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BACKGROUND: Pancreatic cancer is an aggressive, immunologically "cold" tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). METHODS: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). RESULTS: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. CONCLUSION: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.
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Viroterapia Oncolítica , Virus Oncolíticos , Neoplasias Pancreáticas , Telomerasa , Humanos , Animales , Ratones , Adenoviridae/genética , Adenoviridae/metabolismo , Proteína p53 Supresora de Tumor/genética , Telomerasa/genética , Telomerasa/metabolismo , Línea Celular Tumoral , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Adenosina Trifosfato , Virus Oncolíticos/genética , Virus Oncolíticos/metabolismoRESUMEN
INTRODUCTION: Exosomes are cell-derived nanovesicles involved in cell-to-cell communications. These nanovesicles are generally considered to contain important carriers of information such as DNA and RNA, and show specific tropism. AREAS COVERED: The combination of existing therapeutic agents with exosomes enhances therapeutic effects by increasing uptake into the tumor. Induction of immunogenic cell death (ICD) may also be triggered more strongly than with the drug alone. Oncolytic viruses (OVs) are even more effective as a drug in combination with exosomes. Although OVs are more likely to cause immune activity, combination with exosomes can exert synergistic effects. OVs have potent anti-tumor effects, but many limitations, such as being limited to local administration and vulnerability to attack by antibodies. Incorporation into exosomes can overcome these limitations and may allow effects against distant tumors. EXPERT OPINION: Novel therapies using exosomes are very attractive in terms of enhancing therapeutic efficacy and reducing side effects. This approach also contains elements overcoming disadvantages in OVs, which have not been used clinically until now, and may usher in a new era of cancer treatments.
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Primary and metastatic lung cancer is a leading cause of cancer-related death and novel therapies are urgently needed. Epidermal growth factor receptor (EGFR) and death receptor (DR) 4/5 are both highly expressed in primary and metastatic non-small cell lung cancer (NSCLC); however, targeting these receptors individually has demonstrated limited therapeutic benefit in patients. In this study, we created and characterized diagnostic and therapeutic stem cells (SC), expressing EGFR-targeted nanobody (EV) fused to the extracellular domain of death DR4/5 ligand (DRL) (EVDRL) that simultaneously targets EGFR and DR4/5, in primary and metastatic NSCLC tumor models. We show that EVDRL targets both cell surface receptors, and induces caspase-mediated apoptosis in a broad spectrum of NSCLC cell lines. Utilizing real-time dual imaging and correlative immunohistochemistry, we show that allogeneic SCs home to tumors and when engineered to express EVDRL, alleviate tumor burden and significantly increase survival in primary and brain metastatic NSCLC. This study reports mechanistic insights into simultaneous targeting of EGFR- and DR4/5 in lung tumors and presents a promising approach for translation into the clinical setting.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Trasplante de Células Madre Hematopoyéticas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/uso terapéutico , Muerte Celular , Neoplasias Encefálicas/terapia , Proliferación Celular , Encéfalo/patologíaRESUMEN
Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1KO) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAFV600E/PTEN-/- and BRAFV600E/wt/PTEN-/- mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SCN1KO-releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.
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Neoplasias Encefálicas , Melanoma , Viroterapia Oncolítica , Virus Oncolíticos , Animales , Ratones , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Edición Génica , Proteínas Proto-Oncogénicas B-raf , Melanoma/terapia , Melanoma/patología , Simplexvirus/genética , Virus Oncolíticos/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Encéfalo/patología , Inmunoterapia , Células Madre , Melanoma Cutáneo MalignoRESUMEN
We herein report two cases of thymic cancer with Lynch syndrome showing a high frequency of microsatellite instability and loss of mismatch repair protein expression without MLH1 promoter hyper-methylation. In Case 1, a 71-year-old man had a pathogenic germline variant in MLH1 and underwent tumor resection. No relapse has been reported thus far. In Case 2, a 43-year-old man underwent genetic testing that also showed a pathogenic germline variant in MLH1. Since these two cases had MLH variants, we suspect a possible association between thymic cancer with Lynch syndrome and germline pathogenic variants in MLH1.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias del Timo , Masculino , Humanos , Anciano , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Metilación de ADN/genética , Homólogo 1 de la Proteína MutL/genética , Recurrencia Local de Neoplasia/genética , Mutación de Línea Germinal , Neoplasias del Timo/complicaciones , Neoplasias del Timo/genética , Neoplasias del Timo/cirugíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.
