.  https://doi.org/10.1053/ctrv.2000.0210.CrossRefPubMedGoogle Scholar
  72. 72.
    Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2(2):141–50.  https://doi.org/10.1016/j.stem.2007.11.014.CrossRefPubMedGoogle Scholar
  73. 73.
    Cook LM, Shay G, Araujo A, Lynch CC. Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev. 2014;33(2–3):511–25.  https://doi.org/10.1007/s10555-014-9494-4.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584–93.  https://doi.org/10.1038/nrc867.CrossRefPubMedGoogle Scholar
  75. 75.
    Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR75 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62:1832–7.PubMedGoogle Scholar
  76. 76.
    Arai Y, Choi U, Corsino CI, Koontz SM, Tajima M, Sweeney CL, et al. Myeloid conditioning with c-kit-targeted CAR-T cells enables donor stem cell engraftment. Mol Ther. 2018;26(5):1181–97.  https://doi.org/10.1016/j.ymthe.2018.03.003.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, et al. T lymphocytes coexpressing CCR77 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113(25):6392–402.  https://doi.org/10.1182/blood-2009-03-209650.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, et al. Expression of a functional CCR78 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res. 2011;17(14):4719–30.  https://doi.org/10.1158/1078-0432.CCR-11-0351.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR79b. J Immunother. 2010;33(8):780–8.  https://doi.org/10.1097/CJI.0b013e3181ee6675.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Santini D, Martini F, Fratto ME, Galluzzo S, Vincenzi B, Agrati C, et al. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol Immunother. 2009;58(1):31–8.  https://doi.org/10.1007/s00262-008-0521-6.CrossRefPubMedGoogle Scholar
  81. 81.
    Benzaid I, Monkkonen H, Bonnelye E, Monkkonen J, Clezardin P. In vivo phosphoantigen levels in bisphosphonate-treated human breast tumors trigger Vgamma9Vdelta2 T-cell antitumor cytotoxicity through ICAM-1 engagement. Clin Cancer Res. 2012;18(22):6249–59.  https://doi.org/10.1158/1078-0432.CCR-12-0918.CrossRefPubMedGoogle Scholar
  82. 82.
    Benzaid I, Monkkonen H, Stresing V, Bonnelye E, Green J, Monkkonen J, et al. High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res. 2011;71(13):4562–72.  https://doi.org/10.1158/0008-5472.CAN-10-3862.CrossRefPubMedGoogle Scholar
  83. 83.
    Kondo M, Izumi T, Fujieda N, Kondo A, Morishita T, Matsushita H, et al. Expansion of human peripheral blood gammadelta T cells using zoledronate. J Vis Exp. 2011.  https://doi.org/10.3791/3182.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Dieli F, Gebbia N, Poccia F, Caccamo N, Montesano C, Fulfaro F, et al. Induction of gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood. 2003;102(6):2310–1.  https://doi.org/10.1182/blood-2003-05-1655.CrossRefPubMedGoogle Scholar
  85. 85.
    Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G. Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med. 2003;197(2):163–8.CrossRefGoogle Scholar
  86. 86.
    Mirzaei HR, Mirzaei H, Lee SY, Hadjati J, Till BG. Prospects for chimeric antigen receptor (CAR) gammadelta T cells: a potential game changer for adoptive T cell cancer immunotherapy. Cancer Lett. 2016;380(2):413–23.  https://doi.org/10.1016/j.canlet.2016.07.001.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Capsomidis A, Benthall G, Van Acker HH, Fisher J, Kramer AM, Abeln Z, et al. Chimeric antigen receptor-engineered human gamma delta T cells: enhanced cytotoxicity with retention of cross presentation. Mol Ther. 2018;26(2):354–65.  https://doi.org/10.1016/j.ymthe.2017.12.001.CrossRefPubMedGoogle Scholar
  88. 88.
    Fisher J, Abramowski P, Wisidagamage Don ND, Flutter B, Capsomidis A, Cheung GW, et al. Avoidance of on-target off-tumor activation using a co-stimulation-only chimeric antigen receptor. Mol Ther. 2017;25(5):1234–47.  https://doi.org/10.1016/j.ymthe.2017.03.002.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Xiao L, Chen C, Li Z, Zhu S, Tay JC, Zhang X, et al. Large-scale expansion of Vgamma9Vdelta2 T cells with engineered K562 feeder cells in G-Rex vessels and their use as chimeric antigen receptor-modified effector cells. Cytotherapy. 2018;20(3):420–35.  https://doi.org/10.1016/j.jcyt.2017.12.014.CrossRefPubMedGoogle Scholar
  90. 90.
    Brandes M, Willimann K, Lang AB, Nam KH, Jin C, Brenner MB, et al. Flexible migration program regulates gamma delta T-cell involvement in humoral immunity. Blood. 2003;102(10):3693–701.  https://doi.org/10.1182/blood-2003-04-1016.CrossRefPubMedGoogle Scholar
  91. 91.
    Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36(10):2566–73.  https://doi.org/10.1002/eji.200636416.CrossRefPubMedGoogle Scholar
  92. 92.
    Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105(10):4120–6.  https://doi.org/10.1182/blood-2004-02-0586.CrossRefPubMedGoogle Scholar
  93. 93.
    Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood. 2006;107(4):1484–90.  https://doi.org/10.1182/blood-2005-07-2775.CrossRefPubMedGoogle Scholar
  94. 94.
    Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327–33.  https://doi.org/10.1182/blood-2007-02-074997.CrossRefPubMedGoogle Scholar
  95. 95.
    Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.CrossRefGoogle Scholar
  96. 96.
    Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103(12):4619–21.  https://doi.org/10.1182/blood-2003-11-3909.CrossRefPubMedGoogle Scholar
  97. 97.
    Kadle RL, Abdou SA, Villarreal-Ponce AP, Soares MA, Sultan DL, David JA, et al. Microenvironmental cues enhance mesenchymal stem cell-mediated immunomodulation and regulatory T-cell expansion. PLoS One. 2018;13(3):e0193178.  https://doi.org/10.1371/journal.pone.0193178.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Martinet L, Fleury-Cappellesso S, Gadelorge M, Dietrich G, Bourin P, Fournie JJ, et al. A regulatory cross-talk between Vgamma9Vdelta2 T lymphocytes and mesenchymal stem cells. Eur J Immunol. 2009;39(3):752–62.  https://doi.org/10.1002/eji.200838812.CrossRefPubMedGoogle Scholar
  99. 99.
    Li H, Lu Y, Qian J, Zheng Y, Zhang M, Bi E, et al. Human osteoclasts are inducible immunosuppressive cells in response to T cell-derived IFN-gamma and CD40 ligand in vitro. J Bone Miner Res. 2014;29(12):2666–75.  https://doi.org/10.1002/jbmr.2294.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4 + and CD8 + T cells. Blood. 2010;116(2):210–7.  https://doi.org/10.1182/blood-2009-11-255026.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Kraaij MD, Savage ND, van der Kooij SW, Koekkoek K, Wang J, van den Berg JM, et al. Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci USA. 2010;107(41):17686–91.  https://doi.org/10.1073/pnas.1012016107.CrossRefPubMedGoogle Scholar
  102. 102.
    Huber S, Hoffmann R, Muskens F, Voehringer D. Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2. Blood. 2010;116(17):3311–20.  https://doi.org/10.1182/blood-2010-02-271981.CrossRefPubMedGoogle Scholar
  103. 103.
    Attwood JT, Munn DH. Macrophage suppression of T cell activation: a potential mechanism of peripheral tolerance. Int Rev Immunol. 1999;18(5–6):515–25.CrossRefGoogle Scholar
  104. 104.
    Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, et al. Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26(7):1855–66.  https://doi.org/10.1016/j.ymthe.2018.05.003.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Lavoue V, Cabillic F, Toutirais O, Thedrez A, Dessarthe B, de La Pintiere CT, et al. Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vgamma9Vdelta2 T cells impaired by the prostaglandin E2 immunosuppressive factor: implications for immunotherapy. Int J Cancer. 2012;131(4):E449–62.  https://doi.org/10.1002/ijc.27353.CrossRefPubMedGoogle Scholar
  106. 106.
    Najar M, Rouas R, Raicevic G, Boufker HI, Lewalle P, Meuleman N, et al. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy. 2009;11(5):570–83.  https://doi.org/10.1080/14653240903079377.CrossRefPubMedGoogle Scholar
  107. 107.
    Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57(1):11–20.CrossRefGoogle Scholar
  108. 108.
    Zhou Y, Day A, Haykal S, Keating A, Waddell TK. Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway. Cytotherapy. 2013;15(10):1195–207.  https://doi.org/10.1016/j.jcyt.2013.05.009.CrossRefPubMedGoogle Scholar
  109. 109.
    Petrini I, Pacini S, Petrini M, Fazzi R, Trombi L, Galimberti S. Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma-delta T cells. Eur J Clin Investig. 2009;39(9):813–8.  https://doi.org/10.1111/j.1365-2362.2009.02171.x.CrossRefGoogle Scholar
  110. 110.
    Shahrokhi S, Daneshmandi S, Menaa F. Tumor necrosis factor-alpha/CD40 ligand-engineered mesenchymal stem cells greatly enhanced the antitumor immune response and lifespan in mice. Hum Gene Ther. 2014;25(3):240–53.  https://doi.org/10.1089/hum.2013.193.CrossRefPubMedGoogle Scholar
  111. 111.
