Nivolumab-related severe thrombocytopenia in a patient with relapsed lung adenocarcinoma: a case report and review of the literature.

BACKGROUND: Immune checkpoint inhibitor therapy has changed the standard drug therapy for relapsed or advanced non-small cell lung cancer; its efficacy is well-recognized by pulmonary physicians, oncologists, and thoracic surgeons. Nivolumab, one of the anti-programmed cell death 1 antibodies, was the first immune checkpoint inhibitor to be approved and is used as a standard second-line regimen for patients with non-small cell lung cancer irrespective of the expression of programmed cell death ligand 1. Programmed cell death 1 antibodies have been generally confirmed to be less toxic than conventional cytotoxic chemotherapy, although unusual immune-related adverse events such as type I diabetes mellitus, adrenal failure, and myasthenia gravis may occur with a very low incidence. A case of severe grade V immune-related thrombocytopenia after two courses of nivolumab as second-line therapy for relapsed non-small cell lung cancer is reported. CASE PRESENTATION: An 82-year-old Japanese woman with relapsed lung adenocarcinoma was treated with nivolumab as second-line systemic therapy at our institute. Her laboratory data indicated thrombocytopenia suspected to be an immune-related adverse event following two courses of nivolumab. Subsequently, she developed a massive pulmonary hemorrhage and left cerebral infarction despite intensive treatment including systemic steroid therapy. Although there have been a few reports of thrombocytopenia caused by nivolumab, this is the first report of grade V thrombocytopenia following administration of nivolumab for relapsed non-small cell lung cancer. CONCLUSION: A very difficult case of grade V immune-related thrombocytopenia after the administration of nivolumab as second-line therapy for relapsed lung adenocarcinoma was described. Immune-related thrombocytopenia is a rare adverse event, but it must be considered a possible complication because it may become critical once it has occurred.

Prognostic Impact of Tumor Mutation Burden in Patients With Completely Resected Non-Small Cell Lung Cancer: Brief Report.

INTRODUCTION: Tumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis. METHODS: We calculated TMB within individual tumors by whole-exome sequencing analysis using next-generation sequencing. We included that there were 90 patients with NSCLC who underwent surgery in the Hospital of Fukushima Medical University from 2013 to 2016. No patients received chemotherapy or immunotherapy before surgery. We assessed the correlation between TMB and prognosis. RESULTS: TMB greater than 62 was associated with worse overall survival (OS) of patients with NSCLC (hazard ratio [HR] = 6.633, p = 0.0003). Multivariate analysis showed poor prognosis with high TMB (HR = 12.31, p = 0.019). In patients with stage I NSCLC, higher TMB was associated with worse prognosis for both OS (HR = 7.582, p = 0.0018) and disease-free survival (HR = 6.07, p = 0.0072). CONCLUSIONS: High TMB in NSCLC is a poor prognostic factor. If high TMB is a predictor of the efficacy of immune checkpoint inhibitors, postoperative adjuvant therapy with immune checkpoint inhibitors may contribute to improvement of recurrence and OS.

Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor.

Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor (EGFR) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B (FAM83B) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR. Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR. Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR.

Comparison of surgical outcomes after pneumonectomy and pulmonary function-preserving surgery for non-small cell lung cancer.

BACKGROUND: According to previous reports, lobectomy with bronchoplasty or angioplasty is a more feasible surgery than pneumonectomy for central-type non-small cell lung cancer. However, few studies have compared both the short- and long-term outcomes between pneumonectomy and pulmonary function-preserving surgery. METHODS: From January 2004 to December 2015, 18 patients underwent pneumonectomy (Group PN) and 12 patients underwent pulmonary function-preserving surgery (group PS) at Fukushima Medical University Hospital. Clinicopathological factors were statistically compared between the two groups. RESULTS: The operation times in Group PN and Group PS were 285.9±27.9 and 271.3±99.2 min, respectively (p=0.613), while the amounts of intraoperative bleeding were 324.8±248.9 and 164.5±116.6 g, respectively (p=0.020). The duration of chest drainage and hospitalization after surgery in both groups were not significantly different but there was a tendency toward shorter periods of these durations in Group PS. The 5-year disease-free survival (DFS) rate in Group PN and PS was 51.4% and 74.1%, respectively, without a significant difference (p=0.298). The 5-year overall survival (OS) rate in Group PN and PS was 52.5% and 56.6%, respectively, also without a significant difference (p=0.748). The 5-year OS rate was inferior to the 5-year DFS rate in Group PS, and the 5-year OS rate was not better than the 5-year DFS rate in Group PN. CONCLUSIONS: The short-term results were better in Group PS than PN. However, the long-term results in both groups were similar. Other causes of death influenced OS in both groups; this result might have been affected by the surgical procedures.

