The journey from bench to bedside
Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4; also known as CD152) is expressed on the surface of T cells, where it primarily suppresses their early stages of activation by inducing inhibitory downstream T-cell receptor (TCR) signaling and counteracting activity of the T-cell costimulatory receptor, CD28.[1,2] CTLA-4 is thought to outcompete CD28 for B7 ligands (CD80 and CD86) on the surface of antigen-presenting cells by binding them with higher affinity and avidity. In preclinical studies, blockade of CTLA-4 led to a 1.5-fold to 2-fold increase in T-cell proliferation and a 6-fold increase in interleukin-2 production.
The physiologic role of CTLA-4 is not only to suppress effector T cells (Teffs), but also to increase the function of immunosuppressive CD4+FoxP3+ regulatory T cells (Tregs). Treg-specific CTLA-4 deficiency was shown to diminish the suppressive capacity of Tregs in cell culture, resulting in upregulation of CD80 and CD86 expression on dendritic cells (DCs). CTLA-4 blockade has been shown to promote T-cell activation, and in preclinical models, to deplete intratumoral Tregs in a process dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment.[6,7]
CTLA-4 was shown to play a critical role in maintaining immunologic homeostasis when mice genetically deficient in CTLA-4 developed a rapidly progressive, fatal lymphoproliferative disease, characterized by multiorgan T-cell infiltration and death by 3 to 4 weeks of age.[8,9] However, Leach et al subsequently demonstrated in a mouse model that blockade of CTLA-4 with antibodies did not cause lethal systemic autoimmunity. Moreover, anti–CTLA-4 treatment in this preclinical study not only resulted in rejection of pre-established tumors but also in immunity to a secondary exposure to tumor cells without additional CTLA-4 blockade, thereby establishing the development of immune memory.
Based on these preclinical findings, clinical testing of two antibodies that block CTLA-4 in humans, ipilimumab and tremelimumab, was begun. Ipilimumab belongs to the immunoglobulin G (IgG) 1 class of fully human monoclonal antibodies (mAbs) and has a half-life of 12 to 14 days. Tremelimumab belongs to the IgG2 class, which causes less antibody-dependent cellular toxicity than IgG1, and has a half-life of 22 days. Lessons learned from the initial phase I/II studies, which have been summarized in prior reviews, include the emergence of a unique toxicity profile, composed of immune-related adverse events (irAEs), and new response patterns in which new lesions are viewed as part of the total tumor burden and not regarded immediately as progressive disease.[11,12]
US Food and Drug Administration (FDA) approval of ipilimumab was ultimately based on the results of a randomized phase III trial for patients with previously treated, unresectable stage III or IV melanoma who received ipilimumab 3 mg/kg with or without glycoprotein (gp)100 peptide vaccine vs gp100 peptide vaccine alone. Median overall survival (OS) in the ipilimumab and ipilimumab + gp100 cohorts was 10.1 and 10.0 months, respectively, vs 6.4 months for the gp100 control arm (hazard ratio [HR], 0.68; P < .001). More importantly, ipilimumab had an effect on long-term survival, with 18% of the ipilimumab-treated patients surviving beyond 2 years compared with 5% of patients who received the gp100 peptide vaccine alone.
Tremelimumab was tested in a randomized phase III trial in patients with advanced melanoma who received either 15 mg/kg every 3 months as a single agent or dacarbazine/temozolomide. The endpoint of improved OS was not reached despite a proportion of subjects experiencing a durable response after treatment with tremelimumab. The lack of an OS benefit may have been due to crossover to an expanded-access ipilimumab program by patients who received chemotherapy in the control arm. Further, pharmacokinetic simulations subsequently indicated that, despite tremelimumab’s longer half-life, a 15-mg/kg every-3-month dosing strategy resulted in only 50% of subjects reaching the drug’s target concentration. Approximately 90% of subjects reached target levels when treated with tremelimumab 10 mg/kg every 4 weeks for 6 months. Tremelimumab recently showed encouraging clinical activity with the 15-mg/kg every-3-month dosing strategy in previously treated patients with advanced malignant mesothelioma in a phase II trial. For these reasons, tremelimumab continues to be investigated at different doses and in a variety of malignancies and combination regimens, which will be discussed later in this article.
