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. 2013 Nov 6;10(2):352–357. doi: 10.4161/hv.26919

Recent advances in immunotherapy for non-small-cell lung cancer

Hiroyuki Suzuki 1,*, Yuki Owada 1, Yuzuru Watanabe 1, Takuya Inoue 1, Mitsuro Fukuharav 1, Takumi Yamaura 1, Satoshi Mutoh 1, Naoyuki Okabe 1, Hiroshi Yaginuma 1, Takeo Hasegawa 1, Atsushi Yonechi 1, Jun Ohsugi 1, Mika Hoshino 1, Mitsunori Higuchi 1, Yutaka Shio 1, Mitsukazu Gotoh 1
PMCID: PMC4185902  PMID: 24196313

Abstract

Despite of recent development in the field of molecular targeted therapies, lung cancer is a leading cause of cancer death in the world. Remarkable progress has been made recently in immunotherapy for patients with non-small-cell lung cancer (NSCLC), with several modalities, concepts, and treatment settings being investigated. In vaccine development, large-scale clinical trials such as those with L-BLP25, belagenpumatucel-L, TG4010, and talactoferrin are already ongoing and some results have been reported. A trial of a vaccine as adjuvant therapy for patients with completely resected NSCLC is also ongoing with one of the major cancer-testis antigens, melanoma-associated antigen (MAGE)-A3. More recently, the effectiveness of multiple peptide vaccines has also been shown. Recently developed unique treatment modalities are the immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, which also show promise. However, although therapeutic cancer vaccines are generally thought to be safe, severe adverse events should be monitored carefully when using immune checkpoint inhibitors. Here, we discuss recent advances and future perspectives of immunotherapy for patients with NSCLC.

Keywords: non-small-cell lung cancer, therapeutic cancer vaccine, immune checkpoint inhibitor, clinical trial, adjuvant treatment, multiple vaccine

Introduction

Lung cancer is the most frequent cause of cancer-related death in the world.1 Approximately 85% of lung cancer cases are non-small-cell lung cancer (NSCLC), and the outcome is poor.2 About 70% of patients with NSCLC present with advanced or metastatic conditions at the time of diagnosis, by which time the disease is unresectable and incurable. Of the patients diagnosed with resectable NSCLC, 30–40% of cases eventually develop recurrent disease.3 Recently, several types of molecular-targeted drugs such as epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)4,5 or anaplastic lymphoma kinase-echinoderm microtubule-associated protein-like 4 (ALK-EML4) fusion gene inhibitor6 have been developed for the treatment of NSCLC. However, the disease eventually acquires resistance to these drugs.7 Molecular-targeted drugs also have serious adverse effects such as severe skin damage8 or lethal interstitial pneumonia.9 Therefore, there is still a need for safer and more effective treatments for NSCLC.

Recently, significant improvements have been made in vaccine therapy for NSCLC. Several promising cancer vaccines are being developed and global phase III trials are ongoing. Furthermore, antibody-based drugs are being developed, which target the immune checkpoint pathways.10 In this report, we summarize and review these recent improvements in vaccines and immunotherapy for patients with NSCLC.

Therapeutic Cancer Vaccines for Patients with NSCLC

Most of the therapeutic cancer vaccines targeting NSCLC are being developed for patients with advanced disease; however, they have also been trialed as adjuvant therapy in resected NSCLC in a small number of clinical studies. Here, we discuss the use of vaccines both against advanced disease and as an adjuvant therapy. Major trials are listed in Table 1.

Table 1. Major vaccine trials for patients with NSCLC.