A Case of Paraneoplastic Limbic Encephalitis in a Patient with Invasive Thymoma with Anti-Glutamate Receptor Antibody-Positive Cerebrospinal Fluid: A Case Report.

BACKGROUND: Thymoma is known to cause autoimmune neuromuscular disease. However, anti-glutamate receptor antibody limbic encephalitis (LE) with thymoma is relatively rare. CASE PRESENTATION: A 68-year-old woman was admitted with progressive memory impairment and personality change. Brain magnetic resonance imaging (MRI) revealed high intensity in the bilateral limbic areas on T2-weighted fluid-attenuation inversion recovery (FLAIR) images. Chest computed tomography revealed a mass in the anterior mediastinum. Surgical resection of the tumor, which was consistent with a type B3 thymoma, resulted in clinical improvement. After surgery, the cerebrospinal fluid (CSF) was found to be positive for anti-N-methyl-D-aspartate (NMDA) type glutamate receptor antibodies. These findings led to the diagnosis of paraneoplastic LE (PLE) associated with thymoma. CONCLUSION: When a patient presents with neurologic symptoms of unknown origin, the possibility of LE accompanied by thymoma should be considered. Rapid treatment is desirable before the symptoms become irreversible.

The efficacy of the Kampo medicine rikkunshito for chemotherapy-induced anorexia (RICH trial): study protocol for a randomized controlled trial.

BACKGROUND: Cisplatin is a key drug in lung cancer therapy. However, cisplatin is also well known to induce gastrointestinal disorders, such as chemotherapy-induced nausea and vomiting, anorexia, and weight loss. These symptoms sometimes affect patients' quality of life and make continuation of chemotherapy difficult. Anorexia is a cause of concern for patients with cancer because a persistent loss of appetite progresses to cancer cachexia. Although evidence-based management for chemotherapy has recently been established, there is room for improvement. METHODS/DESIGN: This placebo-controlled, double-blind, randomized trial will aim to determine the efficacy of the traditional Japanese Kampo medicine rikkunshito (TJ-43) for preventing anorexia caused by cisplatin-including chemotherapy in patients with lung cancer. Patients with lung cancer who plan to receive cisplatin-including chemotherapy will be recruited. Patients who provide written consent will be randomly allocated to receive either TJ-43 (arm A) or placebo (arm B) for one course of chemotherapy (21 or 28 consecutive days). Investigators and patients will be masked to the treatment assignment throughout the trial. The primary endpoint will be evaluated as the change in dietary intake from day 0 (the day before the start of chemotherapy) to day 7 of cisplatin-including chemotherapy. The two arms of the trial will comprise 30 patients each. From November 2014, a total of 60 patients will be recruited, and recruitment for the study is planned to be complete by October 2017. DISCUSSION: This trial is designed to examine the efficacy of rikkunshito (TJ-43) for reducing anorexia and maintaining food intake caused by cisplatin-including chemotherapy in patients with lung cancer. TRIAL REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC CTI), trial registration: JAPIC CTI-142747 . Registered on 15 December 2014; the RICH trial.

Epidermal growth factor receptor mutation status is strongly associated with smoking status in patients undergoing surgical resection for lung adenocarcinoma.

OBJECTIVES: The purpose of this analysis was to examine the relationship between epidermal growth factor receptor (EGFR) mutation status and clinicopathological factors in a cohort of patients who underwent surgical resections for lung adenocarcinoma. METHODS: From the patients who underwent surgical resections for primary lung cancers between 2005 and 2012, 371 consecutive adenocarcinoma patients were enrolled in this study, and their tumours were analysed for EGFR mutations. We examined the clinicopathological factors of all enrolled patients, including age, sex, pathological stage and smoking status and tested for associations with EGFR mutation status. RESULTS: Among the 371 enrolled patients, 195 (52%) patients had EGFR mutations. There were significantly more women, never smokers and tumours of lower grade histology in the EGFR mutation group than in the wild-type group (P < 0.001 each). However, other factors, such as pathological stage and World Health Organization classification, were not significantly associated with mutation status. Multivariable analysis showed that age, smoking history and histological grade were independently associated with EGFR mutations (P = 0.026, P < 0.001 and P < 0.001, respectively), but sex was not. Regarding smoking status, especially, frequency of EGFR mutation decreased, as smoking index increased. On the other hand, sex and smoking cessation (whether the patients were former or current smokers) were not significantly associated with EGFR mutation status. CONCLUSIONS: In our cohort of patients who underwent surgical resection for lung adenocarcinoma, EGFR mutation status was strongly associated with smoking status, especially smoking index.

