Recent developments in the use of immunotherapy in non-small cell lung cancer

Expert Review of Respiratory Medicine

Volumn 10, Issue 7, 2016, Pages 781-798

  Santarpia, Mariacarmela ^a   Giovannetti, Elisa ^b,c   Rolfo, Christian ^d   Karachaliou, Niki ^e   González Cao, Maria ^e   Altavilla, Giuseppe ^a   Rosell, Rafael ^e,f,g,h,i  

^a UNIVERSITY OF MESSINA   (Italy)

^b VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^c UNIVERSITY OF PISA   (Italy)

^d ANTWERP UNIVERSITY HOSPITAL   (Belgium)

^e INSTITUT UNIVERSITARI DEXEUS   (Spain)

^f Pangaea Biotech   (Spain)

^g HOSPITAL UNIVERSITARI GERMANS TRIAS I PUJOL   (Spain)

^h Germans Trias i Pujol Research Institute in Health Sciences   (Spain)

ⁱ Molecular Oncology Research (MORe) Foundation   (Spain)

Author keywords

cytotoxic T lymphocyte associated antigen 4 (CTLA 4); immune checkpoint inhibitors; Non small cell lung cancer; programmed cell death ligand 1 (PD L1); programmed cell death protein 1 (PD 1)

Indexed keywords

ANTINEOPLASTIC AGENT; ATEZOLIZUMAB; AVELUMAB; B7 ANTIGEN; BELAGENPUMATUCEL L; BMS 936559; CANCER VACCINE; CD28 ANTIGEN; CD86 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DURVALUMAB; EPIDERMAL GROWTH FACTOR VACCINE; IMMUNOMODULATING AGENT; IPILIMUMAB; MELANOMA ANTIGEN 3; NIVOLUMAB; NY ESO 1 ANTIGEN; PEMBROLIZUMAB; PROGRAMMED DEATH 1 RECEPTOR; RACOTUMOMAB; TECEMOTIDE; TG 4010; TICILIMUMAB; TUMOR CELL VACCINE; UNCLASSIFIED DRUG; IMMUNOLOGIC FACTOR;

ADAPTIVE IMMUNITY; ANTIBODY RESPONSE; ANTIGEN EXPRESSION; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER PREVENTION; CANCER RADIOTHERAPY; CHEMORADIOTHERAPY; CYTOTOXIC T LYMPHOCYTE; DRUG EFFICACY; HUMAN; IMMUNE SYSTEM; NON SMALL CELL LUNG CANCER; NONHUMAN; PATIENT SELECTION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; REVIEW; SURVIVAL ANALYSIS; TUMOR CELL; CARCINOMA, NON-SMALL-CELL LUNG; IMMUNOTHERAPY; LUNG NEOPLASMS;

CARCINOMA, NON-SMALL-CELL LUNG; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOTHERAPY; LUNG NEOPLASMS;

EID: 84975475669     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1080/17476348.2016.1182866     Document Type: Review

References (123)

