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AIMS: Therapeutic drug monitoring (TDM) has led to significant improvements in individualized medical care, although its implementation in oncology has been limited to date. Tyrosine kinase inhibitors (TKIs) are a group of therapies for which TDM has been suggested. Osimertinib is one such therapy used in the treatment of epidermal growth factor receptor (EGFR) mutation-driven lung cancer. Herein, we describe a prospective pilot study involving 21 patients on osimertinib primarily as a preliminary evaluation of drug levels in a real-world setting. METHODS: Concentrations of the drug and its primary metabolites were measured with a validated liquid chromatography-mass spectrometry (LC-MS) assay across serial timepoints. As part of this study, inter-individual variability by dose and ethnicity as well as intra-individual variability across timepoints are explored. Furthermore, we attempted to validate dried blood spot (DBS)-based quantitation as an accurate alternative to plasma quantitation. RESULTS: Successful quantitation of osimertinib and primary metabolites was achieved for our subjects. Compound plasma levels were highly correlated to DBS levels. There was no significant difference in concentrations with ethnicity or dosing or intra-individual variability across timepoints. CONCLUSIONS: As such, we demonstrate that TDM for osimertinib is practical for future trials. We also validated the use of DBS as an alternative to conventional quantitation for exploration of TDM for osimertinib in larger trials and for other targeted therapies.
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Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Pruebas con Sangre Seca , Monitoreo de Drogas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Humanos , Compuestos de Anilina/sangre , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacocinética , Acrilamidas/sangre , Acrilamidas/uso terapéutico , Proyectos Piloto , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Monitoreo de Drogas/métodos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Pruebas con Sangre Seca/métodos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Cromatografía Liquida/métodos , Anciano de 80 o más Años , Adulto , Indoles , PirimidinasRESUMEN
Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.
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Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of IDH1 and IDH2 mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent IDH1 and IDH2 mutations on survival was also investigated.
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INTRODUCTION: Men's health research covers a broad range of topics. Men and women face different barriers to health, with men almost universally having a lower life expectancy than women. Access to high-quality information on men's health topics is potentially an important part of engaging men with medical services. We aim to assess the quality of men's health resources available on the internet across 4 developed countries using a tier-based rating system as well as the World Health Organisation Health on the Net (HON) standards. METHODS: The Google search engine imbedded with the Health on the Net toolbar was used to assess 357 websites across Australia, Canada, America and United Kingdom using the search term 'men's health'. The websites were further subdivided into 3 tiers by 2 independent investigators, with tier 1 websites defined as government or health organisation sponsored, tier 2 websites defined as being sponsored by health services such as private clinics and insurance providers, and tier 3 websites being websites that did not meet criteria for the first 2 tiers. RESULTS: Overall, 28% of websites were rated as tier 1, 26% as tier 2 and 46% as tier 3. The HONcode accreditation was overall 39% of tier 1 websites. The majority of websites reviewed were in the tier 3 category, and 35% of overall websites being non-health or non-medically related. DISCUSSION: The lack of 'relevant' and HONcode-accredited websites relating to men's health should be appreciated by health care professionals.
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Acceso a la Información , Información de Salud al Consumidor , Internet , Salud del Hombre , Australia , Canadá , Información de Salud al Consumidor/normas , Humanos , Masculino , Reino Unido , Estados UnidosRESUMEN
BACKGROUND: To evaluate the relative efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of neovascular age-related macular degeneration (AMD). METHODS: Systematic literature review identifying RCTs comparing anti-VEGF agents to another treatment published before June 2016. Efficacy assessed by mean change in best corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline at up to 2 years followup. Safety assessed by proportions of patients with death, arteriothrombotic and venous thrombotic events, and at least one serious systemic adverse event at up to 2 years of followup. RESULTS: Fifteen RCTs selected for meta-analysis (8320 patients). Two trials compared pegaptanib, and three trials compared ranibizumab versus control. Eight trials compared bevacizumab with ranibizumab. Two trials compared aflibercept with ranibizumab. There were no significant differences between bevacizumab and ranibizumab for BCVA at 1 or 2 years (weighted mean difference = - 0.57, 95% CI - 1.55 to 0.41, P = 0.25 and weighted mean difference = - 0.76, 95% CI - 2.25 to 0.73, P = 0.32, respectively). Ranibizumab was more effective in reducing CMT at 1 year (weighted mean difference = 4.49, 95% CI 1.13 to 7.84, P = 0.009). Risk ratios comparing rates of serious systemic adverse events at 1 and 2 years were slightly out of favour for bevacizumab. Aflibercept compared with ranibizumab demonstrated similar mean change in BCVA, reduction in CMT, and safety at 1 year. CONCLUSIONS: Bevacizumab and ranibizumab had equivalent efficacy for BCVA, while ranibizumab had greater reduction in CMT and less rate of serious systemic adverse events. Aflibercept and ranibizumab had comparable efficacy for BCVA and CMT. This provides information to balance comparable effects on vision and risk of adverse events between anti-VEGF agents.
