Pharmacokinetics and Pharmacodynamics of Immunotherapy

  • Lisa H. Lam
  • Swan D. Lin
  • Ji SunEmail author
Part of the Current Cancer Research book series (CUCR)


Over the last decade, there have been exciting advances in the development of monoclonal antibodies (mAbs), adoptive cellular therapies, vaccines, and viruses in eliciting immune responses against tumor cells with promising results in patients. This chapter highlights some of the immunotherapies that are in late-stage development or have received regulatory approval and summarizes their mechanisms of action, pharmacokinetics (PK), and pharmacodynamics (PD). This chapter summarizes the PK and PD of single-agent immunotherapies from publicly available sources through 2016. Advances in the field of immunotherapy have revolutionized oncology practice. The field is rapidly changing, and at any given time, there are hundreds of ongoing clinical trials with immunotherapies as single agents or in various combinations with another immunotherapy, targeted therapy, radiation therapy, or chemotherapy. Available data from new studies may provide additional insight for clinical PK and PD for immunotherapies in new patient populations.


Cellular therapy (CT) products CGT products Gene therapy (GT) products Pharmacology Pharmacokinetics Pharmacodynamics Oncology Cancer immunotherapy Immune checkpoint inhibitors 


  1. 1.
    Coley WB (1991) The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res 262:3–11Google Scholar
  2. 2.
    Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13(5):273–290. doi: 10.1038/nrclinonc.2016.25. Epub 2016 Mar 15. PMID: 26977780CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Brezski RJ, Georgiou G (2016) Immunoglobulin isotype knowledge and application to Fc engineering. Curr Opin Immunol 40:62–69CrossRefPubMedGoogle Scholar
  4. 4.
    Dostalek M, Gardner I, Gurbaxani BM, Rose RH, Chetty M (2013) Pharmacokinetics, pharmacodynamics and physiologically-based pharmacokinetic modelling of monoclonal antibodies. Clin Pharmacokinet 52(2):83–124CrossRefPubMedGoogle Scholar
  5. 5.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10CrossRefPubMedGoogle Scholar
  7. 7.
    Sathyanarayanan V, Neelapu SS (2015) Cancer immunotherapy: strategies for personalization and combinatorial approaches. Mol Oncol 9(10):2043–2053CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T (2015) Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 13:211CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Spain L, Diem S, Larkin J (2016) Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 44:51–60CrossRefPubMedGoogle Scholar
  10. 10.
    Bourke JM, O'Sullivan M, Khattak MA (2016) Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors). Med J Aust 205(9):418–424CrossRefPubMedGoogle Scholar
  11. 11.
    Tarhini AA (2013) Tremelimumab: a review of development to date in solid tumors. Immunotherapy 5(3):215–229CrossRefPubMedGoogle Scholar
  12. 12.
    Center for Drug Evaluation and Research (2016) Yervoy (ipilimumab) Clinical Pharmacology Biopharmaceutics Review(s). Application number 125377Orig1s000. Available at: Accessed 12 Nov 2016
  13. 13.
    Camacho LH (2015) CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer Med 4(5):661–672CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yervoy (ipilimumab) Prescribing Information (2015) Princeton: Bristol-Myers Squibb Co.; October 2015. Available at: Accessed 14 Nov 2016
  15. 15.
    Wolchok JD, Neyns B, Linette G et al (2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11(2):155–164CrossRefPubMedGoogle Scholar
  16. 16.
    Feng Y, Masson E, Dai D et al (2014) Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J Clin Pharmacol 78(1):106–117CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Comin-Anduix B, Escuin-Ordinas H, Ibarrondo FJ (2016) Tremelimumab: research and clinical development. Onco Targets Ther 9:1767–1776PubMedPubMedCentralGoogle Scholar
  18. 18.
    Ribas A, Chesney JA, Gordon MS et al (2012) Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion. J Transl Med 10:236CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ribas A, Camacho LH, Lopez-Berestein G et al (2005) Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 23(35):8968–8977CrossRefPubMedGoogle Scholar
  20. 20.
    Wang E, Kang D, Bae KS et al (2014) Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol 54(10):1108–1116CrossRefPubMedGoogle Scholar
  21. 21.