1. G.J.Riely, H.A.Yu, EGFR: the paradigm of an oncogene-driven lung cancer. Clin Cancer Res. 2015;21(10):2221–2226.
2. B.-C.Liao, -C.-C.Lin, J.-Y.Shih, et al. Treating patients with ALK-positive non-small cell lung cancer: latest evidence and management strategy. Ther Adv Med Oncol. 2015;7(5):274–290.
3. G.A.Masters, S.Temin, C.G.Azzoli, et al. Systemic therapy for stage IV non-small-cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2015;33(30):3488–3515.
4. Cancer Genome Atlas Research Network; P.S.Hammerman, M.S.Lawrence, D.Voet, et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–525. Erratum in: Nature. 2012;491(7423):288.
5. M.Santarpia, N.Gil, R.Rosell Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. Expert Rev Clin Pharmacol. 2015;8(4):461–477.
6. M.S.Lawrence, P.Stojanov, P.Polak, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–218.
7. T.F.Gajewski, H.Schreiber, Y.-X.Fu. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–1022.
8. M.J.Smyth, G.P.Dunn, R.D.Schreiber. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.
9. R.D.Schreiber, L.J.Old, M.J.Smyth. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–1570.
10. C.A.Dasanu, N.Sethi, N.Ahmed. Immune alterations and emerging immunotherapeutic approaches in lung cancer. Expert Opin Biol Ther. 2012;12(7):923–937.
11. D.M.Pardoll. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.
12. C.J.Nirschl, C.G.Drake. Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res. 2013;19(18):4917–4924.
13. D.J.Lenschow, T.L.Walunas, J.A.Bluestone. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233–258.
14. P.S.Linsley, J.L.Greene, W.Brady, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1994;1(9):793–801.
15. C.E.Rudd, A.Taylor, H.Schneider. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229:12–26.
16. O.S.Qureshi, Y.Zheng, K.Nakamura, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–603.
17. J.L.Riley, M.Mao, S.Kobayashi, et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci U S A. 2002;99:11790–11795.
18. E.Chuang, T.S.Fisher, R.W.Morgan, et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity. 2000;13(3):313–322.
19. S.L.Topalian, C.G.Drake, D.M.Pardoll. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–461.
20. K.Wing, Y.Onishi, P.Prieto-Martin, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–275.
21. E.A.Tivol, F.Borriello, A.N.Schweitzer, 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(5):541–547.
22. P.Waterhouse, J.M.Penninger, E.Timms, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–988.
23. D.R.Leach, M.F.Krummel, J.P.Allison. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–1736.
24. F.S.Hodi, S.J.O’Day, D.F.McDermott, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723.
25. C.Robert, L.Thomas, I.Bondarenko, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–2526.
26. T.J.Lynch, I.Bondarenko, A.Luft, 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(17):2046–2054.
27. M.Reck, I.Bondarenko, A.Luft, 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(1):75–83.
28. P.Zatloukal, D.S.Heo, K.Park, et al. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27(suppl; abstract 8071).
29. R.Stewart, S.Mullins, A.Watkins, et al. Preclinical modelling of immune checkpoint blockade. J Immunol. 2013;190(abstract 214.7 (P2012)).
30. S.Antonia, S.B.Goldberg, A.Balmanoukian, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299–308.
31. L.M.Francisco, V.H.Salinas, K.E.Brown, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–3029.
32. M.Terme, E.Ullrich, L.Aymeric, et al. IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 2011;71(16):5393–5399.
33. Y.Ishida, Y.Agata, K.Shibahara, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887–3895.
34. G.J.Freeman, A.J.Long, Y.Iwai, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–1034.
35. M.E.Keir, S.C.Liang, I.Guleria, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–895.
36. H.Nishimura, M.Nose, H.Hiai, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–151.
37. H.Nishimura, T.Okazaki, Y.Tanaka, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319–322.
38. H.Dong, G.Zhu, K.Tamada, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–1369.
39. Y.Latchman, C.R.Wood, T.Chernova, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–268.
40. S.Y.Tseng, M.Otsuji, K.Gorski, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193(7):839–846.
