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1.
Cancer Treat Res Commun ; 40: 100830, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38964205

RESUMEN

BACKGROUND: NY-ESO-1 and XAGE1 cancer/testis antigens elicit humoral and cellular immune responses in NSCLC patients. We aimed to predict clinical benefit with ICI monotherapy, using an automated immunoassay of NY-ESO-1/XAGE1 antibodies (Abs). METHODS: This study enrolled 99 NSCLC patients who received nivolumab after chemotherapy, including 21 patients harboring EGFR, ALK, or KRAS alterations. The cutoff value (10 units/mL) of NY-ESO-1 and XAGE1 Ab was determined based on Ab levels in non-malignant controls, and NY-ESO-1/XAGE1 Abs in NSCLC were measured before nivolumab. Differences in PFS and OS between the Ab-positive and Ab-negative groups were retrospectively analyzed using Cox regression analysis after applying inverse probability of treatment weighting (IPTW). RESULTS: NY-ESO-1/XAGE1 Abs were positive in 28 NSCLC, who responded more highly to nivolumab than the Ab-negatives (response rate 50.0% vs. 15.5 %, p < 0.0007). The IPTW-adjusted positives and negatives for NY-ESO-1/XAGE1 Abs were 24.5 and 70.2, respectively. The Ab-positives showed longer IPTW-adjusted PFS (HR = 0.59, 95 % CI: 0.39-0.90, p = 0.014) and IPTW-adjusted OS (HR = 0.51, 95 % CI: 0.32-0.81, p = 0.004) than the Ab-negatives. Among NSCLC harboring driver genes, the Ab-positives (n = 10) showed longer PFS (HR = 0.34, 95 % CI: 0.13-0.89, p = 0.029) and OS (HR = 0.27, 95 % CI: 0.098-0.75, p = 0.012) than the Ab-negatives (n = 11). CONCLUSION: Our immunoassay of NY-ESO-1/XAGE1 Abs is probably useful for predicting the clinical benefit with nivolumab in NSCLC, including those harboring driver genes. These results suggest that our immunoassay may be useful in ICI monotherapy for NSCLC.

2.
Allergol Int ; 73(3): 390-396, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38341371

RESUMEN

BACKGROUND: Asthma and obstructive sleep apnea (OSA) are prevalent chronic respiratory disorders, which often coexist and interact with each other. Obesity is an important risk factor shared by them. The rate of obesity is lower in Japan versus Western countries. Hence, the co-existence of asthma and OSA has not been investigated in Japan. METHODS: Ninety-seven outpatients with asthma were recruited. Patients wore a portable monitor for sleep study. Background data, pulmonary function, blood tests, and patient-reported outcomes including gastroesophageal reflux disease, sleepiness, sleep quality, asthma control, cough and respiratory symptoms, and health status, were assessed. RESULTS: Of the patients, 19 (19.6 %), 40 (41.2 %), 24 (24.7 %), and 14 (14.4 %) were classified into non-, mild, moderate, and severe OSA groups. Non-OSA patients were younger than those in other groups (p < 0.05). The BMI of patients with moderate and severe OSA, was higher than that of non-OSA patients (p < 0.05). Pulmonary function, FeNO, serum IgE, and the number of peripheral eosinophils were not significantly different between groups. Nonetheless, compared with the other groups, treatment step was the highest, and the Asthma Control Test, Leicester Cough Questionnaire, COPD Assessment Test, and Asthma Health Questionnaire-33 yielded worst scores in the severe OSA group, and predicted the severe OSA after adjustment by BMI. CONCLUSIONS: Moderate and severe OSA are highly prevalent among patients with asthma in Japan. Pulmonary function did not differ between groups. However, patients with asthma and severe OSA were linked to more asthma treatment, worse asthma control, more symptoms and cough, and worse health status.