Vaccines Overview of Trials Status of trial No. of Pts /Estimated enrolment Target stage
/eligibility		 Result
L-BLP25 Randomized phase IIb Terminate 171 Stage IIIB/IV OS: 17.4 vs. 13 Mo. P = 0.112
  Double blind randomized phase III Ongoing 1513 Stage III OS: 25.6 vs. 22.3 Mo.
P = 0.123
Belagenpumatucel-L Randomized phase II Terminate 75 Stage II-IV Better OS in vaccine group, P = 0.0069
  Randomized phase III Ongoing 506 Stage III-IV
2nd line or later treatment		 NA
TG4010 Randomized phase II Terminate 65 Stage IIIB/IV
Combined with platinum containing chemotherapy		 ORR: 29.5%
TTP: 4.8 Mo.
OS: 12.7 Mo.
  Randomized phase IIb
Open-label		 Terminate 148 Stage IIIB/IV
Combined with CDDP/Gemcitabine		 6-Mo. PFS
43.2% vs. 35.1%
  Double-blind
randomized phase III		 Ongoing 1000 Stage IV, MUC-1 positive NA
Telactoferrin Double blind randomized phase II Terminate 110 Stage IIIB/IV, combined with carboplatin/paclitaxel ORR: 44% vs. 29%
P = 0.05
OS: 10.4 vs. 8.5 Mo.
P = 0.11
  Double blind randomized phase III Terminate 742 Stage IIIB/IV, 3rd line or later treatment OS: 7.49 vs. 7.66 Mo.
P = 0.6602
MAGE-A3 Double blind random phase II Terminate 182 Adjuvant,
Resected Stage IB, II		 DFI: 0.75
P = 0.254
  Double blind random phase III Ongoing 2270 Adjuvant,
Resected Stage IB, II, IIIA		 NA
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Abbreviations: OS, overall survival; Mo., months; NA, not available; ORR, objective response rate; TTP, time to progression; DFI, disease-free interval.

Advanced and/or Recurrent NSCLC

L-BLP25

L-BLP25 is a liposome-based therapeutic cancer vaccine that targets the MUC1 antigen and consists of 25 amino acid lipopeptides derived from the tandem repeat region of MUC1.11 MUC1 is a glycoprotein expressed in both normal glands and cancer cells, but its structure differs between normal and cancer cells owing to changes in glycosylation during tumor progression.12 Human T cells are activated upon recognition of MUC1 by these differences in glycosylation.12

A randomized phase IIb trial targeting stage IIIB and IV NSCLC was conducted by Butts et al.13 The trial was designed as maintenance therapy for patients who did not progress after first-line chemotherapy. Patients were randomly assigned to a vaccination plus best supportive care group (n = 88) or a best supportive care-only group (n = 83). The primary endpoint was overall survival (OS) after randomization. Patients in the intervention group received a single dose of cyclophosphamide intravenously (300 mg/m2) before vaccination. OS was longer in the vaccination group than the control group (17.4 mo vs. 13 mo, adjusted hazard ratio [HR]: 0.739, 95% confidence interval [CI]: 0.509–1.073, P = 0.112), but statistical significance was not reached. Updated data have shown that while OS of patients in the vaccination group is still not significantly better than that in the control group (17.2 mo vs. 13 mo), 3-y survival rates are significantly higher (31% vs. 17%, P = 0.035). Furthermore, a subset of patients with locally advanced NSCLC showed a significantly better survival rate after vaccination than those in the control group (30.6 mo vs. 13.3 mo).14

Based on the data of the phase II study, two large-scale, double-blind, randomized, phase III studies were planned. The START trial, which assessed chemoradiotherapy-treated unresectable stage III NSCLC, was terminated and reported recently,15 and did not meet the primary endpoint. OS in the L-BLP25 group was 25.6 mo, compared with 22.3 mo in the placebo group (HR: 0.88, 95% CI: 0.75–1.03, P = 0.123). However, in the subgroup analysis, the survival of patients in the vaccination group was significantly better than that of those in the placebo group in patients receiving concurrent chemoradiotherapy. In the sequential chemoradiotherapy group, OS was not significantly different (19.4 mo in the vaccination group vs. 24.6 mo in the placebo group). The reason for this result was unclear, but concurrent chemoradiotherapy may have induced a strong, nonspecific immune activation or antigen presentation. The INSPIRE trial is similar to the START trial but enrolls patients of East-Asian ethnicity only,16 the rationale being that several recent studies have shown that East-Asian ethnicity may be a favorable prognostic factor.17,18

Belagenpumatucel-L

Belagenpumatucel-L is an allogeneic tumor cell vaccine containing four NSCLC cell lines (H460, H520, SKLU-1, and RH2) and an antisense plasmid of transforming growth factor β (TGF-β) to decrease the expression of TGF-β in the vaccine.19 TGF-β is a negative regulator of cytotoxic T-lymphocyte (CTL) activation and induces FoxP3,20 and could suppress the effective tumor immune response. Therefore, this vaccine aims to increase the local immune response and then activate the systemic immune response to NSCLC by downregulating TGF-β expression.