41. W.Zou, L.Chen. Inhibitory B7-family molecules in the tumor microenvironment. Nat Rev Immunol. 2008;8(6):467–477.
42. H.Dong, S.E.Strome, D.R.Salomao, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.
43. J.Konishi, K.Yamazaki, M.Azuma, et al. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10(15):5094–5100.
44. A.Rosenwald, G.Wright, K.Leroy, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862.
45. J.M.Chemnitz, R.V.Parry, K.E.Nichols, et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173(2):945–954.
46. T.Yokosuka, M.Takamatsu, W.Kobayashi-Imanishi, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–1217.
47. K.-A.Sheppard, L.J.Fitz, J.M.Lee, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574(1–3):37–41.
48. D.L.Barber, E.J.Wherry, D.Masopust, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–687.
49. Y.Iwai, M.Ishida, Y.Tanaka, et al. 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. 2002;99(19):12293–12297.
50. K.E.Pauken, E.J.Wherry. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36(4):265–276.
51. J.M.Chinai, M.Janakiram, F.Chen, et al. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci. 2015;36(9):587–595.
52. C.Wang, K.B.Thudium, M.Han, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2(9):846–856.
53. M.A.Postow, M.K.Callahan, J.D.Wolchok. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–1982.
54. S.L.Topalian, F.S.Hodi, J.R.Brahmer, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454.
55. S.N.Gettinger, L.Horn, L.Gandhi, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33(18):2004–2012.
56. N.A.Rizvi, J.Mazières, D.Planchard, et al. 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. 2015;16(3):257–265.
57. L.Horn, N.Rizvi, J.Mazières, et al. Longer-term follow-up of a phase 2 study (CheckMate 063) of nivolumab in patients with advanced, refractory squamous non-small cell lung cancer (NSCLC). J Thor Oncol. 2015;10(9, supplement 2; abstract 02.03): S175–176.
58. J.Brahmer, K.L.Reckamp, P.Baas, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–135.•• This phase III study demonstrated that nivolumab was superior to docetaxel in terms of overall survival, progression-free survival, and overall response rate and was also associated with lower frequency of treatment-related adverse events.
59. H.Borghaei, L.Paz-Ares, L.Horn, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–1639.•• In this phase III study, nivolumab treatment was associated with a longer overall survival compared with docetaxel in advanced non-squamous NSCLC that had progressed during or after platinum-based chemotherapy.
60. S.J.Antonia, J.R.Brahmer, S.N.Gettinger, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(5 suppl; abstr 8113).
61. S.J.Antonia, S.N.Gettinger, L.Q.Man Chow, 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(5 suppl; abstr 8023).
62. E.B.Garon, N.A.Rizvi, R.Hui, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–2028.
63. R.S.Herbst, P.Baas, D.W.Kim, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet. 2016;387(10027):1540–1550.•• Pembrolizumab had prolonged overall survival and had a more favorable safety profile compared to docetaxel in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.
64. M.J.Butte, M.E.Keir, T.B.Phamduy, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111–122.
65. J.R.Brahmer, S.S.Tykodi, L.Q.Chow, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465.
66. J.R.Brahmer, N.A.Rizvi, J.Lutzky, et al. Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. J Clin Oncol. 2014;32(suppl; abstr 8021).
67. N.A.Rizvi, J.B.Brahmer, S.H.I.Ou, et al. Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr 8032).
68. D.R.Spigel, S.N.Gettinger, L.Horn, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;31(suppl; abstr 8008).
69. R.S.Herbst, J.-C.Soria, M.Kowanetz, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–567.
70. R.Camidge, S.V.Liu, J.Powderly, et al. Atezolizumab (MPDL3280A) combined with platinum-based chemotherapy in non–small cell lung cancer (NSCLC): a phase Ib safety and efficacy update. J Thor Oncol. 2015;10(9, supplement 2; abstract 02.07):S176–177.
71. A.I.Spira, K.Park, J.Mazières, et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;33(suppl; abstr 8010).