Asunto(s)
Asma , Comorbilidad , Apnea Obstructiva del Sueño , Humanos , Asma/epidemiología , Asma/diagnóstico , Asma/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/complicaciones , Masculino , Japón/epidemiología , Femenino , Persona de Mediana Edad , Adulto , Anciano , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad
3.
PLoS One ; 18(9): e0291772, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37729184

RESUMEN

INTRODUCTION: Regulatory T cells (Tregs) have attracted attention as a novel therapeutic target to augment the clinical efficacy of immunotherapy. We conducted phase Ia and Ib trials to examine the safety and efficacy of the anti-CCR4 antibody, KW-0761 (mogamulizumab), which may eliminate effector Tregs (eTregs). We herein overviewed the results of these trials, presented cases with a durable clinical response, and investigated factors associated with the clinical effects of KW-0761. METHODS: Forty-nine patients with CCR4-negative solid cancers were enrolled in the phase Ia and Ib trials on KW-0761. An integral analysis of safety, clinical responses, prognosis, blood laboratory data, and cancer testis antigen-specific immune responses was performed. RESULTS: Grade 3-4 treatment-related adverse events were reported in 21 (42.9%) out of 49 patients, all of which were manageable. A partial response and stable disease were observed in 1 and 9 patients, respectively. A durable clinical response was noted in 2 esophageal and 2 lung cancer patients. eTreg depletion in peripheral blood was confirmed in most patients, and eTreg depletion was sustained during the KW-0761 treatment. High lymphocyte levels at baseline and 2 weeks after the initiation of KW-0761 were associated with a favorable clinical outcome. CONCLUSIONS: A durable clinical response was noted in some patients, and high lymphocyte levels before treatment initiation may be a biomarker for the efficacy of KW-0761. The synergistic effect of KW-0761 for depleting Tregs and other immunotherapies is expected in the future.


Asunto(s)
Neoplasias Pulmonares , Linfocitos T Reguladores , Humanos , Masculino , Inmunoterapia , Ensayos Clínicos Controlados Aleatorios como Asunto
4.
Adv Clin Chem ; 112: 155-204, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36642483

RESUMEN

Immune checkpoint inhibitors (ICI) are key drugs in systemic therapy for advanced non-small-cell lung cancer (NSCLC) and have recently been incorporated into neoadjuvant and adjuvant settings for surgical resection. Currently, ICI combinations with cytotoxic agents are frequently used in clinical practice, although several ICI clinical trials have failed to produce long-term clinical benefits. Unfortunately, clinical benefit is moderate and limited considering physical and financial burden. Therefore, selecting appropriate patients and regimens for ICI therapy is important, and biomarkers are necessary for their selection. Tumor PD-L1 expression is universally used as a biomarker; however, PD-L1 assays show low analytical validity and reproducibility due to the visual-scoring system by pathologists. Recent tumor immunology studies explore that neoantigens derived from somatic mutations and the collaboration between T and B cells efficiently elicit antitumor responses. This suggests that high tumor mutational burden and T-cell infiltration are predictive biomarkers. However, B cells producing antibody (Ab) remain poorly understood and analyzed as biomarkers. We found that NY-ESO-1 and XAGE1 of cancer-testis antigen frequently elicit spontaneous humoral and cellular immune responses in NSCLC. Serum Ab against these antigens were detected in approximately 25% of NSCLC patients and predicted ICI monotherapy responses. In addition, the Ab levels were decreased with tumor shrinkage after ICI therapy. Thus, NY-ESO-1 and XAGE1 Ab are potentially biomarkers predicting and monitoring response to ICI therapy. For clinical applications, a fully-automated assay system measuring the Ab was developed. Here, we review current ICI therapy, tumor immunology, and biomarkers in NSCLC, and discuss the applicability of the serum biomarkers NY-ESO-1 and XAGE1 Ab.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Masculino , Anticuerpos , Antígenos de Neoplasias , Antígeno B7-H1 , Biomarcadores , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Reproducibilidad de los Resultados , Inhibidores de Puntos de Control Inmunológico/uso terapéutico
5.
Respirology ; 28(4): 380-388, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36446578

RESUMEN

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor pneumonitis (CIP), caused by the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high-mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. METHODS: Blood samples, prospectively stored before anti-PD-1/PD-L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non-small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3 months of initiating anti-PD-1/PD-L1 therapy. RESULTS: CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut-off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut-off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. CONCLUSION: Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients.


Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Proteína HMGB1 , Neoplasias Pulmonares , Neumonía , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Antígeno B7-H1 , Estudios Retrospectivos , Antineoplásicos Inmunológicos/efectos adversos , Neumonía/inducido químicamente
6.
Biomed Pharmacother ; 155: 113733, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36271542

RESUMEN

Pancreatic cancer is recalcitrant to treatment as it is highly metastatic and rapidly progressive. While observing the behavior of human pancreatic BxPC-3 cells using an optical assay device called TAXIScan, we found that several synthetic pyrazole and pyrimidine derivatives inhibited cell migration. One such compound, 14-100, inhibited metastasis of fluorescence-labeled BxPC-3 cells, which were transplanted into the pancreas of nude mice as a subcutaneously grown cancer fragment. Surprisingly, despite its low cytotoxicity, the compound also showed an inhibitory effect on cancer cell proliferation in vivo, suggesting that the compound alters cancer cell characteristics needed to grow in situ. Single-cell RNA-sequencing revealed changes in gene expression associated with metastasis, angiogenesis, inflammation, and epithelial-mesenchymal transition. These data suggest that the compound 14-100 could be a good drug candidate against pancreatic cancer.


Asunto(s)
Quimiotaxis , Neoplasias Pancreáticas , Ratones , Animales , Humanos , Ratones Desnudos , Línea Celular Tumoral , Movimiento Celular , Neoplasias Pancreáticas/patología , Páncreas/patología , Transformación Celular Neoplásica , Pirazoles/farmacología , Pirazoles/uso terapéutico , ARN , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Neoplasias Pancreáticas
7.
Nagoya J Med Sci ; 83(4): 827-840, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34916725

RESUMEN

Tregs infiltrate tumors and inhibit antitumor immunity. KW-0761 (Mogamulizumab) is a humanized anti-CCR4 monoclonal antibody that could eliminate activated Tregs with high immunosuppressive activity that express CCR4. In this phase Ib trial, KW-0761 was used as a cancer immunotherapeutic reagent to deplete Tregs in patients with advanced or recurrent solid CCR4-negative tumors. Thirty-nine patients with solid cancer were treated with KW-0761 at a dose of 0.1 or 1.0 mg/kg. The safety, clinical responses, and effects of Treg depletion were analyzed. Any grade and grade 3-4 treatment-related adverse events (AEs) were observed in 36 (92%) and 14 (36%) out of 39 patients, respectively. All treatment-related AEs were manageable. One and 5 patients achieved a partial response and stable disease, respectively, during treatment and were long survivors. The efficient depletion of Treg in peripheral blood was confirmed in both cohorts. Therefore, the administration of KW-0761 was safe, resulting in the depletion of Tregs in peripheral blood and potential immune responses in patients with solid cancer. The combined use of KW-0761 to deplete Tregs and other immunotherapies is a promising approach to augment immune responses.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptores CCR4/antagonistas & inhibidores , Humanos , Neoplasias/inmunología , Receptores CCR4/inmunología , Resultado del Tratamiento
8.
Anticancer Res ; 41(11): 5469-5475, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34732416

RESUMEN

BACKGROUND/AIM: We evaluated the efficacy of "the tumor immune microenvironment (TIME) classification" for predicting clinical response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). In addition, we aimed to evaluate the "modified TIME classification", which adds the vascular endothelial growth factor (VEGF) status to TIME. MATERIALS AND METHODS: Programmed cell death receptor ligand-1 (PD-L1), CD8 T cell tumor-infiltrating lymphocytes (CD8+TILs) count and VEGF expression analyses were performed using immuno - histochemistry in 44 patients who had undergone ICI monotherapy. RESULTS: Regarding TIME classification, type-I (PD-L1 high and CD8+TILs high) had a significantly higher response than the other types. Using the modified TIME classification, type-IA (PD-L1 high, CD8+TILs high, and VEGF low) had a significantly higher response than the other types. CONCLUSION: The modified TIME classification, which adds tumor VEGF expression to "the TIME classification", could be useful in predicting clinical response to ICI monotherapy.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/inmunología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Microambiente Tumoral
9.
Clin Chim Acta ; 519: 51-59, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33865813