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Carcinoma Ductal Pancreático , Células Supresoras de Origen Mieloide , Virus Oncolíticos , Neoplasias Pancreáticas , Ratones , Animales , Humanos , Gemcitabina , Células Supresoras de Origen Mieloide/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Antígeno B7-H1/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Inmunosupresores/uso terapéutico , Microambiente Tumoral , Línea Celular Tumoral , Neoplasias PancreáticasRESUMEN
Background: Biliary tract cancer (BTC) is a Lynch syndrome (LS)-associated cancer with a high mortality rate. This study aimed to clarify the clinical features of BTC in individuals with LS and to discuss its management. Methods: We obtained data from genetically verified Japanese individuals with LS who were diagnosed at a single institution, between January 2003 and April 2021. Moreover, 21 individuals with sporadic BTC (n=15) and LS associated BTC (n=6) underwent microsatellite instability (MSI) testing. Results: Among 92 individuals with LS, 6 individuals with MLH1 variants developed BTCs (10 lesions, male/female, 2:1). The median age at diagnosis of initial BTC was 69 years (range, 34-78 years). Histological examination revealed a predominance of differentiated adenocarcinoma (89%). Then, 2 individuals had multiple BTCs. All available 7 BTC lesions showed high-frequency of microsatellite instability (MSI-H). MLH1 carriers showed a 7.2% cumulative risk of BTC development at an age of 70 years. Five of the six individuals died of BTC. Conclusions: MSI analysis could facilitate LS identification in individuals with BTC. Surveillance for BTC should be considered for MLH1 carriers in Japan.
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Pancreatic cancer has poor prognosis despite the various developed multimodal treatment strategies. Currently, neoadjuvant chemotherapy and immunotherapy have attracted substantial attention as effective treatment strategies. However, amplifying immune response with existing treatments is difficult. We developed telomerase-specific oncolytic adenoviruses (OAs), including OBP-301 that is currently tested in a clinical trial of combined anti-PD-1 antibody and p53-armed OBP- 301 variant(OBP-702). OAs have immune-modulation functions and induce CD8+ T cells into tumors by releasing immunogenic cell death markers, such as extracellular adenosine triphosphate. Here, we investigated the effectiveness of OBP- 702 in pancreatic cancer treatments, focusing on the influence on CD8+ memory T cells.
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Viroterapia Oncolítica , Neoplasias Pancreáticas , Telomerasa , Humanos , Adenosina Trifosfato/metabolismo , Adenoviridae/genética , Adenoviridae/metabolismo , Linfocitos T CD8-positivos , Línea Celular Tumoral , Genes p53 , Células T de Memoria , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Telomerasa/genética , Telomerasa/metabolismo , Proteína p53 Supresora de Tumor/genética , Ensayos Clínicos como Asunto , Neoplasias PancreáticasRESUMEN
Immune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) antibody, provide improved clinical outcome in certain cancers. However, pancreatic ductal adenocarcinoma (PDAC) is refractory to PD-1 blockade therapy due to poor immune response. Oncolytic virotherapy is a novel approach for inducing immunogenic cell death (ICD). We demonstrated the therapeutic potential of p53-expressing telomerase-specific oncolytic adenovirus OBP-702 to induce ICD and anti-tumor immune responses in human PDAC cells with different p53 status (Capan-2, PK-59, PK-45H, Capan-1, MIA PaCa-2, BxPC-3) and murine PDAC cells (PAN02). OBP-702 significantly enhanced ICD with secretion of extracellular adenosine triphosphate and high-mobility group box protein B1 by inducing p53-mediated apoptosis and autophagy. OBP-702 significantly promoted the tumor infiltration of CD8+ T cells and the anti-tumor efficacy of PD-1 blockade in a subcutaneous PAN02 syngeneic tumor model. Our results suggest that oncolytic adenovirus-mediated p53 overexpression augments ICD and the efficacy of PD-1 blockade therapy against cold PDAC tumors. Further in vivo experiments would be warranted to evaluate the survival benefit of tumor-bearing mice in combination therapy with OBP-702 and PD-1 blockade.
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PURPOSE: Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2. METHODS: GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed. RESULTS: Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p < 0.0001) and less blood loss (290 mL vs 125 mL, p < 0.0001) were observed in PHP-D2, and no pancreatic fistulas were observed in PHP-D2. More lymph nodes of #11p (1 vs 1.5, p = 0.0328) and #12a lymph nodes (0 vs 1, p = 0.0034) were retrieved in PHP-D2, with no significant differences in #8a and #9 lymph nodes. Lymphatic recurrence was significantly less in PHP-D2 (p = 0.0166), and univariate and multivariate analyses showed that non-PHP-D2 was a significant risk factor for lymphatic recurrence (p = 0.0158), although there were no significant differences between non-PHP-D2 and PHP-D2 in 5-year overall survival and 5-year relapse-free survival. CONCLUSION: PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC.