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Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Degeneración Macular/tratamiento farmacológico , Inhibidores de la Angiogénesis/efectos adversos , Aptámeros de Nucleótidos , Bevacizumab , Humanos , Inyecciones Intravítreas , Ensayos Clínicos Controlados Aleatorios como Asunto , Ranibizumab , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
INTRODUCTION: Consolidation durvalumab following platinum-based chemoradiotherapy (CRT) significantly improved overall survival for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the PACIFIC trial. However, older patients were underrepresented in PACIFIC, and subsequent analyses suggested trends toward poorer survival and increased toxicity in patients aged ≥70 years old. We assessed the effectiveness and safety of consolidation durvalumab following CRT in older Australian patients with unresectable stage III NSCLC. MATERIALS AND METHODS: This retrospective observational study was conducted across seven sites in Sydney, Australia between January 2018 and September 2021. All adult patients with unresectable stage III NSCLC who received platinum-based chemoradiotherapy followed by at least one cycle of consolidation durvalumab were included. Older patients were defined as being ≥70 years old. RESULTS: Of 152 patients included in the analysis, 42.8% (n = 67) patients were 70 years or older. Median follow-up was 26.1 months. The two-year overall survival and median PFS was similar between older and younger patients. At two years, 74.8% (95% confidence interval [CI]: 65.4-84.2%) of patients <70 years old and 65.2% (95% CI: 53.4-77.0%) of older patients were alive (p = 0.07; hazard ratio [HR] 1.64, 95% CI: 0.95-2.81). Median progression-free survival (PFS) in patients <70 years was 30.3 months (95% CI: 22.2-38.4 months) compared with 26.7 months (95% CI: 12.8-40.6 months) in older patients (p = 0.22; HR 1.46, 95% CI: 0.80-2.65). Toxicity was also similar, with 11.5% of patients <70 years old and 18.5% of older patients experiencing grade 3-4 adverse events (AEs; p = 0.23); 16.1% and 24.6% of the patients, respectively, discontinued treatment due to toxicity (p = 0.19). Grade 3-4 AEs and treatment discontinuation were associated with Charlson Comorbidity Index >5 (p = 0.011) and chronic obstructive pulmonary disease diagnosis at presentation (p = 0.002), respectively. DISCUSSION: Older Australian patients receiving consolidation durvalumab following CRT experienced comparable outcomes to their younger peers. Comorbidity burden may be more important determinants of treatment tolerance than chronological age.
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Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Humanos , Australia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/efectos adversos , Neoplasias Pulmonares/terapia , Estudios RetrospectivosRESUMEN
Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.
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Dendritic cells can take up exogenous tumor antigens and present their antigenic epitopes to CD8⺠T cells (T(CD8âº)), a process called cross-presentation. Cross-presentation is especially important in antitumor immunity because tumor cells, although carrying tumor antigens, do not activate naive T cells efficiently because of a lack of co-stimulatory molecules. Our group has recently shown that influenza A virus (IAV) infection of allogeneic cells lead to enhanced cross-priming of T(CD8âº) specific to cellular antigens. To develop this into a potential vaccine strategy, in this study, we have systematically investigated the numbers of allogeneic cells infected by IAV, IAV doses and their infectious activity, the length of in vitro infection and other associated factors. We have defined the optimal immune-enhancing conditions and we have also shown in vivo that such enhanced cross-priming did lead to enhanced tumor protection. The knowledge should be useful for developing more robust cancer vaccine.
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Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer , Células Dendríticas/inmunología , Virus de la Influenza A/inmunología , Melanoma Experimental/terapia , Infecciones por Orthomyxoviridae/inmunología , Animales , Antígenos de Neoplasias/inmunología , Efecto Espectador/inmunología , Células Cultivadas , Reactividad Cruzada , Células Dendríticas/virología , Virus de la Influenza A/patogenicidad , Melanoma Experimental/inmunología , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Trasplante de NeoplasiasRESUMEN
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.