A randomized phase II trial in patients with stage II–IV NSCLC was conducted by Nemunaitis et al.19 Seventy-five subjects were enrolled in this uniquely designed trial in which patients with a tumor volume of ≤125 mL were eligible and patients who had nodal and bone metastasis were excluded. Three dose cohorts were planned (1.25 × 107, 2.5 × 107, or 5.0 × 107 cells) and the drug showed a good safety profile at all three doses. OS of the two higher dose groups was significantly better than that of the low-dose patients (P = 0.0069). A double-blind, randomized, phase III study is currently ongoing (STOP trial; NCT00676507) and aims to enroll over 500 patients with advanced NSCLC, treated with at least one regimen of platinum doublet chemotherapy and responding to their treatment (stable disease, partial response, or complete response). The primary endpoint of this trial is OS.

TG4010

TG4010 is a cancer vaccine developed using attenuated vaccinia Ankara virus, genetically modified to express both full-length MUC1 and interleukin-2. The vaccine may activate T-cell responses through all types of antigenic epitopes of MUC1.21

In a multicenter, randomized, phase II study of TG4010 in patients with advanced NSCLC, platinum-based chemotherapy (cisplatin/vinorelbine) was administered in combination with TG4010.22 Two types of combination therapy were planned: arm 1, simple TG4010-chemotherapy combination; and arm 2, a sequential protocol in which TG4010 was first administered as monotherapy until partial response then combined with chemotherapy. Forty-four patients were assigned to the simple combination arm and 21 patients to the sequential arm. Objective response rate (ORR) was 29.5% and time to progression was 4.8 mo in arm 1. The median OS was 12.7 mo. Further study was conducted and reported in 2011.23 One hundred and 48 patients with stage IIIB and stage IV NSCLC and expressing MUC1 in their tumor as revealed by immunohistochemistry were enrolled in this open-label randomized trial. Patients were randomly assigned equally to two arms (TG4010 plus cisplatin/gemcitabine vs. cisplatin/gemcitabine alone; 74 patients per group). In the TG4010 arm, 43.2% of patients had 6 mo progression-free survival (PFS) compared with 35.1% in the control arm (P = 0.307); ORR was 41.9% in the TG4010 arm, and 28.4% in the control group (P = 0.082). In this study, the frequency of CD16+CD56+CD69+ cells, which is the phenotype of activated natural killer (NK) cells, in peripheral blood mononuclear cells was analyzed as a biomarker to predict the response to TG4010. A double-blind, randomized, phase IIb/III trial in patients with stage IV NSCLC is currently ongoing in combination with platinum-based chemotherapy (NCT01383148).

Talactoferrin

Talactoferrin is a recombinant human lactoferrin and is isolated from Aspergillus niger var awamori. It is an orally active glycoprotein and can suppress tumor growth through the recruitment of dendritic cells into intestinal lymphoid tissue, activating immune effector cells such as NK and CD8 T cells.24

In a placebo-controlled, randomized trial in 110 patients with stage IIIB/IV NSCLC, ORR was significantly better in the talactoferrin-carboplatin/paclitaxel group than in the placebo-carboplatin/paclitaxel group (44% and 29%, respectively; P = 0.05). The difference in OS was also promising, although not statistically significant (10.4 mo in the talactoferrin group and 8.5 mo in the placebo group; P = 0.11).25

Based on the promising data from the phase II study, large-scale, randomized, phase III trials were planned. The result of one such study was recently reported; the FORTIS-M trial was an international, multicenter, randomized, double-blind comparison study designed with the aim of understanding the survival efficacy of orally administered talactoferrin. An amount of 742 patients with NSCLC who failed two or more chemotherapeutic regimens was enrolled in this study and randomly assigned 2:1 to the talactoferrin or placebo arms. However, the trial failed to show improved survival after talactoferrin. The median OS in the talactoferrin group was 7.66 mo, compared with 7.49 mo in the placebo group (HR: 1.04, 95% CI: 0.873–1.24, P = 0.6602). Six- and 12-mo survival rates were also not significantly different between the talactoferrin and placebo groups (6-mo survival rate: 59.9% vs. 55.7%, respectively; 12-mo survival rate: 32.2% vs. 30.9%, respectively).26 The FORTIS-C trial (NCT00706862), a randomized, double-blind study of talactoferrin combined with first-line chemotherapy, is currently ongoing.