RESUMEN

BACKGROUND: Anti-programmed cell death-1 (PD-1) antibodies (Abs) are key drugs in non-small-cell lung cancer (NSCLC) treatment; however, clinical benefits with anti-PD-1 monotherapy are limited. We reported that serum Abs against cancer-testis antigens NY-ESO-1 and XAGE1 predicted clinical benefits. We aimed to develop a fully automated immunoassay system measuring NY-ESO-1/XAGE1 Abs. METHODS: Sera from 30 NSCLC patients before anti-PD-1 monotherapy were reacted with recombinant NY-ESO-1 protein- or synthetic XAGE1 peptide-coated magnetic beads. ALP-conjugated Ab and chemiluminescent substrate were added and luminescence measured. These procedures were automated using high sensitivity chemiluminescent enzyme immunoassay (HISCL™). NY-ESO-1/XAGE1 Ab stability was tested under various conditions. Response prediction accuracy was evaluated using area under receiver operating curve (AUROC). RESULTS: HISCL detected specific serum NY-ESO-1/XAGE1 Abs, which levels in ELISA and HISCL were highly correlated. The Ab levels in HISCL were stable at four temperatures, five freeze/thaw cycles, and long-term storage; the levels were not interfered by common blood components. The Ab levels in 15 NSCLC responders to anti-PD-1 monotherapy were significantly higher than those in non-responders and healthy donors. The AUROC was the highest (0.91; 95% CI, 0.78-1.0) in combinatory prediction with NY-ESO-1/XAGE1 Abs. CONCLUSION: Our immunoassay system is useful to predict clinical benefits with NSCLC immune-checkpoint therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígenos de Neoplasias , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Inmunoensayo , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Proteínas de la Membrana
10.
Thorac Cancer ; 12(1): 117-121, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33118287

RESUMEN

Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Herpes Zóster/complicaciones , Neoplasias Pulmonares/complicaciones , Neoplasias Cutáneas/secundario , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad
11.
Surg Case Rep ; 6(1): 276, 2020 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-33119806

RESUMEN

BACKGROUND: Nivolumab is effective for gastric cancer and lung cancer, but complete response is rare. We experienced a case of synchronous gastric cancer and lung cancer who was treated by nivolumab and laparoscopic gastrectomy. CASE PRESENTATION: A 63-year-old male consulted our institution and was found to have gastric cancer cT1(SM)N0M0 Stage IA and lung cancer cT2N2M1(PUL) Stage IV. He received eight chemotherapy treatments plus radiation, but the lung disease remained progressive. Finally, he received nivolumab therapy and complete response of both cancers was obtained. The gastric cancer recurred, but was successfully treated by laparoscopic gastrectomy. The resected specimen revealed three lesions, each being pT1aN0M0 Stage IA. The primary gastric cancer seemed to have completely vanished without scarring. CONCLUSIONS: This was thought to be a rare case of gastric cancer recurrence after complete response of gastric cancer and lung cancer to nivolumab.

12.
Respir Med Case Rep ; 29: 101030, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32154100

RESUMEN

Endobronchial ultrasound with a guide sheath (EBUS-GS)-guided transbronchial biopsy offers advantages and is frequently used for the diagnosis of peripheral pulmonary lesions. A previously healthy 75-year-old man was hospitalized to undergo bronchoscopy for the diagnosis of a mass with a diameter of about 40 mm in right S3 area. The mass was detected during a regular medical check-up, and lung cancer was suspected. EBUS-GS guided transbronchial biopsy was performed through the right B3. Following the bronchoscopic procedure and removal of the GS, we observed that an X-ray opaque tip attached to the point of the GS was missing. We examined the lung field through X-ray fluoroscopy and found that the detached opaque tip was located in the right middle lung field. We re-inserted the bronchoscope, and successfully recovered it using transbronchial biopsy forceps. The rate of complications in EBUS-GS is low, and the complication presented in this report is rare. Physicians should exercise caution when performing this procedure and carefully check the condition of the kit to reduce the risk of such complications.