Back to the bench: next-generation sequencing and further insights into the biology of CTLA-4 blockade
Only a subset of patients and tumor types benefits from CTLA-4 blockade. Therefore, immense effort has been expended to understand tumor and host characteristics that contribute to response. Next-generation sequencing may prove to be a valuable tool in helping to achieve this goal.
Approximately 40% of cutaneous metastatic melanomas have an activating mutation that results in the substitution of glutamic acid for valine at codon 600 (BRAF V600E) and leads to constitutive activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway. [17,18] Although this mutation is not thought to correlate with response to anti–CTLA-4 therapy, recent data suggest that a mutation in RAS (rat sarcoma) may correlate with response to ipilimumab. In this retrospective study, patients with metastatic melanoma who harbored a mutation in NRAS (neuroblastoma RAS) had a clinical benefit rate of 41% from ipilimumab therapy vs 22% for wild-type patients (P = .018; N = 137).
Further, a preclinical study found that phosphatase and tensin homolog (PTEN) represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositol 3-kinase (PI3K) pathway, which is a downstream target of RAS. Indeed, PTEN loss in malignant melanoma samples was associated with a host response that was not brisk, which could, in theory, predict a poor response to CTLA-4 blockade. The immunologic consequences of these signaling pathways are an area of active research; whether they influence immunotherapy treatment outcomes requires additional investigation.
Another hypothesis implicates the role of immunogenic neoantigens. Different types of malignancies vary with respect to the number of cancer-causing mutations that may encode proteins foreign to the immune system and directly correlate with response to T cell–based immunotherapy.[22,23] However, there does seem to be checkpoint inhibitor activity in tumors with lower median mutational loads, and there also appears to be a lack of activity in certain subjects with tumors classically associated with a high mutational burden. This discrepancy may be due to interindividual differences in the mutational load across a given tumor type, or there may be specific mutations that are more likely to promote an immune response.
To help shed light on this issue, two recent studies have taken a closer look at cancer genome data to determine whether there are mutations that contribute to a T-cell response. The first used bioinformatics and in vitro strategies in a patient with stage IV melanoma to show that a peptide resulting from a mutation in the ATR (ataxia telangiectasia and Rad3 related) gene generated specific T-cell reactivity that increased strongly after successful treatment with ipilimumab. The second performed whole-exome sequencing of tumor DNA from 11 patients who had long-term benefit and 14 who had minimal or no benefit from ipilimumab treatment for advanced melanoma. A preliminary association between certain neoantigens and clinical outcomes was seen.
Whole-exome sequencing and TCR quantitative sequencing have recently been applied to identify patient germline and immune characteristics that may predict clinical benefit from CTLA-4 blockade. In patients with metastatic melanoma treated with ipilimumab, whole-exome sequencing of germline DNA from 30 objective responders and 30 nonresponders identified several single nucleotide polymorphisms that cosegregated with clinical outcomes. Although these results need to be confirmed in functional and larger prospective studies, the genes identified represent chemokine receptors and thus support the biologic plausibility of this result. The effects of anti–CTLA-4 therapy on the T-cell repertoire were recently studied using next-generation sequencing of the TCRβ gene from T cells isolated from samples of peripheral blood mononuclear cells; 25 metastatic castration-resistant prostate cancer (CRPC) patients treated with ipilimumab and granulocyte macrophage colony-stimulating factor (GM-CSF), 21 metastatic melanoma patients treated with tremelimumab, and 9 untreated healthy control subjects were included. Although blockade of CTLA-4 caused global turnover of the T-cell repertoire and an increase in TCR diversity, improved OS was associated only with maintenance of high-frequency TCR clonotypes throughout treatment. This result suggests that high-avidity, pre-existing T cells may be important to the antitumor response seen with CTLA-4 blockade.