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Platinum-based chemotherapy combined with anti-PD-1 or PD-L1 monoclonal antibodies (mAbs) is now standard first-line therapy for mNSCLC patients without sensitizing driver mutations. Anti-PD-1 and anti-PD-L1 mAbs are considered to be equivalent in efficacy. In the absence of head-to-head randomized control trials (RCTs), we utilized network meta-analysis (NWM) to provide an indirect comparison of their efficacy. A systematic literature review and NWM were performed using RCTs that investigated anti-PD-1 or PD-L1 mAbs ± chemotherapy in patients with mNSCLC in the first-line setting. The primary outcome was comparative overall survival (OS), while secondary outcomes were comparative progression-free survival (PFS), objective response rate (ORR), and rate of grade 3 and higher toxicities. We identified 24 RCTs. Patients treated with anti-PD-1 mAb + chemotherapy compared with anti-PD-L1 mAb + chemotherapy showed superior mOS, mPFS, and ORR with a similar rate of grade 3 and higher toxicities. This difference in mOS was most pronounced in the PD-L1 TPS 1-49% population. The two mAbs were equivalent as single agents. Anti-PD-1 mAb + chemotherapy improved mOS when compared to anti-PD-1 mAb monotherapy, whereas anti-PD-L1 mAbs + chemotherapy did not when compared to anti-PD-L1 mAb monotherapy. Head-to-head RCTs are warranted in the future.
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BACKGROUND: Glioblastomas are the most common and fatal primary brain malignancy in adults. There is a growing interest in identifying the molecular mechanisms of these tumors to develop novel treatments. Glioblastoma neo-angiogenesis is driven by VEGF, and another potential molecule linked to angiogenesis is PSMA. Our study suggests the potential for an association between PSMA and VEGF expression in glioblastoma neo-vasculature. METHODS: Archived IDH1/2 wild-type glioblastomas were accessed; demographic and clinical outcomes were recorded. PSMA and VEGF expression by IHC were examined. Patients were dichotomized into PSMA expression high (3+) and low (0-2+) groups. The association between PSMA and VEGF expression was evaluated using Chi2 analysis. OS in PSMA high and low expression groups were compared using multi-linear regression. RESULTS: In total, 247 patients with IDH1/2 wild-type glioblastoma with archival tumor samples (between 2009-2014) were examined. PSMA expression correlated positively with VEGF expression (p = 0.01). We detected a significant difference in median OS between PSMA vascular endothelial expression high and low groups-16.1 and 10.8 months, respectively (p = 0.02). CONCLUSION: We found a potential positive correlation between PSMA and VEGF expression. Secondly, we showed a potential positive correlation between PSMA expression and overall survival.
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Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival. Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis. Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2-4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01). Conclusions: Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.
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The initiation of antitumor immunity relies on dendritic cells (DCs) to cross-present cell-associated tumor Ag to CD8(+) T cells (T(CD8+)) due to a lack of costimulatory molecules on tumor cells. Innate danger signals have been demonstrated to enhance cross-priming of T(CD8+) to soluble as well as virally encoded Ags; however, their effect on enhancing T(CD8+) cross-priming to cell genome-encoded Ags remains unknown. Furthermore, influenza A virus (IAV) has not been shown to enhance antitumor immunity. Using influenza-infected allogeneic cell lines, we show in this study that T(CD8+) responses to cell-associated Ags can be dramatically enhanced due to enhanced T(CD8+) expansion. This enhanced cross-priming in part involves TLR7- but not TLR3-mediated sensing of IAV and is entirely dependent on MyD88 and IFN signaling pathways. We also showed that the inflammasome-induced IL-1 and IFN-γ did not play a role in enhancing cross-priming in our system. We further demonstrated in our ex vivo system that CD8(+) DCs are the only APCs able to prime TCR-transgenic T(CD8+). Importantly, plasmacytoid DCs and CD8(-) DCs were both able to enhance such priming when provided in coculture. These observations suggest that IAV infection of tumor cells may facilitate improved cross-presentation of tumor Ags and may be used to augment clinical vaccine efficacy.