    Pardoll D (2015) Cancer and the immune system: basic concepts and targets for intervention. Semin Oncol 42(4):523–538CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856CrossRefPubMedGoogle Scholar
  23. 23.
    Goodman A, Patel SP, Kurzrock R (2016) PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol 14:203–220CrossRefPubMedGoogle Scholar
  24. 24.
    Patnaik A, Kang SP, Rasco D et al (2015) Phase I study of pembrolizumab (MK-3475; Anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 21(19):4286–4293CrossRefPubMedGoogle Scholar
  25. 25.
    Farolfi A, Schepisi G, Conteduca V et al (2016) Pharmacokinetics, pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma. Expert Opin Drug Metab Toxicol 12(9):1089–1096CrossRefPubMedGoogle Scholar
  26. 26.
    Wong RM, Scotland RR, Lau RL et al (2007) Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol 19(10):1223–1234CrossRefPubMedGoogle Scholar
  27. 27.
    Iwai Y, Ishida M, Tanaka Y et al (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99(19):12293–12297CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 56(5):739–745CrossRefPubMedGoogle Scholar
  29. 29.
    Lu J, Lee-Gabel L, Nadeau MC, Ferencz TM, Soefje SA (2015) Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. J Oncol Pharm Pract 21(6):451–467CrossRefPubMedGoogle Scholar
  30. 30.
    Homet Moreno B, Ribas A (2015) Anti-programmed cell death protein-1/ligand-1 therapy in different cancers. Br J Cancer 112(9):1421–1427CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Center for Drug Evaluation and Research (2016) Opdivo (nivolumab) Pharmacology Review(s). Application number. Available at: Accessed 12 Nov 2016
  32. 32.
    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Center for Drug Evaluation and Research (2016) Opdivo (nivolumab) Clinical Pharmacology Biopharmaceutics Review(s). Application number 125554Orig1s000. Available at: Accessed 12 Nov 2016
  34. 34.
    Center for Drug Evaluation and Research (2016) Opdivo (nivolumab) Clinical Pharmacology Biopharmaceutics Review(s). Application number 125527Orig1s000. Available at: Accessed 12 Nov 2016
  35. 35.
    Weber JS, D’Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384CrossRefPubMedGoogle Scholar
  36. 36.
    Rizvi NA, Mazieres J, Planchard D et al (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16(3):257–265CrossRefPubMedGoogle Scholar
  37. 37.
    Opdivo (nivolumab) Prescribing Information (2016) Princeton: Bristol-Myers Squibb Co; November 2016. Available at: Accessed 14 Nov 2016
  38. 38.
    Bajaj G, Wang X, Agrawal S et al (2016) Model-Based Population Pharmacokinetic Analysis of Nivolumab in Patients With Solid Tumors. CPT Pharmacometrics Syst Pharmacol 6:58–66CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    U.S. Food and Drug Administration (2016) Modification of the Dosage Regimen for Nivolumab. Published online September 2016. Available at: Accessed 14 November 2016
  40. 40.
    Zhao X, Suryawanshi S, Hruska M, et al (2016) Assessment of nivolumab (NIVO) benefit-risk profile from a 240 mg flat dose versus a 3 mg/kg dosing regimen in patients with solid tumor. Presented at the European Society for Medical Oncology Congress 2016, Copenhagen, Denmark, 7–11 October 2016Google Scholar
  41. 41.
    Center for Drug Evaluation and Research (2016) Keytruda (pembrolizumab) Pharmacology Review(s). Application number 125514Orig1s000. Available at: Accessed 13 Nov 2016
  42. 42.