These advances also suggest that a more personalized strategy may ultimately be feasible for the application of CTLA-4 blockade. If expeditious and reproducible prescreening methods could be developed, those patients and tumor types most likely to benefit could be identified. Further, these techniques give important mechanistic insights that could aid in the design of combination approaches for the treatment of patients who are unlikely to respond to anti–CTLA-4 monotherapy.
1. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992;71:1065-8.
2. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459-65.
3. Linsley PS, Brady W, Urnes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561-9.
4. Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183:2533-40.
5. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-5.
6. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies. J Exp Med. 2009;206:1717-25.
7. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-
dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J Exp Med. 2013;210:1695-710.
8. 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;3:541-7.
9. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science. 1995;270:985-8.
10. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-6.
11. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-7.
12. 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;15:7412-20.
13. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.
14. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616-22.
15. Tarhini AA. Tremelimumab: a review of development to date in solid tumors. Immunotherapy. 2013;5:215-29.
16. 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;14:1104-11.
17. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-54.
18. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-47.
19. Shahabi V, Whitney G, Hamid O, et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61:733-7.
20. Johnson DB, Lovly CM, Flavin M, et al. NRAS mutation: a potential biomarker of clinical response to immune-based therapies in metastatic melanoma (MM). J Clin Oncol. 2013;31(suppl):abstr 9019.
21. Dong Y, Richards J-A, Gupta R, et al. PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene. 2014;33:4632-42.
22. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-21.
23. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339:1546-58.
24. van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31:e439-e442.
25. Charen AS, Makarov V, Merghoub T, et al. The neoantigen landscape underlying clinical response to ipilimumab. J Clin Oncol. 2014;32(suppl 5S):abstr 3003.
26. Adaniel C, Rendleman J, Polsky D, et al. Germline genetic determinants of immunotherapy response in metastatic melanoma. J Clin Oncol. 2014;32(suppl 5S): abstr 3004.
27. Cha E, Klinger M, Hou Y, et al. Improved survival with T cell clonotype stability after anti–CTLA-4 treatment in cancer patients. Sci Transl Med. 2014;6:238ra70.
28. Green DR, Ferguson T, Zitvogel L, et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353-63.
29. Shurin MR. Dual role of immunomodulation by anticancer chemotherapy. Nat Med. 2013;19:20-2.
30. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202:1691-701.
31. Emens LA, Jaffee EM. Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res. 2005;65:8059-64.
32. Tanaka F, Yamaguchi H, Ohta M, et al. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer. 2002;101:265-9.
33. Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell–dependent antitumor immunity. Cancer Res. 2010;70:3052-61.
34. Suzuki E, Kapoor V, Jassar AS, et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11:6713-21.
35. Kitano S, Postow MA, Ziegler CGK, et al. Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol Res. 2014;8:812-21.
36. Weide B, Martens A, Zelba H, et al. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A–specific T cells. Clin Cancer Res. 2014;20:1601-9.
37. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364: 2517-26.
38. Weber J, Hamid O, Amin A, et al. Randomized phase I pharmacokinetic study of ipilimumab with or without one of two different chemotherapy regimens in patients with untreated advanced melanoma. Cancer Immun. 2013;13:7.
39. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364:2507-16.
40. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24:75-83.
41. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-54.
42. Ruffini E, Asioli S, Filosso PL, et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg. 2009;87:365-71.
43. Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol. 2012;30:34-41.
44. Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol. 1998;160:1224-32.
45. Dikov MM, Ohm JE, Ray N, et al. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol. 2005;174:215-22.
46. Yuan J, Zhou J, Dong Z, et al. Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res. 2014;2:127-32.
47. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632-42.
48. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925-31.
49. Barker CA, Postow MA, Khan SA, et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res. 2013;1:92-8.
50. Waitz R, Solomon SB, Petre EN, et al. Potent induction of tumor immunity by combining tumor cryoablation with anti–CTLA-4 therapy. Cancer Res. 2012;72:430-9.