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Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Reactividad Cruzada/inmunología , Interferón Tipo I/inmunología , Glicoproteínas de Membrana/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptor Toll-Like 7/inmunología , Animales , Presentación de Antígeno/inmunología , Antígenos de Neoplasias/inmunología , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/inmunología , Ensayo de Inmunoadsorción Enzimática , Virus de la Influenza A/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inmunología , Reacción en Cadena de la Polimerasa , Transducción de Señal/inmunologíaRESUMEN
Six four-coordinated complexes of the chemical formulae [Hg(2-N CH2COOCH2CH3-21-H-NCTPP)X] with X = Cl (5), Br (6), I (7), [Hg(2-NCH3-21-H-NCTPP)Cl] (4) and [Hg(2-NCH2COOCH2C6H5-21-H-NCTPP)X] with X = Cl (8), I (9) are synthesized and structurally determined. The bond path for the weak η1-H(17)-C(17)Hg agostic interactions between the Hg center and H(17) in complexes 4-9 was a through-space interaction from Hg to agostic carbon [C(17)] followed by a through-bond interaction from C(17) to an agostic proton [H(17)]. The magnitude of J[Hg-H(17)] [or the agostic upfield shift Δδago of the C(17)] for these complexes increases as the halide ligand varies from iodide to chloride, ranging from 33.2 Hz (or 14.3 ppm) for I- to 36 Hz (or 15.8 ppm) for Br- and 36.9 Hz (or 16.0 ppm) for Cl-. The plot of J[Hg-H(17)] for the agostic proton H(17) versus |Δδago| for the agostic carbon atom C(17) in compounds 3-9 was linearly expressed as J[Hg-H(17)] = 2.29 |Δδago| + 0.13.
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In order to further our basic understanding of antigen processing and presentation as well as to translate that knowledge into clinically effective vaccines and immunotherapies, having appropriate tools to study MHC class I-peptide presentation is highly desirable. Current methods are based upon HPLC fractionation of extracted peptides, monoclonal Ab, multivalent T cell receptors (TCR), T cell hybridomas, TCR transgenic cells, and T cell lines. However, each of these is associated with problems that make them either difficult to apply generally or too insensitive to adequately quantitate antigen presentation. We have developed a method based upon intracellular cytokine staining (ICS) that dynamically and relatively quantitates MHC class I-peptide presentation to CD8+ T cells in a manner that is both widely applicable and highly sensitive. It is well-suited to assess antigen presentation in its early stages, does not require fixation nor labeling of antigen presenting cells (APC), can be used to examine cross-presentation, and is able to directly employ ex vivo T cells which obviates the need for the development and maintenance of T cell lines and hybridomas. Our method represents a simple yet powerful tool that others interested in studying antigen processing and presentation should find of great practical value.
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Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Animales , Brefeldino A/química , Colorantes/química , Citocinas/aislamiento & purificación , Pruebas Inmunológicas de Citotoxicidad , Células Dendríticas/inmunología , Femenino , Citometría de Flujo , Virus de la Influenza A/inmunología , Cinética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Virus Vaccinia/inmunologíaRESUMEN
Expression of the cancer/germ-line antigen NY-ESO-1 by tumors elicits spontaneous humoral and cellular immune responses in some cancer patients. Development of vaccines capable of stimulating such comprehensive immune responses is desirable. We have produced recombinant lentivectors directing the intracellular synthesis of NY-ESO-1 (rLV/ESO) and have analyzed the in vivo immune response elicited by this vector. Single injection of rLV/ESO into HLA-A2-transgenic mice elicited long-lasting B and T cell responses against NY-ESO-1. CD8+ T cells against the HLA-A2-restricted peptide NY-ESO-1(157-165) were readily detectable ex vivo and showed restricted TCR Vbeta usage. Moreover, rLV/ESO elicited a far greater anti-NY-ESO-1(157-165) CD8+ T cell response than peptide- or protein-based vaccines. Anti-NY-ESO-1 antibodies were rapidly induced after immunization and their detection preceded that of the antigen-specific CD8+ T cells. The rLV/ESO also induced CD4+ T cells. These cells played an essential role as their depletion completely abrogated B cell and CD8+ T cell responses against NY-ESO-1. The induced CD4+ T cells were primarily directed against a single NY-ESO-1 epitope spanning amino acids 81-100. Altogether, our study shows that rLV/ESO induces potent and comprehensive immune responses in vivo.