    Chatterjee M, Turner DC, Felip E et al (2016) Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol 27(7):1291–1298CrossRefPubMedGoogle Scholar
  43. 43.
    de Greef R, Elassaiss-Schaap J, Chatterjee M et al (2016) Pembrolizumab: role of modeling and simulation in bringing a novel immunotherapy to patients with melanoma. CPT Pharmacometrics Syst Pharmacol 6:5–7CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Elassaiss-Schaap J, Rossenu S, Lindauer A et al (2016) Using model-based "Learn and confirm" to reveal the pharmacokinetics-pharmacodynamics relationship of pembrolizumab in the KEYNOTE-001 trial. CPT Pharmacometrics Syst Pharmacol 6:21–28CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ahamadi M, Freshwater T, Prohn M et al (2016) Model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors. CPT Pharmacometrics Syst Pharmacol 6:49–57CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Keytruda (pembrolizumab) Prescribing Information (2016) Whitehouse Station: Merck & Co, Inc.; October 2016. Available at: Accessed 6 Nov 2016
  47. 47.
    Center for Drug Evaluation and Research (2016) Keytruda (pembrolizumab) Clinical Pharmacology and Biopharmaceutics Review(s). Application number 125514Orig1s000. Available at: Accessed 13 Nov 2016
  48. 48.
    Chatterjee M, Turner DC, Ahamadi M, et al (2015) Model-based analysis of the relationship between pembolizumab exposure and efficacy in patients with melanoma and NSCLC: across indication comparison. Presented at the Annual Meeting of the Population Approach Group in Europe, Hersonissos, Greece, 2–5 June 2015Google Scholar
  49. 49.
    Freshwater T, Stone J, de Greef R, et al (2015) Assessment of pembrolizumab (MK-3475) dosing strategy based on population pharmacokinetics and exposure-response models. Presented at the 6th American Conference on Pharmacometrics, Arlington, 3–7 October 2015Google Scholar
  50. 50.
    Reck M, Rodriguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833CrossRefPubMedGoogle Scholar
  51. 51.
    Center for Drug Evaluation and Research (2016) Tecentriq (atezolizumab) Clinical Pharmacology Review(s). Application number 761034Orig1s000. Available at: Accessed 14 Nov 2016
  52. 52.
    Herbst RS, Soria JC, Kowanetz M et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Center for Drug Evaluation and Research (2016) Tecentriq (atezolizumab) Clinical Pharmacology and Biopharmaceutics Review(s). Application number 761034Orig1s000. Available at: Accessed 12 Nov 2016
  54. 54.
    Tecentriq (atezolizumab) Prescribing Information (2016) South San Francisco: Genentech, Inc; October 2016. Available at: Accessed 5 Nov 2016
  55. 55.
    Stroh M, Winter H, Marchand M et al (2016) The clinical pharmacokinetics and pharmacodynamics of atezolizumab in metastatic urothelial carcinoma. Clin Pharmacol Ther 102:305–312CrossRefGoogle Scholar
  56. 56.
    Powles T, Eder JP, Fine GD et al (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515(7528):558–562CrossRefPubMedGoogle Scholar
  57. 57.
    Mizugaki H, Yamamoto N, Murakami H et al (2016) Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Investig New Drugs 34(5):596–603CrossRefGoogle Scholar
  58. 58.
    Massard C, Gordon MS, Sharma S et al (2016) Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol 34(26):3119–3125CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Planchard D, Yokoi T, McCleod MJ et al (2016) A phase III study of durvalumab (MEDI4736) with or without tremelimumab for previously treated patients with advanced NSCLC: rationale and protocol design of the ARCTIC study. Clin Lung Cancer 17(3):232–236 e231CrossRefPubMedGoogle Scholar
  60. 60.
    Song X, Pak M, Chavez C, et al (2015) Population pharmacokinetics of MEDI4736, a fully human antiprogrammed death ligand 1 (PD-L1) monoclonal antibody, in patients with advanced solid tumors. Presented at the European Cancer Congress 2015, Vienna, Austria, 25–29 September 2015Google Scholar
  61. 61.
    Song X, Pak M, Liang M, et al (2015) Pharmacokinetics and pharmacodynamics of MEDI4736, a fully human anti-programmed death ligand 1 (PD-L1) monoclonal antibody, in patients with advanced solid tumors. Abstract submitted to the 2015 Americal Society of Clinical Oncology Annual Meeting, Chicago, 29 May–2 June 2015Google Scholar
  62. 62.