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Laparoscopía , Neoplasias Gástricas , Gastrectomía/métodos , Humanos , Escisión del Ganglio Linfático/métodos , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments. METHODS: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. RESULTS: Of the 13 patients, 7, 3 and 3 patients were treated with 1010, 1011 and 1012 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8+ cells and increased PD-L1 expression. CONCLUSION: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments.
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Adenovirus Humanos/fisiología , Neoplasias Esofágicas/terapia , Viroterapia Oncolítica/métodos , Anciano , Anciano de 80 o más Años , Endoscopía , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/radioterapia , Femenino , Humanos , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Virus Oncolíticos/fisiología , Regiones Promotoras Genéticas , Telomerasa/genéticaRESUMEN
Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.
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Adenoviridae/genética , Neoplasias del Colon/terapia , Vesículas Extracelulares/trasplante , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Animales , Línea Celular Tumoral , Supervivencia Celular , Vesículas Extracelulares/virología , Células HCT116 , Humanos , Ratones , Virus Oncolíticos/genética , Tropismo Viral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Patients with extracranial tumors, like lung, breast, and skin cancers, often develop brain metastases (BM) during the course of their diseases and BM commonly represent the terminal stage of cancer progression. Recent insights in the immune biology of BM and the increasing focus of immunotherapy as a therapeutic option for cancer has prompted testing of promising biological immunotherapies, including immune cell-targeting, virotherapy, vaccines, and different cell-based therapies. Here, we review the pathobiology of BM progression and evaluate the potential of next-generation immunotherapies for BM tumors. We also provide future perspectives on the development and implementation of such therapies for brain metastatic cancer patients.
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Neoplasias Encefálicas , Viroterapia Oncolítica , Encéfalo , Neoplasias Encefálicas/terapia , Humanos , InmunoterapiaRESUMEN
Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different patterns of BMs and explored the versatility of estem cell (SC)-mediated bi-functional EGFR and DR4/5-targeted treatment in these models. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL secreting stem cells alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. This study reports mechanism based simultaneous targeting of EGFR and DR4/5 in BLBC and defines a new treatment paradigm for treatment of BM.
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Neoplasias Encefálicas , Neoplasias de la Mama , Trasplante de Células Madre Hematopoyéticas , Animales , Encéfalo/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/patología , Línea Celular Tumoral , Receptores ErbB/genética , Femenino , Humanos , Ligandos , Ratones , Receptores de Muerte Celular/metabolismoRESUMEN
Several virulence factors of Aeromonas such as hemolysin, proteases and lipases have been characterized. The relationship between these virulence factors and disease remains unclear. A 71-year-old man underwent thoracoscopic esophagectomy, lymph node dissection and Roux-en-Y reconstruction for esophageal cancer. On postoperative day 1, redness around the wound on the thoracic abdominal wall gradually enlarged and necrosis became apparent with septic shock. Necrotizing soft tissue infection was suspected and emergency surgical debridement was performed. Blood and wound cultures were positive for Aeromonas hydrophila. The strain was found to have hemolytic activity, proteolytic activity and extremely high elastolytic activity. In addition, the strain actively produced elastolytic metalloprotease, which may contribute to extensive tissue necrosis.
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Pared Abdominal/patología , Aeromonas hydrophila/aislamiento & purificación , Esofagectomía/efectos adversos , Infecciones por Bacterias Gramnegativas/diagnóstico , Infección de la Herida Quirúrgica/diagnóstico , Toracoscopía/efectos adversos , Pared Abdominal/microbiología , Pared Abdominal/cirugía , Anciano , Desbridamiento , Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/cirugía , Humanos , Masculino , Necrosis/diagnóstico , Necrosis/microbiología , Necrosis/cirugía , Índice de Severidad de la Enfermedad , Infección de la Herida Quirúrgica/microbiología , Infección de la Herida Quirúrgica/cirugíaRESUMEN
The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.