72. K.Kelly, M.R.Patel, J.R.Infante, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic or locally advanced solid tumors: assessment of safety and tolerability in a phase I, open-label expansion study. J Clin Oncol. 2015;33(suppl; abstr 3044).
73. J.L.Gulley, D.Spigel, K.Kelly, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: a phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J Clin Oncol. 2015;33(suppl; abstr 8034).
74. M.Santarpia, N.Karachaliou. Tumor immune microenvironment characterization and response to anti-PD-1 therapy. Cancer Biol Med. 2015;12(2):74–78.
75. J.M.Taube, A.Klein, J.R.Brahmer, 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;20:5064–5074.• Assessment of the predictive value of PD-L1 expression and multiple immune biomarkers of tumor microenvironment in pretreatment samples from patients with advanced solid tumors treated with nivolumab.
76. B.H.Moreno, A.Ribas. Anti-programmed cell death protein-1/ligand-1 therapy in different cancers. Br J Cancer. 2015;112(9):1421–1427.
77. A.T.Parsa, J.S.Waldron, A.Panner, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–88.
78. M.Marzec, Q.Zhang, A.Goradia, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008;105:20852–20857.
79. M.Atefi, E.Avramis, A.Lassen, et al. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res. 2014;20:3446–3457.
80. E.A.Akbay, S.Koyama, J.Carretero, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355–1363.
81. O.Hamid, H.Schmidt, A.Nissan, 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.
82. Z.-Y.Dong, S.-P.Wu, R.-Q.Liao, et al. Potential biomarker for checkpoint blockade immunotherapy and treatment strategy. Tumour Biol. 2016 Jan 16;37:4251–4261.
83. J.F.Gainor, L.V.Sequist, A.T.Shaw, et al. Clinical correlation and frequency of programmed death ligand-1 (PD-L1) expression in EGFR-mutant and ALK-rearranged non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr 8012).
84. P.C.Tumeh, C.L.Harview, J.H.Yearley, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–571.
85. N.A.Rizvi, M.D.Hellmann, A.Snyder, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–128.•• This study showed that a higher mutational burden, as assessed by whole-exome sequencing in NSCLC samples from patients treated with pembrolizumab, was strongly associated with better response to treatment. Efficacy was also correlated with a molecular smoking marker, specific DNA repair pathway mutations, and a higher burden of candidate neoantigens, which can trigger specific immune responses.
86. A.Snyder, V.Makarov, T.Merghoub, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–2199.
87. G.Y.Ku, J.Yuan, D.B.Page, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116(7):1767–1775.
88. T.Jiang, C.Zhou. The past, present and future of immunotherapy against tumor. Transl Lung Cancer Res. 2015;4(3):253–264.
89. C.I.Liakou, A.Kamat, D.N.Tang, et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008;105(39):14987–14992.
90. B.C.Carthon, J.D.Wolchok, J.Yuan, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16:2861–2871.
91. E.B.Golden, S.Demaria, P.B.Schiff, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1(6):365–372.
92. Y.Lou, L.Diao, L.A.Byers, et al. Association of epithelial-mesenchymal transition status with PD1/PDL1 expression and a distinct immunophenotype in non-small cell lung cancer: implications for immunotherapy biomarkers. J Clin Oncol. 2014;32(suppl; abstr 3018).
93. M.Santarpia, M.González-Cao, S.Viteri, et al. Programmed cell death protein-1/programmed cell death ligand-1pathway inhibition and predictive biomarkers: understanding transforming growth factor-beta role. Transl Lung Cancer Res. 2015;4(6):728–742.
94. M.Hasmim, M.Z.Noman, Y.Messai, et al. Cutting edge: hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-β1. J Immunol. 2013;191:5802–5806.
95. M.Freeman-Keller, J.Goldman, J.Gray. Vaccine immunotherapy in lung cancer: clinical experience and future directions. Pharmacol Ther. 2015;153:1–9.
96. J.Samuel, W.A.Budzynski, M.A.Reddish, et al. Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine. Int J Cancer. 1998;75(2):295–302.
97. S.B.Ho, G.A.Niehans, C.Lyftogt, et al. Heterogeneity of mucin gene expression in normal and neoplastic tissues. Cancer Res. 1993;53:641–651.
98. C.Butts, N.Murray, A.Maksymiuk, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol. 2005;23(27):6674–6681.