    Grenga I, Donahue RN, Lepone LM, Richards J, Schlom J (2016) A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses. Clin Transl Immunology 5(5):e83CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Boyerinas B, Jochems C, Fantini M et al (2015) Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res 3(10):1148–1157CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Kaufman HL, Russell J, Hamid O et al (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Heery CR, O'Sullivan Coyne GH, Marte JL, et al (2015) Pharmacokinetic profile and receptor occupancy of avelumab (MSB0010718C), an anti-PD-L1 monoclonal antibody, in a phase I, open-label, dose escalation trial in patients with advanced solid tumors. Presented at the 2015 Americal Society of Clinical Oncology Annual Meeting, Chicago, 29 May–2 June 2015Google Scholar
  66. 66.
    Arkenau H-T, Kelly K, Patel MR, et al (2015) Phase I JAVELIN solid tumor trial of avelumab (MSB0010718C), an anti-PD-L1 antibody: Safety and pharmacokinetics. Presented at the European Society for Medical Oncology Symposium on Immuno-Oncology 2015, Lausanne, Switzerland, 20–21 November 2015Google Scholar
  67. 67.
    MedImmune LLC (2016) A Phase 1 Study of MEDI0562 in Adult Subjects With Selected Advanced Solid Tumors. In: [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Nov 11]. Available from: NLM Identifier: NCT02318394
  68. 68.
    Segal NH, Logan TF, Hodi FS et al (2016) Results From an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. Clin Cancer Res 23:1929–1936CrossRefPubMedGoogle Scholar
  69. 69.
    Pfizer, Inc and Merck Sharp & Dohme Corp (2016) A Study Of 4-1BB Agonist PF-05082566 Plus PD-1 Inhibitor MK-3475 In Patients With Solid Tumors (B1641003/KEYNOTE-0036). In: [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Nov 11]. Available from: NLM Identifier: NCT02179918
  70. 70.
    Pfizer, Inc and Kyowa Hakko Kirin Company, Ltd (2016) A Study of PF-05082566 In Combination With Mogamulizumab In Patients With Advanced Solid Tumors. In: [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Nov 11]. Available from: NLM Identifier: NCT02444793
  71. 71.
    Chester C, Ambulkar S, Kohrt HE (2016) 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol Immunother 65(10):1243–1248CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Makkouk A, Chester C, Kohrt HE (2016) Rationale for anti-CD137 cancer immunotherapy. Eur J Cancer 54:112–119CrossRefPubMedGoogle Scholar
  73. 73.
    GITR, Inc. and Cancer Research Institute (2016) Trial of TRX518 (Anti-GITR mAb) in Stage III or IV Malignant Melanoma or Other Solid Tumors (TRX518–001). In: [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2016 Nov 11]. Available from: NLM Identifier: NCT01239134
  74. 74.
    Knee DA, Hewes B, Brogdon JL (2016) Rationale for anti-GITR cancer immunotherapy. Eur J Cancer 67:1–10CrossRefPubMedGoogle Scholar
  75. 75.
    Zonder JA, Mohrbacher AF, Singhal S et al (2012) A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120(3):552–559CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Center for Drug Evaluation and Research (2016) Empliciti (elotuzumab) Clinical Pharmacology and Biopharmaceutics Review(s). Application number 761035Orig1s000. Available at: Accessed 11 Nov 2016
  77. 77.
    Empliciti (elotuzumab) Prescribing Information (2016) Princeton: Bristol-Myers Squibb Co.; November 2015. Available at: Accessed 11 Nov 2016
  78. 78.
    Berdeja J, Jagannath S, Zonder J et al (2016) Pharmacokinetics and safety of elotuzumab combined with lenalidomide and dexamethasone in patients with multiple myeloma and various levels of renal impairment: results of a phase Ib study. Clin Lymphoma Myeloma Leuk 16(3):129–138CrossRefPubMedGoogle Scholar
  79. 79.
    Lonial S, Dimopoulos M, Palumbo A et al (2015) Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373(7):621–631CrossRefPubMedGoogle Scholar
  80. 80.
    Gibiansky L, Passey C, Roy A, Bello A, Gupta M (2016) Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma. J Pharmacokinet Pharmacodyn 43(3):243–257CrossRefPubMedGoogle Scholar
  81. 81.