13.
Respir Med Case Rep ; 29: 101017, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32071855

RESUMEN

Mechanical insufflation-exsufflation (MI-E) devices are frequently used in patients with respiratory muscle weakness to increase their cough peak flow and assist them in improving cough effectiveness and clearing mucus from the airways. An 89-year-old male was admitted to our university hospital due to fever and loss of appetite. He was diagnosed with lung abscess and pulmonary nontuberculous mycobacterial disease. He was unable to independently expectorate phlegm due to frailty. Subsequently, MI-E was introduced. On day 3 after its introduction, chest X-ray examination revealed bilateral pneumothorax, and use of the MI-E device was discontinued. After conservatively observing the clinical course, pneumothorax was improved on day 12 after it occurred. Although scientific evidence regarding MI-E is currently limited, healthcare professionals often do not have an alternative in clinical practice. However, treating physicians should consider the risk of MI-E-related pneumothorax, despite its low occurrence rate.

14.
Intern Med ; 59(2): 257-260, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31554752

RESUMEN

A 46-year-old Japanese man was admitted to our hospital with a 1-year history of dyspnea and persistent right-dominant bilateral pleural effusions. Chest and abdominal computed tomography (CT) revealed no notable findings apart from the bilateral pleural effusions. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography-CT showed no accumulation of FDG in the thorax and abdomen. Thoracoscopy revealed numerous small (approximately 2-3 mm in size), blister-like nodules on the left parietal pleura extending from the lower third of the chest wall to the diaphragm. A pathological examination revealed lymphocyte and plasma cell infiltrates with increasing numbers of IgG4-positive plasma cells in the fibrotic pleura, indicating IgG4-related pleuritis.


Asunto(s)
Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico por imagen , Pleuresia/diagnóstico por imagen , Humanos , Inmunoglobulina G/sangre , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/patología , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Células Plasmáticas/metabolismo , Pleura/patología , Derrame Pleural/patología , Pleuresia/diagnóstico , Pleuresia/patología , Toracoscopía
15.
J Thorac Oncol ; 14(12): 2071-2083, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31449889

RESUMEN

INTRODUCTION: Programmed cell death-1 (PD-1) inhibitors effectively treat NSCLC and prolong survival. Robust biomarkers for predicting clinical benefits of good response and long survival with anti-PD-1 therapy have yet to be identified; therefore, predictive biomarkers are needed to select patients with benefits. METHODS: We conducted a prospective study to explore whether serum antibody against NY-ESO-1 and/or XAGE1 cancer-testis antigens predicted primarily good clinical response and secondarily long survival with anti-PD-1 therapy for NSCLC. The serum antibody was detected by enzyme-linked immunosorbent assay, and tumor immune microenvironment and mutation burden were analyzed by immunohistochemistry and next-generation sequencing. RESULTS: In the discovery cohort (n = 13), six antibody-positive NSCLC cases responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC cases did not. Antibody positivity was associated with good response and survival, regardless of tumor programmed death ligand 1 (PD-L1) expression, mutation burden, and CD8+ T-cell infiltration. In the validation cohort (n = 75), 17 antibody-positive NSCLC cases responded well to anti-PD-1 therapy as compared with 58 negative NSCLC cases (objective response rate 65% versus 19%, p = 0.0006) and showed significantly prolonged progression-free survival and overall survival. Antibody titers highly correlated with tumor reduction rates. In the multivariate analysis, response biomarkers were tumor programmed death ligand 1 expression and antibody positivity, and only antibody positivity was a significantly better predictive biomarker of progression-free survival (hazard ratio = 0.4, p = 0.01) and overall survival (hazard ratio = 0.2, p = 0.004). CONCLUSIONS: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Carcinoma de Pulmón de Células no Pequeñas/microbiología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Supervivencia
17.
J Immunother ; 40(4): 140-147, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28338507