[Exploring the Possibility of New Biomarkers of Immune Checkpoint Inhibitors for Non-Small Cell Lung Cancer (NSCLC)].

Mutation burden in a tumor, presumably involving neo-antigens in the tumor tissue, is also thought to be one of the better predictors for the efficacy of immune checkpoint inhibitors. However, it is difficult to analyze the mutation burden routinely in the clinic. Here, we describe more convenient factors that can be used as surrogate markers of mutation burden. Ninety-four patients with NSCLC who underwent resection in our institution were recruited for this study. Mutation burden and major gene alterations were analyzed by using next generation sequencing. Several immunological parameters were also assessed using immunohistochemistry. Statistical analysis was performed on mutation burden, major gene alternations, immunohistochemistry, and clinical parameters. The median mutation load was 54 mutations(range, 10-363 mutations). Squamous cell carcinoma, EGFRmutation -negativity, and TP53 alteration-positivity were closely connected with higher mutation burden. Multiple regression analysis showed that mutation burden in the tumor could be associated with EGFRmutation and TP53 alteration status.

Clinical and pathological aspects of microscopic thymoma with myasthenia gravis and review of published reports.

BACKGROUND: Microscopic thymomas, defined as epithelial proliferations smaller than 1 mm in diameter, characteristically occur in patients with myasthenia gravis without macroscopic thymic epithelial tumors. However, some clinical and pathological aspects of this entity are still unclear. METHODS: This retrospective study includes five consecutive patients who had undergone extended thymectomy for myasthenia gravis at our institution from April 2007 to March 2016 and in whom microscopic thymomas were diagnosed by histopathological examination of the resected specimens. During the same period, we performed 32 extended transsternal thymothymectomies/thymectomies in patients with myasthenia gravis, including the above five cases. We here review 18 cases of microscopic thymoma, including our five cases and 13 previously reported cases. RESULTS: The incidence of previously undiagnosed microscopic thymoma in patients undergoing thymectomy for myasthenia gravis in our institution is 15.2%. Serum preoperative anti-acetylcholine receptor antibody (anti-AchR Ab) titers were abnormally high in all of our five cases h (74.4±53.3 nmol/L) and decreased significantly after surgery (11.7±13.5 nmol/L, P=0.037). We divided our cases into the following three groups: microscopic thymoma group (Group M), thymoma group (Group T) and non-thymic tumor group (Group N). The mean preoperative anti-AchR Ab titers of these groups were 74.4, 26.5, and 368 nmol/L, respectively. All these values decreased postoperatively. The mean anti-AchR Ab titer was significantly higher in Group M than in Group T (P=0.034). All five cases in Group M were found by post-operative pathological examination to have multifocal type A thymomas. CONCLUSIONS: Microscopic thymomas tend to be multifocal type A thymomas. Anti-AchR Ab titers decreased significantly in all groups. It is very important to both perform complete extended thymectomies in patients with myasthenia gravis and pathological examination of thin slices of thymic tissue to maximize detection of microscopic thymomas.

Efficacy and tolerability of nanoparticle albumin-bound paclitaxel in combination with carboplatin as a late-phase chemotherapy for recurrent and advanced non-small-cell lung cancer: A multi-center study of the Fukushima lung cancer association group of surgeons.