    Zhu M, Wu B, Brandl C et al (2016) Blinatumomab, a bispecific T-cell engager (BiTE((R))) for CD-19 targeted cancer immunotherapy: clinical pharmacology and its implications. Clin Pharmacokinet 55(10):1271–1288CrossRefPubMedGoogle Scholar
  82. 82.
    Blincyto (blinatumomab) Prescribing Information (2016) Thousand Oaks: Amgen Inc.; September 2016. Available at: Accessed 11 Nov 2016
  83. 83.
    Center for Drug Evaluation and Research (2016) Blincyto (blinatumomab) Clinical Pharmacology Biopharmaceutics Review(s). Application number 125557Orig1s000. Available at: Accessed 11 Nov 2016
  84. 84.
    Goebeler ME, Knop S, Viardot A et al (2016) Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-hodgkin Lymphoma: final results from a phase I study. J Clin Oncol 34(10):1104–1111CrossRefPubMedGoogle Scholar
  85. 85.
    Agrawal S, Statkevich P, Bajaj G et al (2016) Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors. J Clin Pharmacol 26:202–204Google Scholar
  86. 86.
    Newick K, O'Brien S, Moon E, Albelda SM (2016) CAR T Cell Therapy for Solid Tumors. Annu Rev Med 68:139–152CrossRefPubMedGoogle Scholar
  87. 87.
    Holzinger A, Barden M, Abken H (2016) The growing world of CAR T cell trials: a systematic review. Cancer Immunol Immunother 65(12):1433–1450CrossRefPubMedGoogle Scholar
  88. 88.
    Jackson HJ, Rafiq S, Brentjens RJ (2016) Driving CAR T-cells forward. Nat Rev Clin Oncol 13(6):370–383CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Allegra A, Innao V, Gerace D, Vaddinelli D, Musolino C (2016) Adoptive immunotherapy for hematological malignancies: current status and new insights in chimeric antigen receptor T cells. Blood Cells Mol Dis 62:49–63CrossRefPubMedGoogle Scholar
  90. 90.
    Jensen MC, Popplewell L, Cooper LJ 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):1245–1256CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Lamers CH, Sleijfer S, van Steenbergen S et al (2013) Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 21(4):904–912CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Till BG, Jensen MC, Wang J et al (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112(6):2261–2271CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Savoldo B, Ramos CA, Liu E et al (2011) CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121(5):1822–1826CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M 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):517–528CrossRefPubMedGoogle Scholar
  95. 95.
    Carpenito C, Milone MC, Hassan R et al (2009) Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A 106(9):3360–3365CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M (2010) 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 18(2):413–420CrossRefPubMedGoogle Scholar
  97. 97.
    Chmielewski M, Kopecky C, Hombach AA, Abken H (2011) IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res 71(17):5697–5706CrossRefPubMedGoogle Scholar
  98. 98.
    Kerkar SP, Goldszmid RS, Muranski P et al (2011) IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest 121(12):4746–4757CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Pegram HJ, Lee JC, Hayman EG et al (2012) Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119(18):4133–4141CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Zhang L, Morgan RA, Beane JD et al (2015) Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res 21(10):2278–2288CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Xu Y, Zhang M, Ramos CA et al (2014) Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood 123(24):3750–3759CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Riddell SR, Sommermeyer D, Berger C et al (2014) Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition. Cancer J 20(2):141–144CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Turtle CJ, Berger C, Sommermeyer D, et al. (2015) Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition. Presented at the 2015 Annual Society of Clinical Oncology Annual Meeting, Chicago, 29 May–2 June 2015Google Scholar
  104. 104.
    Brentjens RJ, Riviere I, Park JH et al (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118(18):4817–4828CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Kochenderfer JN, Dudley ME, Feldman SA et al (2012) 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 119(12):2709–2720CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Porter DL, Hwang WT, Frey NV et al (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7(303):303ra139CrossRefPubMedGoogle Scholar
  107. 107.
    Kochenderfer JN, Dudley ME, Kassim SH et al (2015) 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 33(6):540–549CrossRefPubMedGoogle Scholar
  108. 108.
    Croft M (2003) Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 3(8):609–620CrossRefPubMedGoogle Scholar
  109. 109.
