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Principles of cancer immunotherapy

Authors
Alexander N Shoushtari, MD
Alexandra Snyder Charen, MD
Michael Postow, MD
Jedd Wolchok, MD, PhD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD

INTRODUCTION

The fields of immunology and oncology have been linked since the late 19th century, when the surgeon William Coley reported that an injection of killed bacteria into sites of sarcoma could lead to tumor shrinkage [1]. Since that time, exponential advances in the understanding of the intersection between immune surveillance and tumor growth and development have led to broad therapeutic advances that are now being studied in all cancer types.

The basic immunology and the various approaches to immunotherapy for tumors are discussed here. The details of immunology’s role in specific malignancies are discussed in the relevant tumor-oriented topics.

TUMOR IMMUNOLOGY

Cell types involved in tumor recognition and rejection — An efficient and specific cytotoxic immune response against a tumor requires a complex, rapidly evolving interaction between various immune cell types in the adaptive and innate immune system.

CD8+ lymphocytes and Th1/Th2 subclasses of CD4+ T lymphocytes, traditionally referred to as cytotoxic T cells and helper T cells. CD8+ and CD4+ lymphocytes initiate the distinction between self and non-self antigens, through recognition at the "immune synapse." (See 'The "immune synapse"' below.)

Natural killer (NK) cells do not require antigen presentation by the major histocompatibility complex (MHC) for cytotoxic activity. In fact, NK cells target cells with low MHC class 1 expression for destruction. Like T cells, NK cells express numerous inhibitory molecules as well, most notably various killer immunoglobulin-like receptor (KIR) subtypes [2].

                         