Multiple peptide vaccine

Multiple peptide vaccines are being developed for several types of solid tumor. Itoh et al. have developed a personalized peptide vaccination,27 in which a maximum of four human leukocyte A-matched peptides are selected based on the pre-existing host immunity before vaccination. A multiple peptide vaccine trial for patients with renal cell cancer using 11 kinds of peptides has also been reported.28 In this trial, the authors investigated whether survival rates were higher in patients who had immune responses to at least three of the peptides than in other patients.

More recently, we reported the effectiveness of a multiple peptide vaccine trialed in 15 patients with advanced or recurrent NSCLC.29 In this phase I study, we administered five kinds of peptides that originated from novel cancer-testis antigens and were developed from vascular endothelial growth factor receptors using a microarray-based technique. If the patients responded against multiple peptides, survival rate was significantly better than that in patients who responded to a single peptide or no peptides (P = 0.00176). A multiple peptide vaccine is therefore a promising modality. A randomized and multicenter phase II study of multiple peptides for patients with advanced NSCLC is now ongoing (NCT01592617).

Vaccines as Adjuvant Therapy for NSCLC

Melanoma-associated antigen (MAGE)-A3

Cancer-testis antigens are well-analyzed tumor-associated antigens in several types of cancer tissues.30 The expression of these antigens in healthy tissue is restricted to the testis, and they are thought to be promising candidates for an effective cancer vaccine. The MAGE gene family is one of the earliest discovered cancer testis antigen families and MAGE-A3 is expressed in about 35–40% of NSCLC.31,32 Recombinant MAGE-A3 protein is developed as a vaccine to prevent recurrence after surgery in MAGE-A3-positive NSCLC.

In a phase II, randomized study, patients with completely resected and MAGE-A3-positive stage IB and II NSCLC were randomly assigned 2:1 to postoperative MAGE-A3 vaccination or placebo. Vaccinations were performed by immunizing five times across 15 weeks after surgery, followed by eight 3-moly booster vaccinations. One hundred and 82 patients were enrolled in this study. The disease-free interval was longer in the vaccination group than in the placebo group but the difference was not significant (HR: 0.75, 95% CI: 0.46–1.23, P = 0.254).33 Based on this result of the phase II study, a large-scale phase III trial, similar in design to the previous phase II trial, has started in patients with completely resected stage IB–IIIA NSCLC (MAGRIT study; NCT00480025).

Immune checkpoint inhibitor

One of the recent surprises in the field of cancer immunotherapy is the development of the immune checkpoint inhibitor. It is well known that the immune system has several inhibitory mechanisms, known as immune checkpoints, including regulatory T cells, CTL antigen 4 (CTLA-4)/CD80 or CD86,34-36 and the programmed cell death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) pathway.36 Under healthy conditions, these pathways act to maintain the immune balance; however, under conditions in which a tumor forms, these inhibitory mechanisms are thought to be superior to immune-activating mechanisms.37 This is the rationale of immune checkpoint modification in cancer therapy.

Ipilimumab, the blocking antibody for CTLA-4, has already been approved for the therapy of melanoma. In patients with NSCLC, a randomized phase II trial in which ipilimumab was combined with chemotherapy, specifically immune-related response criteria (ir-RC) (which differed from the Response Evaluation Criteria in Solid Tumors (RECIST) or WHO response criteria) were used38,39 to evaluate the efficacy of the treatment. Patients were treated with a combination of concurrent chemotherapy (concurrent group) or chemotherapy followed by ipilimumab (phased group). In the phased group, ipilimumab significantly improved the ir-PFS (HR: 0.72, P = 0.05). Interestingly, this benefit occurred mainly in squamous cell carcinoma (HR: 0.55, 95% CI: 0.27–1.12).40 A further clinical trial in squamous cell carcinoma is planned (NCT01285609).

The PD-1 and PD-L1 pathways are also a promising target in cancer therapy. Early phase clinical trials of humanized monoclonal antibodies have been conducted in patients with lung cancer who all had several prior treatments. In trials of PD-1 and PD-L1, objective clinical responses were found using monotherapy of antibodies against these molecules. Notably, a 33% response rate was observed in advanced squamous cell lung cancer.41 Currently, treatment for squamous cell cancer is limited, therefore this would have great impact for these patients42 (Table 2).

Table 2. Clinical trials of immune checkpoint inhibitors for patients with NSCLC.