The present retrospective multi-center study aimed to evaluate the efficacy and feasibility of nanoparticle albumin-bound (nab)-paclitaxel plus carboplatin as a second or late-phase chemotherapy in patients with non-small cell lung cancer (NSCLC). A total of 25 patients with recurrent or advanced NSCLC who had received previous chemotherapy were treated with nab-paclitaxel (70-100 mg/m2, intravenously) on days 1, 8 and 15 every 28 days with a carboplatin area under the concentration-time curve of 4-6 on day 1. The overall response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicities were statistically evaluated. Of the 25 patients, there were 9 cases of recurrent disease following surgery, 16 cases of advanced disease, 13 cases of adenocarcinoma, 11 cases of squamous cell carcinoma and 1 case of large cell carcinoma. A total of 13 patients received second-line chemotherapy and 12 received fourth-line or later chemotherapy. One patient exhibited a complete response, 7 had a partial response, 10 exhibited stable disease and 7 had progressive disease. The overall response rate was 32.0% and the disease control rate was 72.0%. The median PFS and median OS following nab-paclitaxel treatment were 4.0 and 14.0 months, respectively. Frequent treatment-associated adverse events were myelosuppression, peripheral neuropathy, gastrointestinal symptoms and baldness, the majority of which were grade 1-2. Grade 3-4 neutropenia, thrombocytopenia and anemia occurred in 7 (28.0%), 3 (12.0%) and 2 (8.0%) patients, respectively. No patients experienced grade 3-4 sensory neuropathy and no grade 5 adverse effects were observed. Nab-paclitaxel plus carboplatin as second-phase or later chemotherapy provided a small but significant survival benefit for patients with recurrent or advanced NSCLC, with tolerable adverse effects. To the best of our knowledge, the results of the present study demonstrated for the first time that nab-paclitaxel plus carboplatin is a promising and feasible late-phase chemotherapeutic agent for NSCLC.

Serum Nitric Oxide as a Predictive Biomarker for Bevacizumab in Non-small Cell Lung Cancer Patients.

BACKGROUND/AIM: Reportedly, hypertension tends to be associated with response to bevacizumab therapy, because bevacizumab suppresses vascular nitric oxide production. In this study we examined the predictive value of nitric oxide in bevacizumab-treated non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifteen patients with advanced or recurrent NSCLC treated with bevacizumab-based regimens were evaluated retrospectively. Serum NOx (NO2-/NO3-) was assayed by the Griess method. RESULTS: Serum nitric oxide levels were decreased after two courses of bevacizumab treatment in our responder group (p=0.02). According to the change in nitric oxide levels after the second course of treatment, median progression-free survival was 11.0 months in the group with decreased serum nitric oxide and 7.6 months in the group with increased serum nitric oxide (p=0.08). CONCLUSION: Serum nitric oxide levels could be a predictive biomarker for response to bevacizumab in NSCLC patients.

Texture Analysis and Synthesis of Malignant and Benign Mediastinal Lymph Nodes in Patients with Lung Cancer on Computed Tomography.

Texture analysis of computed tomography (CT) imaging has been found useful to distinguish subtle differences, which are in- visible to human eyes, between malignant and benign tissues in cancer patients. This study implemented two complementary methods of texture analysis, known as the gray-level co-occurrence matrix (GLCM) and the experimental semivariogram (SV) with an aim to improve the predictive value of evaluating mediastinal lymph nodes in lung cancer. The GLCM was explored with the use of a rich set of its derived features, whereas the SV feature was extracted on real and synthesized CT samples of benign and malignant lymph nodes. A distinct advantage of the computer methodology presented herein is the alleviation of the need for an automated precise segmentation of the lymph nodes. Using the logistic regression model, a sensitivity of 75%, specificity of 90%, and area under curve of 0.89 were obtained in the test population. A tenfold cross-validation of 70% accuracy of classifying between benign and malignant lymph nodes was obtained using the support vector machines as a pattern classifier. These results are higher than those recently reported in literature with similar studies.

Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement.

We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.

FDG-PET in the evaluation of response to nivolumab in recurrent non-small-cell lung cancer.

BACKGROUND: Nivolumab, an immune checkpoint inhibitor, is recently clinically applied to non-small cell lung cancer (NSCLC) treatment, and this causes T cell activation and T cell infiltration to tumor tissue through the blockade of the interaction between programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) sometimes shows false positive because of the recruitment of neutrophils, lymphocytes, and macrophages. To date, there is only one report except our case, which described the correlation between FDG-PET and nivolumab. CASE PRESENTATION: We report on a 75-year-old man on nivolumab treatment for metastatic non-small cell lung cancer. He had undergone right lower lobectomy for lung adenocarcinoma in the right S8 segment 10 months prior to recurrence. Pathological findings revealed invasive adenocarcinoma, pT1bN2M0 stage IIIA. Epidermal growth factor receptor (EGFR) mutation was positive for de novo T790M and anaplastic lymphoma kinase (ALK) rearrangement was negative. Immunohistochemistry was negative for PD-L1. He underwent chemotherapy with a combination of cisplatin and pemetrexed for four cycles but developed progressive disease involving the right hemithorax, multiple lymph nodes, and multiple osseous sites. Nivolumab was instituted as a second-line chemotherapy. After six courses of this immunotherapy, FDG-PET scan showed decreased FDG uptake in each recurrent lesion despite T lymphocyte activation by nivolumab. Serum carcinoembryonic antigen (CEA) level was also remarkably decreased. CONCLUSIONS: Nivolumab's effect on recurrent NSCLC may be monitored by PET; larger studies are needed.