RESUMEN

We conducted a clinical trial of a cancer vaccine using NY-ESO-1 protein with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) and/or OK-432 against solid tumors. A total of 15 patients were sequentially enrolled in 4 cohorts. Patients in cohort 1 received NY-ESO-1 protein; cohort 2a received NY-ESO-1 protein+OK-432; cohort 2b received NY-ESO-1 protein+poly-ICLC; cohort 3 received NY-ESO-1 protein+OK-432+poly-ICLC with Montanide ISA-51. The endpoints of this trial were safety, NY-ESO-1 immune responses, and clinical response. Vaccine-related adverse events observed were fever and injection-site reaction (grade 1). Two patients showed stable disease after vaccination. NY-ESO-1 antibodies were observed in 4 patients at the baseline (sero-positive) and augmented in all patients after vaccination. Eleven patients showed a conversion of negative antibody responses at baseline to positive after vaccination (seroconversion). The seroconversions were observed in all 11 sero-negative patients by the fourth immunization; in particular, it was observed by the second immunization in patients with poly-ICLC, and these induced antibody responses were stronger than those in patients immunized without poly-ICLC. The number of NY-ESO-1-specific interferon (IFN)γ-producing T cells was increased in patients immunized with poly-ICLC and/or OK-432, and furthermore, the increase of IFNγ-producing CD8 T cells in patients immunized with poly-ICLC was significantly higher than that in patients without poly-ICLC. Nonspecific activations of T-cell or antigen presenting cells were not observed. Our present study showed that poly-ICLC is a promising adjuvant for cancer vaccines.

18.
Nihon Rinsho ; 75(2): 209-215, 2017 02.
Artículo en Japonés | MEDLINE | ID: mdl-30562854

RESUMEN

CCR4 is one of the receptors for chemokines and is expressed on Th2, Th17, skin-homing T cells and regulatory T cells (Tregs). Activated Tregs highly express CCR4 and are induced into tumor environment by M2 macrophages-producing CCL22. Tregs show strong suppres- sive functions in cancer immunity, resulting in tumor progression. On the other hand, moga- mulizumab is a humanized anti-human CCR4 monoclonal antibody with a defucosylated Fe region which markedly enhances ADCC activity, and the antibody has been shown to effi- ciently deplete CCR4-positive cells. Therefore, a phase Ia clinical study of mogamulizumab was conducted in the treatment of solid cancers. Mogamulizumab almost depeleted activated Tregs in peripheral blood, and then re-activated CTL function with low grade of adverse events. However, no clinical responses were observed in ten patients. A phase lb study is now on-going, and further clinical studies may be needed in combination with other anti- tumor drugs.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia , Neoplasias/terapia , Receptores CCR4/inmunología , Anticuerpos Monoclonales/inmunología , Humanos , Neoplasias/inmunología
19.
Cancer Immunol Res ; 4(12): 1049-1060, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27799141

RESUMEN

The immune status of tumors varies, and this may affect the overall survival (OS) of patients. We examined tumors from 120 patients with lung adenocarcinomas with a tissue microarray for T-cell infiltration and the expression of PD-L1 and Galectin-9 (both ligands for inhibitory receptors on T cells), and cancer/testis (CT) antigen XAGE1 (GAGED2a; a tumor antigen often found on lung tumors) expression, to determine their relevance to OS. Patients defined as pStage I-IIIA could be grouped, based on the expression profiles of PD-L1, Galectin-9, and XAGE1, into cluster A, who had prolonged survival, and cluster B, who had shorter survival. The difference in survival of the clusters was confirmed separately for pStage I and pStage II-IIIA patients. Cluster A patients who also had CD4 and CD8 T-cell infiltration showed even better survival, as expected. The findings were confirmed by examining an independent validation cohort of 68 pStage I lung adenocarcinoma patients. Our data showed that PD-L1 expression was a positive indicator, whereas Galectin-9 and XAGE1 expression was negative. In vitro analyses suggested that PD-L1 expression was upregulated by IFNγ secreted from activated T cells in the tumor and Galectin-9 expression was counteracting those T cells. Thus, use of these immune markers enables the creation of a discriminant function with which to classify tumors and predict survival. Cancer Immunol Res; 4(12); 1049-60. ©2016 AACR.


Asunto(s)
Adenocarcinoma/metabolismo , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/metabolismo , Galectinas/metabolismo , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma del Pulmón , Afatinib , Biomarcadores de Tumor/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Análisis de Supervivencia
20.
Clin Cancer Res ; 21(19): 4327-36, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26429981

RESUMEN

PURPOSE: FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. EXPERIMENTAL DESIGN: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed. RESULTS: The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. CONCLUSIONS: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Depleción Linfocítica , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptores CCR4/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Granulocitos/inmunología , Granulocitos/metabolismo , Humanos , Inmunofenotipificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Neoplasias/metabolismo , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Resultado del Tratamiento
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