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Literature review current through: Nov 2016. | This topic last updated: Mon Nov 02 00:00:00 GMT 2015.
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References
Top
  1. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci 1893; 105:487.
  2. Gras Navarro A, Björklund AT, Chekenya M. Therapeutic potential and challenges of natural killer cells in treatment of solid tumors. Front Immunol 2015; 6:202.
  3. Savage PA, Leventhal DS, Malchow S. Shaping the repertoire of tumor-infiltrating effector and regulatory T cells. Immunol Rev 2014; 259:245.
  4. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 2015; 125:3356.
  5. Bailey SR, Nelson MH, Himes RA, et al. Th17 cells in cancer: the ultimate identity crisis. Front Immunol 2014; 5:276.
  6. Laoui D, Van Overmeire E, De Baetselier P, et al. Functional Relationship between Tumor-Associated Macrophages and Macrophage Colony-Stimulating Factor as Contributors to Cancer Progression. Front Immunol 2014; 5:489.
  7. van der Merwe PA, Dushek O. Mechanisms for T cell receptor triggering. Nat Rev Immunol 2011; 11:47.
  8. Hennecke J, Wiley DC. T cell receptor-MHC interactions up close. Cell 2001; 104:1.
  9. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990; 248:1349.
  10. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12:492.
  11. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331:1565.
  12. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014; 344:641.
  13. Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012; 482:400.
  14. Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015; 35 Suppl:S185.
  15. Johnsen AK, Templeton DJ, Sy M, Harding CV. Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol 1999; 163:4224.
  16. Donia M, Andersen R, Kjeldsen JW, et al. Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity. Cancer Res 2015; 75:3747.
  17. Rooney MS, Shukla SA, Wu CJ, et al. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 2015; 160:48.
  18. Catalán E, Charni S, Jaime P, et al. MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells. Oncoimmunology 2015; 4:e985924.
  19. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 2015; 125:1061.
  20. Amend SR, Pienta KJ. Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget 2015; 6:9669.
  21. Guo F, Wang Y, Liu J, et al. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene 2016; 35:816.
  22. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515:568.
  23. Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 2011; 17:1094.
  24. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015; 523:231.
  25. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 2012; 12:180.
  26. Krieg C, Létourneau S, Pantaleo G, Boyman O. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci U S A 2010; 107:11906.
  27. Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108:390.
  28. Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007; 26:371.
  29. Kryczek I, Wei S, Zou L, et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 2007; 178:6730.
  30. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994; 271:907.
  31. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
  32. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014; 343:305.
  33. Avitahl N, Winandy S, Friedrich C, et al. Ikaros sets thresholds for T cell activation and regulates chromosome propagation. Immunity 1999; 10:333.
  34. Quintana FJ, Jin H, Burns EJ, et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat Immunol 2012; 13:770.
  35. Lesinski GB, Anghelina M, Zimmerer J, et al. The antitumor effects of IFN-alpha are abrogated in a STAT1-deficient mouse. J Clin Invest 2003; 112:170.
  36. Carson WE. Interferon-alpha-induced activation of signal transducer and activator of transcription proteins in malignant melanoma. Clin Cancer Res 1998; 4:2219.
  37. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer--a current perspective. Nat Rev Urol 2014; 11:153.
  38. Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 1997; 7:885.
  39. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3:541.
  40. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995; 270:985.
  41. Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 2011; 11:852.
  42. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271:1734.
  43. Schadendorf D, Hodi FS, Robert C, et al. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015; 33:1889.
  44. Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14:1104.
  45. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009; 206:3015.
  46. Amarnath S, Mangus CW, Wang JC, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med 2011; 3:111ra120.
  47. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 2013; 5:200ra116.
  48. Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181:6738.
  49. Yang J, Riella LV, Chock S, et al. The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 2011; 187:1113.
  50. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372:2509.
  51. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443.
  52. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372:311.
  53. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 2014; 15:69.
  54. Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol 2013; 31:4199.
  55. Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 33, 2015 (suppl; abstr 4502).
  56. Rosenberg J, Petrylak C, Abidoye O, et al. Atezolizumab in patients with locally-advanced or metastatic urothelial carcinoma: Results from a pivotal multicenter phase II study (IMvigor 210). Abstract 21LBA, European Society of Medical Oncology, 2105.
  57. Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol 33, 2015 (suppl; abstr LBA6008).
  58. Watanabe N, Gavrieli M, Sedy JR, et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 2003; 4:670.
  59. Murphy KM, Nelson CA, Sedý JR. Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol 2006; 6:671.
  60. Fourcade J, Sun Z, Pagliano O, et al. CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 2012; 72:887.
  61. Lines JL, Pantazi E, Mak J, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res 2014; 74:1924.