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Adenoviridae/inmunología , Antineoplásicos Inmunológicos/farmacología , Terapia Genética , Inmunomodulación , Viroterapia Oncolítica , Virus Oncolíticos/inmunología , Telomerasa/inmunología , Adenoviridae/genética , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Línea Celular Tumoral , Terapia Combinada , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Terapia Genética/efectos adversos , Terapia Genética/métodos , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Viroterapia Oncolítica/efectos adversos , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
While the importance of programmed death-ligand 1 (PD-L1), mutation burden caused by microsatellite instability (MSI), and CD8+ tumor infiltrating lymphocytes (TILs) has become evident, the significance of PD-L1 expression on prognosis still remains controversial. We evaluated the usefulness of combined markers of PD-L1 and MSI or CD8+ TILs as a prognostic biomarker in gastric cancer. A total of 283 patients with gastric cancer were reviewed retrospectively. PD-L1 expression on >5% tumor cells was defined as PD-L1-positive. PD-L1-positive rate was 15.5% (44/283). PD-L1 positivity was significantly correlated with invasive and advanced cancer and also significantly correlated with MSI, whereas no significance was observed with CD8+ TILs. Kaplan-Meier analysis showed that PD-L1 positivity significantly correlated with a poor prognosis (p = 0.0025). Multivariate analysis revealed that PD-L1 positivity was an independent poor prognostic factor (hazard ratio [HR]: 1.97, p = 0.0106) along with diffuse histological type and lymph node metastases. Combinations of PD-L1 and MSI (HR: 2.18) or CD8+ TILs (HR: 2.57) were stronger predictive factors for prognosis than PD-L1 alone. In conclusion, combined markers of PD-L1 and MSI or CD8+ TILs may be more useful prognostic biomarkers in gastric cancer, and better clarify the immune status of gastric cancer patients.
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Antígeno B7-H1/genética , Linfocitos T CD8-positivos/inmunología , Neoplasias Gástricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/sangre , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática/patología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Inestabilidad de Microsatélites , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Neoplasias Gástricas/inmunologíaRESUMEN
BACKGROUND: Lynch syndrome (LS) is a predominantly inherited syndrome caused by a pathological germline mutation in one of the mismatch repair (MMR) genes. Whether breast cancer (BC) is one of the LS-associated tumors is controversial. The aim of this retrospective cohort study was to evaluate the clinical features of BC in Japanese patients with LS. METHODS: Of 38 mutation carriers, 4 females with BC were examined in this study. RESULTS: Two of the four patients had multiple BC. Their median age at the diagnosis of BC was 63 (range, 47-84) years. The TNM (6th revision) stages of the six BCs were as follows: stage I, 33% (2/6); stage IIA, 50% (3/6); and stage IIB, 17% (1/6). Histological examination revealed four scirrhous, one papillotubular, and one medullary carcinoma. The positive ratios for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth receptor 2 (HER2) were 83.3% (5/6), 83.3% (5/6), and 16.7% (1/6), respectively. Two of the three specimens showed MSI-H and one showed MSS. These MSI-H BCs had tumor-infiltrating lymphocytes. Two of the three specimens showed an absence of MLH1 and PMS2 proteins on immunohistochemistry. The cumulative risks for a person with LS to develop BC were 4.35% at the age of 50 years, 8.70% at 60 years, and 21.5% at 70 years. CONCLUSIONS: Our study results showed BC in Japanese females with LS to be an MSI-H tumor, which was ER and PgR positive and HER2 negative.
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Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Femenino , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Japón , Inestabilidad de Microsatélites , Persona de Mediana Edad , Clasificación del Tumor , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios RetrospectivosRESUMEN
An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Oro/química , Nanopartículas del Metal/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Trastuzumab/administración & dosificación , Animales , Anticuerpos Monoclonales Humanizados/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Nanopartículas del Metal/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Gástricas/patología , Trastuzumab/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Evaluation of the blood supply to gastric conduits is critically important to avoid complications after esophagectomy. We began visual evaluation of blood flow using indocyanine green (ICG) fluorescent imaging in July 2015, to reduce reconstructive complications. In this study, we aimed to statistically verify the efficacy of blood flow evaluation using our simplified ICG method. STUDY DESIGN: A total of 285 consecutive patients who underwent esophagectomy and gastric conduit reconstruction were reviewed and divided into 2 groups: before and after introduction of ICG evaluation. The entire cohort and 68 patient pairs after propensity score matching (PS-M) were evaluated for clinical outcomes and the effect of visualized evaluation on reducing the risk of complication. RESULTS: The leakage rate in the ICG group was significantly lower than in the non-ICG group for each severity grade, both in the entire cohort (285 subjects) and after PS-M; the rates of other major complications, including recurrent laryngeal nerve palsy and pneumonia, were not different. The duration of postoperative ICU stay was approximately 1 day shorter in the ICG group than in the non-ICG group in the entire cohort, and approximately 2 days shorter after PS-M. Visualized evaluation of blood flow with ICG methods significantly reduced the rate of anastomotic complications of all Clavien-Dindo (CD) grades. Odds ratios for ICG evaluation decreased with CD grade (0.3419 for CD ≥ 1; 0.241 for CD ≥ 2; and 0.2153 for CD ≥ 3). CONCLUSIONS: Objective evaluation of blood supply to the reconstructed conduit using ICG fluorescent imaging reduces the risk and degree of anastomotic complication.