    Center for Biologics Evaluation and Research. Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products. June 2015. Available at: Accessed 30 Dec 2016
  110. 110.
    Liu BL, Robinson M, Han ZQ et al (2003) ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther 10(4):292–303CrossRefPubMedGoogle Scholar
  111. 111.
    Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL (1995) Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1(9):938–943CrossRefPubMedGoogle Scholar
  112. 112.
    Spivack JG, Fareed MU, Valyi-Nagy T et al (1995) Replication, establishment of latent infection, expression of the latency-associated transcripts and explant reactivation of herpes simplex virus type 1 gamma 34.5 mutants in a mouse eye model. J Gen Virol 76(Pt 2):321–332CrossRefPubMedGoogle Scholar
  113. 113.
    Andtbacka RH, Ross M, Puzanov I et al (2016) Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol 23(13):4169–4177CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Fukuhara H, Ino Y, Todo T (2016) Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci 107(10):1373–1379CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Mohr I, Sternberg D, Ward S et al (2001) A herpes simplex virus type 1 gamma34.5 second-site suppressor mutant that exhibits enhanced growth in cultured glioblastoma cells is severely attenuated in animals. J Virol 75(11):5189–5196CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Poppers J, Mulvey M, Khoo D, Mohr I (2000) Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein. J Virol 74(23):11215–11221CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    He B, Chou J, Brandimarti R et al (1997) Suppression of the phenotype of gamma(1)34.5- herpes simplex virus 1: failure of activated RNA-dependent protein kinase to shut off protein synthesis is associated with a deletion in the domain of the alpha47 gene. J Virol 71(8):6049–6054PubMedPubMedCentralGoogle Scholar
  118. 118.
    MacKie RM, Stewart B, Brown SM (2001) Intralesional injection of herpes simplex virus 1716 in metastatic melanoma. Lancet 357(9255):525–526CrossRefPubMedGoogle Scholar
  119. 119.
    Markert JM, Medlock MD, Rabkin SD et al (2000) Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 7(10):867–874CrossRefPubMedGoogle Scholar
  120. 120.
    Sundaresan P, Hunter WD, Martuza RL, Rabkin SD (2000) Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J Virol 74(8):3832–3841CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Advani SJ, Weichselbaum RR, Whitley RJ, Roizman B (2002) Friendly fire: redirecting herpes simplex virus-1 for therapeutic applications. Clin Microbiol Infect 8(9):551–563CrossRefPubMedGoogle Scholar
  122. 122.
    Hu JC, Coffin RS, Davis CJ et al (2006) A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res 12(22):6737–6747CrossRefPubMedGoogle Scholar
  123. 123.
    Rehman H, Silk AW, Kane MP, Kaufman HL (2016) Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer 4:53CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Andtbacka RH, Kaufman HL, Collichio F et al (2015) Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 33(25):2780–2788CrossRefPubMedGoogle Scholar
  125. 125.
    Imlygic (talimogene laherparepvec) Prescribing Information. Thousand Oaks: Amgen Inc.; October 2015. Available at: Accessed 21 November 2016
  126. 126.
    Center for Biologics Evaluation and Research. Imlygic (talimogene laherparepvec, T-VEC, OncoVEX). Clinical Review. Submission tracking number 125518. Available at: Accessed 20 Nov 2016
  127. 127.
    Center for Biologics Evaluation and Research. Imlygic (talimogene laherparepvec, T-VEC, OncoVEX). Clinical Pharmacology and Toxicology Review. Submission tracking number 125518. Accessed 20 Nov 2016. Available at:
  128. 128.
    Kaufman HL, Kim DW, DeRaffele G et al (2010) Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol 17(3):718–730CrossRefPubMedGoogle Scholar
  129. 129.
    Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol. 2016;13(1):25-40. doi: 10.1038/nrclinonc.2015.187. Epub 2015 Nov 3. PMID: 26525683

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Genentech, Inc.South San FranciscoUSA
  2. 2.Skaggs School of Pharmacy & Pharmaceutical SciencesUniversity of California, San DiegoLa JollaUSA
  3. 3.Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA

Personalised recommendations