  62. Wang L, Rubinstein R, Lines JL, et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 2011; 208:577.
  63. Le Mercier I, Chen W, Lines JL, et al. VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res 2014; 74:1933.
  64. Monney L, Sabatos CA, Gaglia JL, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415:536.
  65. Anderson AC, Anderson DE, Bregoli L, et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 2007; 318:1141.
  66. Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005; 6:1245.
  67. Sabatos CA, Chakravarti S, Cha E, et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 2003; 4:1102.
  68. Ngiow SF, von Scheidt B, Akiba H, et al. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res 2011; 71:3540.
  69. Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol 2005; 35:2081.
  70. Grosso JF, Goldberg MV, Getnet D, et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 2009; 182:6659.
  71. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012; 72:917.
  72. Wilcox RA, Chapoval AI, Gorski KS, et al. Cutting edge: Expression of functional CD137 receptor by dendritic cells. J Immunol 2002; 168:4262.
  73. McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16:311.
  74. Vinay DS, Kwon BS. 4-1BB signaling beyond T cells. Cell Mol Immunol 2011; 8:281.
  75. Hernandez-Chacon JA, Li Y, Wu RC, et al. Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function. J Immunother 2011; 34:236.
  76. Melero I, Shuford WW, Newby SA, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 1997; 3:682.
  77. Uno T, Takeda K, Kojima Y, et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med 2006; 12:693.
  78. Takeda K, Kojima Y, Uno T, et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J Immunol 2010; 184:5493.
  79. Youlin K, Jianwei Z, Xin G, et al. 4-1BB protects dendritic cells from prostate cancer-induced apoptosis. Pathol Oncol Res 2013; 19:177.
  80. Sznol M, Hodi FS, Margolin K, et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody in patients with advanced cancer (abstract 3007). 2008 American Society of Clinical Oncology meeting.
  81. Segal NH GA, Bhatia S, Kohrt HE, et al. A phase 1 study of PF-05082566 (anti-4-1BB) in patients with advanced cancer. J Clin Oncol 2014; 32:Abstract 3007.
  82. Weinberg AD, Morris NP, Kovacsovics-Bankowski M, et al. Science gone translational: the OX40 agonist story. Immunol Rev 2011; 244:218.
  83. Takeda I, Ine S, Killeen N, et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol 2004; 172:3580.
  84. Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med 2010; 207:699.
  85. Valzasina B, Guiducci C, Dislich H, et al. Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 2005; 105:2845.
  86. Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol 2010; 28:57.
  87. Weinberg AD, Rivera MM, Prell R, et al. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol 2000; 164:2160.
  88. Gough MJ, Crittenden MR, Sarff M, et al. Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. J Immunother 2010; 33:798.
  89. Pan PY, Zang Y, Weber K, et al. OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol Ther 2002; 6:528.
  90. Watanabe A, Hara M, Chosa E, et al. Combination of adoptive cell transfer and antibody injection can eradicate established tumors in mice--an in vivo study using anti-OX40mAb, anti-CD25mAb and anti-CTLA4mAb-. Immunopharmacol Immunotoxicol 2010; 32:238.
  91. Hirschhorn-Cymerman D, Rizzuto GA, Merghoub T, et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J Exp Med 2009; 206:1103.
  92. Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 2013; 73:7189.
  93. Nocentini G, Ronchetti S, Petrillo MG, Riccardi C. Pharmacological modulation of GITRL/GITR system: therapeutic perspectives. Br J Pharmacol 2012; 165:2089.
  94. Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Curr Opin Immunol 2012; 24:217.
  95. Lacal PM, Petrillo MG, Ruffini F, et al. Glucocorticoid-induced tumor necrosis factor receptor family-related ligand triggering upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and promotes leukocyte adhesion. J Pharmacol Exp Ther 2013; 347:164.
  96. Shimizu J, Yamazaki S, Takahashi T, et al. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3:135.
  97. Stephens GL, McHugh RS, Whitters MJ, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 2004; 173:5008.
  98. Ko K, Yamazaki S, Nakamura K, et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 2005; 202:885.
  99. Schaer DA, Cohen AD, Wolchok JD. Anti-GITR antibodies--potential clinical applications for tumor immunotherapy. Curr Opin Investig Drugs 2010; 11:1378.
  100. Cohen AD, Schaer DA, Liu C, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One 2010; 5:e10436.
  101. Simpson TR, Quezada SA, Allison JP. Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr Opin Immunol 2010; 22:326.
  102. Fan X, Quezada SA, Sepulveda MA, et al. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med 2014; 211:715.
  103. Hassan SB, Sørensen JF, Olsen BN, Pedersen AE. Anti-CD40-mediated cancer immunotherapy: an update of recent and ongoing clinical trials. Immunopharmacol Immunotoxicol 2014; 36:96.
  104. de Vos S, Forero-Torres A, Ansell SM, et al. A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors. J Hematol Oncol 2014; 7:44.
  105. Fayad L, Ansell SM, Advani R, et al. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leuk Lymphoma 2015; 56:2569.
  106. Fanale M, Assouline S, Kuruvilla J, et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol 2014; 164:258.
  107. Bensinger W, Maziarz RT, Jagannath S, et al. A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol 2012; 159:58.
  108. Byrd JC, Kipps TJ, Flinn IW, et al. Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk Lymphoma 2012; 53:2136.
  109. Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355:1018.
  110. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015; 373:23.
  111. Davila ML, Brentjens R, Wang X, et al. How do CARs work?: Early insights from recent clinical studies targeting CD19. Oncoimmunology 2012; 1:1577.
  112. Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013; 3:388.