51. Slovin SF, Higano CS, Hamid O, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24:1813-21.
52. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-12.
53. Dhodapkar MV, Sznol M, Zhao B, et al. Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205. Sci Transl Med. 2014;6:232ra51.
54. Neyns B, Wilgenhof S, Corthals J, et al. Phase II study of autologous mRNA electroporated dendritic cells (TriMixDC-MEL) in combination with ipilimumab in patients with pretreated advanced melanoma.
J Clin Oncol. 2014;32(suppl 5S):abstr 3014.
55. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36:382-9.
56. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti–cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190:355-66.
57. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl):abstr CRA9007.
58. Hauschild A, Grob J-J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-65.
59. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-703.
60. Hu-Lieskovan S, Robert L, Moreno BH, et al. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges.
J Clin Oncol. 2014;32:2248-54.
61. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab.
N Engl J Med. 2013;368:1365-6.
62. Puzanov I, Callahan MK, Linette GP, et al. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM).
J Clin Oncol. 2014;32(suppl 5S):abstr 2511.
63. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120:1695-701.
64. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225-31.
65. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-64.
66. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366:2517-9.
67. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl 5S):abstr LBA9003.
68. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
69. Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl 5S):abstr 4504.
70. Melero I, Shuford WW, Newby SA, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3:682-5.
71. Sznol M, Hodi FS, Margolin K, et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). J Clin Oncol. 2008;26(15 suppl):abstr 3007.
72. Segal NH, Gopal AK, Bhatia S, et al. A phase 1 study of PF-05082566 (anti-4-1BB) in patients with advanced cancer. J Clin Oncol. 2014;32(suppl 5S):abstr 3007.
73. Kocak E, Lute K, Chang X, et al. Combination therapy with anti–CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res. 2006;66:7276-84.
74. Belcaid Z, Phallen JA, Zeng J, et al. Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One. 2014;9:e101764.
75. Sugamura K, Ishii N, Weinberg AD. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol. 2004;4:420-31.
76. Curti BD, Kovacsovics-Bankowski M, Morris N, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73:7189-98.
77. Redmond WL, Linch SN, Kasiewicz MJ. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector t cells capable of driving robust antitumor immunity. Cancer Immunol Res. 2014;2:142-53.
78. Ribas A, Comin-Anduix B, Economou JS, et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res. 2009;15:390-9.
79. Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9:204.
80. Munn DH, Sharma MD, Baban B, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633-42.
81. Holmgaard RB, Zamarin D, Munn DH, et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210:1389-402.
82. Hanks BA, Holtzhausen A, Evans KS, et al. Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest. 2013;123:3925-40.
83. Gibney GT, Hamid O, Gangadhar TC, et al. Preliminary results from a phase 1/2 studyof INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma. J Clin Oncol. 2014;32(suppl 5s):abstr 3010.
84. Hanks BA, Holtzhausen A, Evans K, et al. Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma.
J Clin Oncol. 2014;32(suppl 5S):abstr 3011.
85. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5:201-14.
86. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-64.
87. Antonia SJ, Gettinger SN, Chow LQM, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: interim phase I results. J Clin Oncol. 2014;32(suppl 5S):abstr 8023.
88. Coit DG, Andtbacka R, Anker CJ, et al. Melanoma, version 2.2013: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013;11:395-407.
89. Teply BA, Lipson EJ. Identification and management of toxicities from immune checkpoint–blocking drugs. Oncology (Williston Park). 2014;28(suppl3)30-8.
90. Russell SJ, Peng K-W, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30:658-70.
91. Schirrmacher V, Fournier P. Newcastle disease virus: a promising vector for viral therapy, immune therapy, and gene therapy of cancer. Methods Mol Biol. 2009;542:565-605.
92. Kaufman HL, Kim DW, DeRaffele G, et al. 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. 2010;17:718-30.
93. 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.
94. Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin Oncol. 2014;32(suppl 5S):abstr 9029.