    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(23):6050–6.  https://doi.org/10.1182/blood-2011-05-354449.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    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(11):1264–70.  https://doi.org/10.1038/nm.1882.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Shalabi H, Wolters PL, Martin S, Toledo-Tamula MA, Roderick MC, Struemph K, et al. Systematic evaluation of neurotoxicity in children and young adults undergoing CD22 chimeric antigen receptor T-cell therapy. J Immunother. 2018;41(7):350–8.  https://doi.org/10.1097/CJI.0000000000000241.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Investig. 2016;126(6):2123–38.  https://doi.org/10.1172/JCI85309.CrossRefPubMedGoogle Scholar
  115. 115.
    Fu X, Rivera A, Tao L, Zhang X. Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery. Int J Cancer. 2013;133(10):2483–92.  https://doi.org/10.1002/ijc.28269.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168–74.  https://doi.org/10.1158/0008-5472.CAN-14-2458.CrossRefPubMedGoogle Scholar
  117. 117.
    Pascual-Garcia M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8(+) T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019;10(1):2416.  https://doi.org/10.1038/s41467-019-10369-9.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    He B, Jabouille A, Steri V, Johansson-Percival A, Michael IP, Kotamraju VR, et al. Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules. J Pathol. 2018;245(2):209–21.  https://doi.org/10.1002/path.5080.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017.  https://doi.org/10.1126/scitranslmed.aaa0984.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Brown CE, Aguilar B, Starr R, Yang X, Chang WC, Weng L, et al. Optimization of IL13Ralpha2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol Ther. 2018;26(1):31–44.  https://doi.org/10.1016/j.ymthe.2017.10.002.CrossRefPubMedGoogle Scholar
  121. 121.
    Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 2017;3(8):1094–101.  https://doi.org/10.1001/jamaoncol.2017.0184.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Mount CW, Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nat Med. 2018;24(5):572–9.  https://doi.org/10.1038/s41591-018-0006-x.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Jin L, Ge H, Long Y, Yang C, Chang YE, Mu L, et al. CD70, a novel target of CAR T-cell therapy for gliomas. Neuro Oncol. 2018;20(1):55–65.  https://doi.org/10.1093/neuonc/nox116.CrossRefPubMedGoogle Scholar
  124. 124.
    Pellegatta S, Savoldo B, Di Ianni N, Corbetta C, Chen Y, Patane M, et al. Constitutive and TNFalpha-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: implications for CAR-T cell therapy. Sci Transl Med. 2018.  https://doi.org/10.1126/scitranslmed.aao2731.CrossRefPubMedGoogle Scholar
  125. 125.
    Zhu X, Prasad S, Gaedicke S, Hettich M, Firat E, Niedermann G. Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57. Oncotarget. 2015;6(1):171–84.  https://doi.org/10.18632/oncotarget.2767.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, et al. Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Investig. 2016;126(8):3036–52.  https://doi.org/10.1172/JCI83416.CrossRefPubMedGoogle Scholar
  127. 127.
    Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro Oncol. 2018;20(4):506–18.  https://doi.org/10.1093/neuonc/nox182.CrossRefPubMedGoogle Scholar
  128. 128.
    Yin Y, Boesteanu AC, Binder ZA, Xu C, Reid RA, Rodriguez JL, et al. Checkpoint blockade reverses anergy in IL-13Ralpha2 humanized scFv-based CAR T cells to treat murine and canine gliomas. Mol Ther Oncolytics. 2018;11:20–38.  https://doi.org/10.1016/j.omto.2018.08.002.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Woroniecka KI, Rhodin KE, Chongsathidkiet P, Keith KA, Fecci PE. T-cell dysfunction in glioblastoma: applying a new framework. Clin Cancer Res. 2018;24(16):3792–802.  https://doi.org/10.1158/1078-0432.CCR-18-0047.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Eroglu Z, Holmen SL, Chen Q, Khushalani NI, Amaravadi R, Thomas R, et al. Melanoma central nervous system metastases: an update to approaches, challenges, and opportunities. Pigment Cell Melanoma Res. 2019.  https://doi.org/10.1111/pcmr.12771.CrossRefPubMedGoogle Scholar
  131. 131.
    Abate-Daga D, Ramello MC, Smalley I, Forsyth PA, Smalley KSM. The biology and therapeutic management of melanoma brain metastases. Biochem Pharmacol. 2018;153:35–45.  https://doi.org/10.1016/j.bcp.2017.12.019.CrossRefPubMedGoogle Scholar
  132. 132.
    Tran E, Longo DL, Urba WJ. A milestone for CAR T cells. N Engl J Med. 2017;377(26):2593–6.  https://doi.org/10.1056/NEJMe1714680.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of ImmunologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Department of Tumor BiologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  3. 3.Department of Cutaneous OncologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  4. 4.Department of Gastrointestinal OncologyH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  5. 5.Department of Oncologic Sciences, Morsani School of MedicineUniversity of South FloridaTampaUSA

Personalised recommendations