Advertisement

Medical Oncology

, 35:70 | Cite as

Prospects of chimeric antigen receptor T cell therapy in ovarian cancer

  • Vishal Jindal
  • Ena Arora
  • Sorab Gupta
  • Amos Lal
  • Muhammad Masab
  • Rashmika Potdar
Review Article

Abstract

Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Immunotherapy provides a promising and novel treatment option for ovarian cancer. Recently, chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematological tumors and current research is going on in various solid tumors like ovarian cancer. CAR T cells are genetically engineered T cells with major histocompatibility complex-independent, tumor-specific, immune-mediated cytolytic actions against cancer cells. Initial studies of CAR T cell therapy have shown promising results in ovarian cancer, but there are some obstacles like impaired T cell trafficking, lack of antigenic targets, cytokine release syndrome and most important immunosuppressive tumor microenvironment. Optimization of design, improving tumor microenvironment and combinations with other therapies may help us in improving CAR T cell efficacy. In this review article, we highlight the current knowledge regarding CAR T cell therapy in ovarian cancer. We have discussed basic functioning of CAR T cells, their rationale and clinical outcome in ovarian cancer with limitations.

Keywords

Ovarian cancer Chimeric antigen receptor Immunotherapy 

Notes

Acknowledgement

Special thanks to Dr. Manisha Dhananjaya.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer Statistics. CA Cancer J Clin. 2017;67(1):7–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1. 0, Cancer incidence and mortality worldwide: IARC cancerbase no. 11. Lyon, France: International Agency for Research on Cancer; 2013. Accessed Apr 2014.Google Scholar
  3. 3.
    Goff BA, Mandel L, Muntz HG, Melancon CH. Ovarian carcinoma diagnosis. Cancer. 2000;89:2068–75.CrossRefPubMedGoogle Scholar
  4. 4.
    Herzog TJ. The current treatment of recurrent ovarian cancer. Curr Oncol Rep. 2006;8:448–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I, et al. Ten-year relative survival for epithelial ovarian cancer. Obstet Gynecol. 2012;120:612–8.CrossRefPubMedGoogle Scholar
  6. 6.
    June CH. Adoptive T cell therapy for cancer in the clinic. J Clin Invest. 2007;117:1466–76.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995;1:501–7.PubMedGoogle Scholar
  8. 8.
    Aoki Y, Takakuwa K, Kodama S, Tanaka K, Takahashi M, Tokunaga A, Takahashi T. Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer. Cancer Res. 1991;51:1934–9.PubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Song DG, Ye Q, Carpenito C, Poussin M, Wang LP, Ji C, Figini M, June CH, Coukos G, Powell DJ Jr. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res. 2011;71:4617–27.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Campoli M, Ferrone S. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene. 2008;27:5869–85.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chang CC, Campoli M, Ferrone S. Classical and nonclassical HLA class I antigen and NK Cell-activating ligand changes in malignant cells: current challenges and future directions. Adv Cancer Res. 2005;93:189–234.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhao Z, Condomines M, van der Stegen SJ, Perna F, Kloss CC, Gunset G, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28(4):415–28.  https://doi.org/10.1016/j.ccell.2015.09.004.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388–98.  https://doi.org/10.1158/2159-8290.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chmielewski M, Hombach AA, Abken H. Antigen-specific T-cell activation independently of the MHC: chimeric antigen receptor-redirected T cells. Front Immunol. 2013;4:371.  https://doi.org/10.3389/fimmu.2013.00371.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Riddell SR, Sommermeyer D, Berger C, Liu LS, Balakrishnan A, Salter A, Hudecek M, Maloney DG, Turtle CJ. Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition. Cancer J. 2014;20:141–4.  https://doi.org/10.1097/PPO.0000000000000036.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kershaw MH, Westwood JA, Slaney CY, Darcy PK. Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunol. 2014;3(5):e16.CrossRefGoogle Scholar
  18. 18.
    Yasukawa M, Ohminami H, Arai J, Kasahara Y, Ishida Y, Fujita S. Granule exocytosis, and not the fas/fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4(+) as well as CD8(+)cytotoxic T lymphocytes in humans. Blood. 2000;95(7):2352–5.PubMedGoogle Scholar
  19. 19.
    Hombach A, Kohler H, Rappl G, Abken H. Human CD4 + T cells lyse target cells via granzyme/perforin upon circumvention of MHC class II restriction by an antibody-like immunoreceptor. J Immunol. 2006;177(8):5668–75.  https://doi.org/10.1186/s12967-015-0460-x.CrossRefPubMedGoogle Scholar
  20. 20.
    Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625–35.  https://doi.org/10.1182/blood-2013-11-492231.5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Pegram HJ, Park JH, Brentjens RJ. CD28z CARs and armored CARs. Cancer J. 2014;20(2):127.  https://doi.org/10.1097/PPO.0000000000000034.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Med Sci Transl. 2015; 7:303ra139.Google Scholar
  24. 24.
    Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040–7.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.CrossRefPubMedGoogle Scholar
  27. 27.