  113. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5:177ra38.
  114. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368:1509.
  115. Porter DL GS, Kalos M, Loren AW, et al. Chimeric antigen receptor T cells directed against CD19 induce durable responses and transient cytokine release syndrome in relapsed, refractory CLL and ALL. ASH Annu Meet Abstr 2012; 120:717 26.
  116. Park JH RI, Wang X, Stefanski J, et al. Impact of the conditioning chemotherapy on outcomes in adoptive T cell therapy: results from a phase I clinical trial of autologous CD19-targeted T cells for patients with relapsed CLL. ASH Annu Meet Abstr 2012; 120:1797.
  117. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348:62.
  118. Lu YC, Yao X, Crystal JS, et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res 2014; 20:3401.
  119. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17:4550.
  120. Stevanović S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol 2015; 33:1543.
  121. Liddy N, Bossi G, Adams KJ, et al. Monoclonal TCR-redirected tumor cell killing. Nat Med 2012; 18:980.
  122. Oates J, Hassan NJ, Jakobsen BK. ImmTACs for targeted cancer therapy: Why, what, how, and which. Mol Immunol 2015; 67:67.
  123. Cameron BJ, Gerry AB, Dukes J, et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med 2013; 5:197ra103.
  124. de Gruijl TD, Janssen AB, van Beusechem VW. Arming oncolytic viruses to leverage antitumor immunity. Expert Opin Biol Ther 2015; 15:959.
  125. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 2015; 33:2780.
  126. Westphal M, Ylä-Herttuala S, Martin J, et al. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14:823.
  127. Freytag SO, Stricker H, Lu M, et al. Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2014; 89:268.
  128. Dreno B, Urosevic-Maiwald M, Kim Y, et al. TG1042 (Adenovirus-interferon-γ) in primary cutaneous B-cell lymphomas: a phase II clinical trial. PLoS One 2014; 9:e83670.
  129. Dong J, Li W, Dong A, et al. Gene therapy for unresectable hepatocellular carcinoma using recombinant human adenovirus type 5. Med Oncol 2014; 31:95.
  130. Kicielinski KP, Chiocca EA, Yu JS, et al. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol Ther 2014; 22:1056.
  131. Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 2014; 6:226ra32.
  132. Shifrin N, Raulet DH, Ardolino M. NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol 2014; 26:138.
  133. Kmiecik J, Zimmer J, Chekenya M. Natural killer cells in intracranial neoplasms: presence and therapeutic efficacy against brain tumours. J Neurooncol 2014; 116:1.
  134. Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000; 88:577.
  135. Villegas FR, Coca S, Villarrubia VG, et al. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 2002; 35:23.
  136. Kohrt HE, Thielens A, Marabelle A, et al. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 2014; 123:678.
  137. Nijhof IS, Lammerts van Bueren JJ, van Kessel B, et al. Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Haematologica 2015; 100:263.
  138. Romagné F, André P, Spee P, et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 2009; 114:2667.
  139. Vey N, Bourhis JH, Boissel N, et al. A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 2012; 120:4317.
  140. Benson DM Jr, Hofmeister CC, Padmanabhan S, et al. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 2012; 120:4324.
  141. Benson DM Jr, Cohen AD, Jagannath S, et al. A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res 2015; 21:4055.
  142. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci 2014; 105:1.
  143. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell 2015; 27:462.
  144. DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011; 1:54.
  145. Ruffell B, Chang-Strachan D, Chan V, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 2014; 26:623.
  146. Shiao SL, Ruffell B, DeNardo DG, et al. TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res 2015; 3:518.
  147. Priceman SJ, Sung JL, Shaposhnik Z, et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 2010; 115:1461.
  148. Mok S, Koya RC, Tsui C, et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res 2014; 74:153.
  149. Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014; 74:5057.
  150. Cassier PA, Italiano A, Gomez-Roca CA, et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Lancet Oncol 2015; 16:949.
  151. Tap WD, Wainberg ZA, Anthony SP, et al. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med 2015; 373:428.
  152. Brana I, Calles A, LoRusso PM, et al. Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study. Target Oncol 2015; 10:111.
  153. Hwu P, Du MX, Lapointe R, et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 2000; 164:3596.
  154. Katz JB, Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 2008; 222:206.
  155. Newton RC SP, Bowman K et al. Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients. J Clin Oncol 2012; 30:Abstract 2500.
  156. Gibney GT HO, Gangadhar TC et al. Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma. J Clin Oncol 2014; 32:Abstract 3010.
  157. Ozao-Choy J, Lee DJ, Faries MB. Melanoma vaccines: mixed past, promising future. Surg Clin North Am 2014; 94:1017.
  158. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411.
  159. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011; 364:2119.
  160. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711.
  161. Carreno BM, Magrini V, Becker-Hapak M, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 2015; 348:803.
  162. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412.
  163. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372:320.
  164. Weber JS, D'Angelo SP, Minor D, et al. 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 2015; 16:375.
  165. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol 2013; 31:4311.
  166. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373:123.
  167. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20:5064.
  168. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014; 371:2189.
  169. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348:124.