Recurrent Intrapulmonary Solitary Fibrous Tumor With Malignant Transformation.

Intrapulmonary solitary fibrous tumor (SFT) of the pleura; the so-called inverted pattern, which appears to grow into the lung parenchyma, is extremely rare. We experienced a 66-year-old woman with an intrapulmonary SFT that recurred locally with malignant transformation 2 years after wedge resection of the left upper lobe for the primary tumor. Subsequently, she underwent a lobectomy of the residual left upper lobe. Six years after the second operation she was well, without rerecurrence. Complete excision and long-term follow-up of intrapulmonary SFTs of the pleura are important, even when the primary tumor displays benign histopathologic features.

Clinical significance of expanded Foxp3⁺ Helios⁻ regulatory T cells in patients with non-small cell lung cancer.

The functions of different regulatory T cell (Treg) types in cancer progression are unclear. Recently, expression of the transcription factor Helios was proposed as a marker for natural (non-induced) Tregs. The present study investigated the clinical significance of Helios expression in patients with non-small cell lung cancer (NSCLC). We enrolled 64 patients with NSCLC, of whom 45 were treated surgically and 19 received chemotherapy because of advanced/recurrent disease. Their peripheral blood mononuclear cells were examined by flow cytometry. From the 45 surgery patients, we matched 9 patients with recurrent disease with 9 stage-matched patients without recurrence (n=18), compared their specimens immunohistochemically for tumor infiltrating lymphocytes (TILs) and analyzed these data against clinicopathological factors. Helios expression in Foxp3+ Tregs was 47.5±13.3% in peripheral blood and 18.1±13.4% in tumor specimens. Percentage of Helios- Tregs among CD4+ T cells were significantly higher in the cancer patients (2.4%), especially those with stage IA disease (2.6%) than in healthy donors (1.5%; P<0.001). Patients with low levels of Helios expression in Tregs among their TILs had significantly poorer survival (P=0.038). Helios- Tregs may affect immune suppression, even in early stage NSCLC; they could also be a useful prognostic biomarker in patients with NSCLC, and possibly a novel cancer immunotherapy target.

Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma.

Objective. The aim of this study was to investigate the prognostic value of MicroRNA-210 (miR-210) expression in patients with non-small-cell lung cancer (NSCLC). Methods. We examined the miR-210 expression of samples of 80 patients, who underwent surgical resection at Fukushima Medical University from 2004 to 2007, by using quantitative RT-PCR. The relationship between miR-210 expression and clinicopathological factors as well as histological subtype was statistically analyzed. Results. miR-210 expression showed an inverse correlation with disease-free and overall survival in patients with NSCLC. Significant correlations were found between miR-210 expression and lymph node metastasis, late disease stages, and poor prognosis in patients with adenocarcinoma. Multivariate Cox analysis indicated that miR-210 expression was an independent prognostic factor for disease-free survival in patients with adenocarcinoma. Conclusions. We showed that miR-210 may be a prognostic biomarker for patients with NSCLC, especially for those with lung adenocarcinoma.

[Two cases of thymic carcinoid treated with octreotide long-acting repeatable].

Thymic carcinoid is a rare disease that accounts for 3.1% of thymic tumors and 1.8-6% of all carcinoid tumors in Japan. Advanced thymic carcinoid has a 5-year survival rate of 28-31%.Compared with carcinoid tumors that arise in other organs, thyroid carcinoid tumors carry a relatively worse prognosis, and the most effective therapeutic strategy is thought to be surgical resection.However, for patients with recurrence and distant metastases, multimodal therapy including radiotherapy and/or chemotherapy is usually applied.No chemotherapy treatment regimen has been established in Japan, although the National Comprehensive Cancer Network Guidelines proposed the application of octreotide long-acting repeatable(LAR).In this report, we present two cases of thymic carcinoid that were treated with octreotide LAR and achieved long-term survival.

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

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.