    Tomsova M, Melichar B, Sedlakova I, Steiner I. Prognostic significance of CD3 + tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008;108:415–20.CrossRefPubMedGoogle Scholar
  28. 28.
    Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, et al. Intraepithelial CD8 + tumorinfiltrating lymphocytes and a high CD8 +/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–43.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon- Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Kenemans P. CA 125 and OA 3 as target antigens for immunodiagnosis and immunotherapy in ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 1990;36:221–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Rosenblum MG, Verschraegen CF, Murray JL, Kudelka AP, Gano J, Cheung L, Kavanagh JJ. Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity. Clin Cancer Res. 1999;5:953–61.PubMedGoogle Scholar
  32. 32.
    Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol. 2002;20:2624–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Disis ML, Goodell V, Schiffman K, Knutson KL. Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J Clin Immunol. 2004;24:571–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ. MUC1 immunobiology: from discovery to clinical applications. Adv Immunol. 2004;82:249–93.CrossRefPubMedGoogle Scholar
  35. 35.
    Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA. 1996;93:136–40.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Coliva A, Zacchetti A, Luison E, Tomassetti A, Bongarzone I, Seregni E, Bombardieri E, Martin F, Giussani A, Figini M, Canevari S. 90Y Labeling of monoclonal antibody MOv18 and preclinical validation for radio immunotherapy of human ovarian carcinomas. Cancer Immunol Immunother. 2005;54:1200–13.CrossRefPubMedGoogle Scholar
  37. 37.
    Odunsi K, Jungbluth AA, Stockert E, Qian F, Gnjatic S, Tammela J, Intengan M, Beck A, Keitz B, Santiago D, et al. NY-ESO-1 and LAGE-1 cancer-testis antigens are potential targets for immunotherapy in epithelial ovarian cancer. Cancer Res. 2003;63:6076–83.PubMedGoogle Scholar
  38. 38.
    Felder M, Kapur A, Gonzalez-Bosquet J, Horibata S, Heintz J, et al. MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Mol Cancer. 2014;13:129.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Das S, Batra SK. Understanding the unique attributes of MUC16 (CA125): potential implications in targeted therapy. Cancer Res. 2015;75:4669–74.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Haridas D, Ponnusamy MP, Chugh S, Lakshmanan I, Seshacharyulu P, et al. MUC16: molecular analysis and its functional implications in benign and malignant conditions. Faseb J. 2014;28:4183–99.CrossRefPubMedGoogle Scholar
  41. 41.
    Liu Q, Cheng Z, Luo L, Yang Y, Zhang Z, et al. C-terminus of MUC16 activates Wnt signaling pathway through its interaction with beta-catenin to promote tumorigenesis and metastasis. Oncotarget. 2016;7:36800–13.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Togami S, Nomoto M, Higashi M, Goto M, Yonezawa S, et al. Expression of mucin antigens (MUC1 and MUC16) as a prognostic factor for mucinous adenocarcinoma of the uterine cervix. J Obstet Gynaecol Res. 2010;36:588–97.CrossRefPubMedGoogle Scholar
  43. 43.
    Streppel MM, Vincent A, Mukherjee R, Campbell NR, Chen SH, et al. Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon. Hum Pathol. 2012;43:1755–63.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Rao TD, Tian H, Ma X, Yan X, Api S, et al. Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion. PLoS ONE. 2015;10(e0126633):32.Google Scholar
  45. 45.
    McLemore MR, Aouizerat B. Introducing the MUC16 gene: implications for prevention and early detection in epithelial ovarian cancer. Biol Res Nurs. 2005;6:262–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Chekmasova AA, Rao TD, Nikhamin Y, et al. Successful eradication of established peritoneal ovarian tumors in SCID-Beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(14):3594–606.  https://doi.org/10.1158/1078-0432.CCR-10-0192.CrossRefGoogle Scholar
  47. 47.
    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(3):e994446.  https://doi.org/10.4161/2162402X.2014.994446.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Salazar MD, Ratnam M. The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev. 2007;26:141–52.CrossRefPubMedGoogle Scholar
  49. 49.
    Kelemen LE. The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer. 2006;119:243–50.CrossRefPubMedGoogle Scholar
  50. 50.
    Toffoli G, Cernigoi C, Russo A, Gallo A, Bagnoli M, Boiocchi M. Overexpression of folate binding protein in ovarian cancers. Int J Cancer. 1997;74:193–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Shi H, Guo J, Li C, Wang Z. A current review of folate receptor alpha as a potential tumor target in non-small-cell lung cancer. Drug Des Devel Ther. 2015;9:4989–96.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Boogerd LS, Boonstra MC, Beck AJ, Charehbili A, Hoogstins CE, Prevoo HA, Singhal S, Low PS, van de Velde CJ, Vahrmeijer AL. Concordance of folate receptor-alpha expression between biopsy, primary tumor and metastasis in breast cancer and lung cancer patients. Oncotarget. 2016.  https://doi.org/10.18632/oncotarget.7856.PubMedPubMedCentralGoogle Scholar
  53. 53.
    O’shannessy DJ, Somers EB, Maltzman J, Smale R, Fu YS. Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease. Springerplus. 2012; 1:22.Google Scholar
  54. 54.