99. C.Butts, A.Maksymiuk, G.Goss, et al. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial. J Cancer Res Clin Oncol. 2011;137(9):1337–1342.
100. C.Butts, M.A.Socinski, P.L.Mitchell, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomized, double-blind, phase 3 trial. Lancet Oncol. 2014;15(1):59–68.• This phase III trial study assessing BLP25 administered after chemoradiotherapy in patients with unresectable stage III NSCLC did not show any survival benefit compared with placebo. In the subgroup analysis, a survival improvement in the BPL25 group was observed in those patients who had received previous concurrent instead of sequential chemoradiotherapy.
101. C.Rochlitz, R.Figlin, P.Squiban, et al. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer. J Gene Med. 2003;5(8):690–699.
102. R.Ramlau, E.Quoix, J.Rolski, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV non-small cell lung cancer. J Thorac Oncol. 2008;3(7):735–744.
103. E.Quoix, R.Ramlau, V.Westeel, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12(12):1125–1133.
104. G.González, T.Crombet, M.Catalá, et al. A novel cancer vaccine composed of human recombinant epidermal growth factor linked to a carrier protein: report of a pilot clinical trial. Ann Oncol. 1998;9(4):431–435.
105. G.Gonzalez, T.Crombet, F.Torres, et al. Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy. Ann Oncol. 2003;14(3):461–466.
106. P.C.Rodríguez, G.Rodríguez, G.González, et al. Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy. MEDICC Rev. 2010;12(1):17–23.
107. E.Neninger Vinageras, A.de la Torre, M.O.Rodríguez, et al. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. J Clin Oncol. 2008;26(9):1452–1458.
108. S.J.Jang, J.C.Soria, L.Wang, et al. Activation of melanoma antigen tumor antigens occurs early in lung carcinogenesis. Cancer Res. 2011;61(21):7959–7963.
109. J.Vansteenkiste, M.Zielinski, A.Linder, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol. 2013;31(19):2396–2403.
110. F.Ulloa-Montoya, J.Louahed, B.Dizier, et al. Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol. 2013;31(19):2388–2395.
111. J.F.Vansteenkiste, B.Cho, T.Vanakesa, et al. MAGRIT, a double-blind, randomized, placebocontrolled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC). Ann Oncol. 2014;25(suppl 4):iv409.
112. S.Alfonso, R.M.Diaz, A.de la Torre, et al. 1E10 anti-idiotype vaccine in non-small cell lung cancer: experience in stage IIIb/IV patients. Cancer Biol Ther. 2007;6(12):1847–1852.
113. C.Rolfo, G.Sortino, E.Smits, et al. Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer? Expert Rev Anticancer Ther. 2014;14(10):1173–1187.
114. S.Alfonso, A.Valdés-Zayas, E.R.Santiesteban, et al. A randomized, multicenter, placebo controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res. 2014;20(14):3660–3671.
115. S.Gnjatic, H.Nishikawa, A.A.Jungbluth, et al. NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res. 2006;95:1–30.
116. K.Kakimi, M.Isobe, A.Uenaka, et al. A phase I study of vaccination with NY-ESO-1f peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen. Int J Cancer. 2011;129(12):2836–2846.
117. J.Nemunaitis, R.O.Dillman, P.O.Schwarzenberger, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol. 2006;24(29):4721–4730.
118. J.Nemunaitis, M.Nemunaitis, N.Senzer, et al. Phase II trial of belagenpumatucel-L, a TGF beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther. 2009;16(8):620–624.
119. G.Giaccone, L.A.Bazhenova, J.Nemunaitis, et al. A phase III study of belagenpumatucel-L, an allogeneic tumor cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer. 2015;51(16):2321–2329.• In this phase III study, belagenpumatucel-L given as maintenance therapy in stage III/IV NSCLC patients was not shown to improve survival compared to placebo. However, a survival benefit with the vaccine was observed in those patients who were randomized within 12 weeks of completion of chemotherapy as well as those who had received prior radiation.
120. S.N.Seyedin, J.E.Schoenhals, D.A.Lee, et al. Strategies for combining immunotherapy with radiation for anticancer therapy. Immunotherapy. 2015;7(9):967–980.
121. S.C.Formenti, S.Demaria. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256–265.
122. M.A.Postow, M.K.Callahan, C.A.Barker, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–931.
123. C.Twyman-Saint Victor, A.J.Rech, A.Maity, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–377.