Target Antibody Overview of trials Status of trial No. of Pts/Estimated enrolment Target stage
/eligibility		 Result
CTLA-4 Ipilimumab Randomized phase II Terminate 138 Advanced disease,
Concurrent or phased with Carboplatin/Paclitaxel		 Concurrent group
HR of ir-PFS: 0.81, P = 0.13
Phased group
HR of ir-PFS: 0.72, P = 0.05
PD-1 BMS-936558 Phase I Terminate 122 Advanced disease RR at 1, 3 and 10 mg/Kg:
6, 32 and 18%
PD-L1 BMS-936559 Phase I Terminate 75 Advanced solid cancer included 75 patients with NSCLC ORR: 10%
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HR, hazard ratio; ir-PFS, immune-related progression-free survival; ORR, objective response rate.

Antibodies against PD-1 and PDL-1 are a promising treatment; however, adverse events may be severe. Grade 3–4 liver dysfunction or pneumonitis were observed and two patients died from pneumonitis after taking the PD-1 antibody.10 With PD-L1, severe pneumonitis has not been observed to date,10 but we should be aware of adverse immunogenic events, and careful management is needed as for PD-1.

Future Perspectives

In this report, we have discussed the recent advances made in immunotherapy for patients with NSCLC through major clinical trials, and anticipate more effective immunotherapy in the future.

First, we should try to apply immunotherapy in earlier stages of the disease, for example combining immunotherapy with a first-line treatment or as an adjuvant treatment after surgery. Several recent studies including our own have shown that good PS is a significant prognostic factor.29,43,44 Regarding multiple peptide therapy, as we mentioned previously, recent data showed the effectiveness of vaccines containing multiple epitopes. More recently, dendritic cell immunotherapy using multiple epitopes has also been reported in the treatment of brain tumors.45 Finally, we should consider how we apply immune checkpoint inhibitors in the field of lung cancer. Combination with chemotherapy, molecular-targeted therapy, and other vaccine therapies could be promising choices.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Glossary

Abbreviations:

95% CI

95% confidence interval

CTL

cytotoxic T lymphocyte

HR

hazard ratio

NSCLC

non-small cell lung cancer

NK cell

natural killer cell

OS

overall survival

PFS

progression-free survival

10.4161/hv.26919

References

  • 1.Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. [DOI] [PubMed] [Google Scholar]
  • 2.Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L, International Association for the Study of Lung Cancer International Staging Committee. Participating Institutions The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706–14. doi: 10.1097/JTO.0b013e31812f3c1a. [DOI] [PubMed] [Google Scholar]
  • 3.Sawabata N, Miyaoka E, Asamura H, Nakanishi Y, Eguchi K, Mori M, Nomori H, Fujii Y, Okumura M, Yokoi K, Japanese Joint Committee for Lung Cancer Registration Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol. 2011;6:1229–35. doi: 10.1097/JTO.0b013e318219aae2. [DOI] [PubMed] [Google Scholar]
  • 4.Petrelli F, Borgonovo K, Cabiddu M, Barni S. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer. 2012;13:107–14. doi: 10.1016/j.cllc.2011.08.005. [DOI] [PubMed] [Google Scholar]
  • 5.Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–74. doi: 10.1056/NEJMra0707704. [DOI] [PubMed] [Google Scholar]
  • 6.Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci. 2008;99:2349–55. doi: 10.1111/j.1349-7006.2008.00972.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res. 2011;17:5530–7. doi: 10.1158/1078-0432.CCR-10-2571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Melosky B. Supportive care treatments for toxicities of anti-egfr and other targeted agents. Curr Oncol. 2012;19(Suppl 1):S59–63. doi: 10.3747/co.19.1054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Barber NA, Ganti AK. Pulmonary toxicities from targeted therapies: a review. Target Oncol. 2011;6:235–43. doi: 10.1007/s11523-011-0199-0. [DOI] [PubMed] [Google Scholar]
  • 10.Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013;31:1021–8. doi: 10.1200/JCO.2012.45.8703. [DOI] [PubMed] [Google Scholar]
  • 11.Sangha R, Butts C. L-BLP25: a peptide vaccine strategy in non small cell lung cancer. Clin Cancer Res. 2007;13:s4652–4. doi: 10.1158/1078-0432.CCR-07-0213. [DOI] [PubMed] [Google Scholar]
  • 12.Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ. MUC1 immunobiology: from discovery to clinical applications. Adv Immunol. 2004;82:249–93. doi: 10.1016/S0065-2776(04)82006-6. [DOI] [PubMed] [Google Scholar]
  • 13.Butts C, Murray N, Maksymiuk A, Goss G, Marshall E, Soulières D, Cormier Y, Ellis P, Price A, Sawhney R, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol. 2005;23:6674–81. doi: 10.1200/JCO.2005.13.011. [DOI] [PubMed] [Google Scholar]
  • 14.Butts C, Maksymiuk A, Goss G, Soulières D, Marshall E, Cormier Y, Ellis PM, Price A, Sawhney R, Beier F, 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;137:1337–42. doi: 10.1007/s00432-011-1003-3. [DOI] [PubMed] [Google Scholar]
  • 15.Charles Andrew Butts MAS. Paul Mitchell, Nick Thatcher, Libor Havel, Maciej Jerzy Krzakowski, Sergiusz Nawrocki, Tudor-Eliade Ciuleanu, Lionel Bosquée, Jose Manuel Trigo Perez, Alexander I. Spira, Lise Tremblay, Jan Nyman, Rodryg Ramlau, Christoph Helwig, Martin H. Falk and Frances A. Shepherd. START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2013;31:7500. [Google Scholar]
  • 16.Wu YL, Park K, Soo RA, Sun Y, Tyroller K, Wages D, Ely G, Yang JC, Mok T. INSPIRE: A phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer. 2011;11:430. doi: 10.1186/1471-2407-11-430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Soo RA, Loh M, Mok TS, Ou SH, Cho BC, Yeo WL, Tenen DG, Soong R. Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials. J Thorac Oncol. 2011;6:1030–8. doi: 10.1097/JTO.0b013e3182199c03. [DOI] [PubMed] [Google Scholar]
  • 18.Kawaguchi T, Matsumura A, Fukai S, Tamura A, Saito R, Zell JA, Maruyama Y, Ziogas A, Kawahara M, Ignatius Ou SH. Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases. J Thorac Oncol. 2010;5:1001–10. doi: 10.1097/JTO.0b013e3181e2f607. [DOI] [PubMed] [Google Scholar]
  • 19.Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J, Tong A, Kumar P, Pappen B, Hamilton C, 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;24:4721–30. doi: 10.1200/JCO.2005.05.5335. [DOI] [PubMed] [Google Scholar]
  • 20.Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10:415–24. doi: 10.1038/nrc2853. [DOI] [PubMed] [Google Scholar]
  • 21.Limacher JM, Quoix E. TG4010: A therapeutic vaccine against MUC1 expressing tumors. Oncoimmunology. 2012;1:791–2. doi: 10.4161/onci.19863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Ramlau R, Quoix E, Rolski J, Pless M, Lena H, Lévy E, Krzakowski M, Hess D, Tartour E, Chenard MP, 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;3:735–44. doi: 10.1097/JTO.0b013e31817c6b4f. [DOI] [PubMed] [Google Scholar]
  • 23.Quoix E, Ramlau R, Westeel V, Papai Z, Madroszyk A, Riviere A, Koralewski P, Breton J-L, Stoelben E, Braun D, 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;12:1125–33. doi: 10.1016/S1470-2045(11)70259-5. [DOI] [PubMed] [Google Scholar]