    Siu MK, Kong DS, Chan HY, Wong ES, Ip PP, Jiang L, Ngan HY, Le XF, Cheung AN. Paradoxical impact of two folate receptors, FRalpha and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome. PLoS ONE. 2012;7:e47201.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Canevari S, Stoter G, Arienti F, Bolis G, Colnaghi MI, Di Re EM, Eggermont AM, Goey SH, Gratama JW, Lamers CH, et al. Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody. J Natl Cancer Inst. 1995;87:1463–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006;12:6106–15.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Chang K, Pastan I, Willingham MC. Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int J Cancer. 1992;50:373–81.CrossRefPubMedGoogle Scholar
  58. 58.
    Ordonez NG. Value of mesothelin immunostaining in the diagnosis of mesothelioma. Mod Pathol. 2003;16:192–7.CrossRefPubMedGoogle Scholar
  59. 59.
    Argani P, Iacobuzio-Donahue C, Ryu B, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001;7:3862–8.PubMedGoogle Scholar
  60. 60.
    Hassan R, Kreitman RJ, Pastan I, et al. Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol. 2005;13:243–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Ordonez NG. Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 2003;27:1418–28.CrossRefPubMedGoogle Scholar
  62. 62.
    Rump A, Morikawa Y, Tanaka M, et al. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem. 2004;279:9190–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Cheng WF, Huang CY, Chang MC, Hu YH, Chiang YC, Chen YL, Hsieh CY, Chen CA. High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. Br J Cancer. 2009;100:1144–53.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    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 USA. 2009;106:3360–5.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lanitis E, Poussin M, Hagemann IS, Coukos G, Sandaltzopoulos R, Scholler N, Powell DJ Jr. Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. Mol Ther. 2012;20:633–43.CrossRefPubMedGoogle Scholar
  66. 66.
    Tanyi JL, Haas AR, Beatty GL, Stashwick CJ, O’Hara MH, Morgan MA. Anti-mesothelin chimeric antigen receptor T cells in patients with epithelial ovarian cancer. J Clin Oncol. 2016;34(15):5511.  https://doi.org/10.1200/JCO.2016.34.15_suppl.5511.Google Scholar
  67. 67.
    Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol. 2001;12(Suppl 1):S3–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986;319:226–30.CrossRefPubMedGoogle Scholar
  69. 69.
    Neve RM, Lane HA, Hynes NE. The role of overexpressed HER2 in transformation. Ann Oncol. 2001;12(Suppl 1):S9–13.CrossRefPubMedGoogle Scholar
  70. 70.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.CrossRefPubMedGoogle Scholar
  71. 71.
    Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, Zeng C, Baron A, Bunn PA Jr. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer. 2002;86:1449–56.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Tan AR, Swain SM. Ongoing adjuvant trials with trastuzumab in breast cancer. Semin Oncol. 2003;30(Suppl 16):54–64.CrossRefPubMedGoogle Scholar
  73. 73.
    Spector N, et al. HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors. Breast Cancer Res. 2007;9(2):205.CrossRefPubMedCentralGoogle Scholar
  74. 74.
    Sun M, Shi H, Liu C, Liu J, Liu X, Sun Y. Construction and evaluation of a novel humanized HER2-specific chimeric receptor. Breast Cancer Res. 2014;16:R61.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    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. 2017.  https://doi.org/10.1093/neuonc/nox182.Google Scholar
  76. 76.
    Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Can Res. 2015;75:3505–18.CrossRefGoogle Scholar
  77. 77.
    Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Frontiers Pharmacol. 2014;5.Google Scholar
  78. 78.
    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 CCR2b. J Immunother. 2010;33(8):780–8.  https://doi.org/10.1097/CJI.0b013e3181ee6675.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    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(18):5195–205.  https://doi.org/10.1158/0008-5472.CAN-14-0697.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015;21(5):524–9.  https://doi.org/10.1038/nm.3833.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ligtenberg MA, Mougiakakos D, Mukhopadhyay M, Witt K, Lladser A, Chmielewski M, et al. Coexpressed catalase protects chimeric antigen receptor–redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. J Immunol. 2016;196(2):759–66.  https://doi.org/10.4049/jimmunol.1401710.CrossRefPubMedGoogle Scholar
  82. 82.
    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(6):541–51.  https://doi.org/10.1158/2326-6066.CIR-15-0263.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    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 lymphodepletingdrugs. Blood. 2015;125(25):3905–16.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Quatromoni JG, Wang Y, Vo DD, et al. T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ) signaling mediate superior tumor regression in an animal model of adoptive cell therapy. J Transl Med. 2012;10:127.  https://doi.org/10.1186/1479-5876-10-127.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Internal MedicineSaint Vincent HospitalWorcesterUSA
  2. 2.Department of Internal MedicineGovernment Medical College and HospitalChandigarhIndia
  3. 3.Department of Internal MedicineEinstein Healthcare NetworkPhiladelphiaUSA
  4. 4.Department of Hematology and OncologyEinstein Healthcare NetworkPhiladelphiaUSA

Personalised recommendations