  • 24.Varadhachary A, Wolf JS, Petrak K, O’Malley BW, Jr., Spadaro M, Curcio C, Forni G, Pericle F. Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy. Int J Cancer. 2004;111:398–403. doi: 10.1002/ijc.20271. [DOI] [PubMed] [Google Scholar]
  • 25.Digumarti R, Wang Y, Raman G, Doval DC, Advani SH, Julka PK, Parikh PM, Patil S, Nag S, Madhavan J, et al. A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer. J Thorac Oncol. 2011;6:1098–103. doi: 10.1097/JTO.0b013e3182156250. [DOI] [PubMed] [Google Scholar]
  • 26.Ramalingam S, Crawford J, Chang A, Manegold C, Perez-Soler R, Douillard JY, Thatcher N, Barlesi F, Owonikoko T, Wang Y, et al. FORTIS-M Study Investigators Talactoferrin alfa versus placebo in patients with refractory advanced non-small-cell lung cancer (FORTIS-M trial) Ann Oncol. 2013;24:2875–80. doi: 10.1093/annonc/mdt371. [DOI] [PubMed] [Google Scholar]
  • 27.Noguchi M, Sasada T, Itoh K. Personalized peptide vaccination: a new approach for advanced cancer as therapeutic cancer vaccine. Cancer Immunol Immunother. 2013;62:919–29. doi: 10.1007/s00262-012-1379-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012;18:1254–61. doi: 10.1038/nm.2883. [DOI] [PubMed] [Google Scholar]
  • 29.Suzuki H, Fukuhara M, Yamaura T, Mutoh S, Okabe N, Yaginuma H, Hasegawa T, Yonechi A, Osugi J, Hoshino M, et al. Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer. J Transl Med. 2013;11:97. doi: 10.1186/1479-5876-11-97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Caballero OL, Chen YT. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci. 2009;100:2014–21. doi: 10.1111/j.1349-7006.2009.01303.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Sienel W, Varwerk C, Linder A, Kaiser D, Teschner M, Delire M, Stamatis G, Passlick B. Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study. Eur J Cardiothorac Surg. 2004;25:131–4. doi: 10.1016/j.ejcts.2003.09.015. [DOI] [PubMed] [Google Scholar]
  • 32.Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA, Gnjatic S, Ritter G, Simpson AJ, Chen YT, Old LJ, et al. Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin Cancer Res. 2005;11:8055–62. doi: 10.1158/1078-0432.CCR-05-1203. [DOI] [PubMed] [Google Scholar]
  • 33.Vansteenkiste J, Zielinski M, Linder A, Dahabreh J, Gonzalez EE, Malinowski W, Lopez-Brea M, Vanakesa T, Jassem J, Kalofonos H, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol. 2013;31:2396–403. doi: 10.1200/JCO.2012.43.7103. [DOI] [PubMed] [Google Scholar]
  • 34.Chen L, Ashe S, Brady WA, Hellström I, Hellström KE, Ledbetter JA, McGowan P, Linsley PS. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992;71:1093–102. doi: 10.1016/S0092-8674(05)80059-5. [DOI] [PubMed] [Google Scholar]
  • 35.Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. 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. doi: 10.1016/1074-7613(95)90125-6. [DOI] [PubMed] [Google Scholar]
  • 36.Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients. Clin Cancer Res. 2013;19:5300–9. doi: 10.1158/1078-0432.CCR-13-0143. [DOI] [PubMed] [Google Scholar]
  • 37.Wei S, Shreiner AB, Takeshita N, Chen L, Zou W, Chang AE. Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor beta. Cancer Res. 2008;68:5432–8. doi: 10.1158/0008-5472.CAN-07-6598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20. doi: 10.1158/1078-0432.CCR-09-1624. [DOI] [PubMed] [Google Scholar]
  • 39.Genova C, Rijavec E, Barletta G, Sini C, Dal Bello MG, Truini M, Murolo C, Pronzato P, Grossi F. Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer. Expert Opin Biol Ther. 2012;12:939–48. doi: 10.1517/14712598.2012.681371. [DOI] [PubMed] [Google Scholar]
  • 40.Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, 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. doi: 10.1200/JCO.2011.38.4032. [DOI] [PubMed] [Google Scholar]
  • 41.Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. doi: 10.1056/NEJMoa1200690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Stinchcombe TE. Targeted Therapies for Locally Advanced or Metastatic Squamous Cell Carcinoma of the Lung. Curr Treat Options Oncol. 2013 doi: 10.1007/s11864-013-0256-2. Forthcoming. [DOI] [PubMed] [Google Scholar]
  • 43.Dillman RO, Fogel GB, Cornforth AN, Selvan SR, Schiltz PM, DePriest C. Features associated with survival in metastatic melanoma patients treated with patient-specific dendritic cell vaccines. Cancer Biother Radiopharm. 2011;26:407–15. doi: 10.1089/cbr.2011.0973. [DOI] [PubMed] [Google Scholar]
  • 44.Sawada Y, Yoshikawa T, Nobuoka D, Shirakawa H, Kuronuma T, Motomura Y, Mizuno S, Ishii H, Nakachi K, Konishi M, et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res. 2012;18:3686–96. doi: 10.1158/1078-0432.CCR-11-3044. [DOI] [PubMed] [Google Scholar]
  • 45.Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuño MA, Richardson JE, Fan X, Ji J, Chu RM, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2013;62:125–35. doi: 10.1007/s00262-012-1319-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

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