Takafumi Minami

A Phase 2 Randomized Controlled Trial of Personalized Peptide Vaccine Immunotherapy with Low-dose Dexamethasone Versus Dexamethasone Alone in Chemotherapy-naive Castration-resistant Prostate Cancer

BACKGROUND It is well known that the prognosis of castration-resistant prostate cancer (CRPC) is poor, and several immunotherapeutic strategies have been applied to the clinical trials. Research on immunotherapy has been of special interest for the treatment of CRPC for years. OBJECTIVE To evaluate the safety of personalized peptide vaccine (PPV) immunotherapy and its clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS A phase 2 randomized controlled trial of PPV immunotherapy with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive CRPC began in 2008. Eligible patients (prostate-specific antigen [PSA] <10 ng/ml) were human leukocyte antigen (HLA) A02, A24, or A03 superfamily positive and had asymptomatic or minimally symptomatic CRPC. Patients were allocated (1:1) to PPV plus dexamethasone (1mg/d) or to dexamethasone (1mg/d) alone. A maximum of four HLA-matched peptides (each 3mg) was selected based on the preexisting immunoglobulin G responses against the 24 warehouse peptides and administered every 2 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PSA, progression-free survival (PFS), time to initiation of chemotherapy, and overall survival (OS) were analyzed using the Kaplan-Meier method, a log-rank test, and proportional hazard analysis. RESULTS AND LIMITATIONS Overall, 37 patients received peptide vaccinations and 35 received dexamethasone alone. The primary end point was PSA PFS, which was significantly longer in the vaccination group than in the dexamethasone group (22.0 vs 7.0 mo; p=0.0076). Median OS was also significantly longer in the vaccination group (73.9 vs 34.9 mo; p=0.00084). The relatively small number of patients enrolled is the major limitation of the study. CONCLUSIONS PPV immunotherapy was well tolerated and associated with longer PSA PFS and OS in men with chemotherapy-naive CRPC. A larger phase 3 study is needed to confirm our findings. PATIENT SUMMARY We compared clinical outcomes of the treatment with personalized peptide vaccine plus dexamethasone versus dexamethasone alone. Our data provide promising evidence of clinical benefit for peptide vaccines. TRIAL REGISTRATION UMIN-CTR: 000000959.

Sorafenib rechallenge in patients with metastatic renal cell carcinoma

Study Type – Therapy (case series)

Identification of SART3-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from prostate cancer patients with HLA-A3 supertype alleles

SART3-derived peptides applicable to prostate cancer patients with HLA-A3 supertype alleles were identified in order to expand the possibility of an anti-cancer vaccine, because the peptide vaccine candidates receiving the most attention thus far have been the HLA-A2 and HLA-A24 alleles. Twenty-nine SART3-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11, -A31, and -A33) were first screened for their recognizability by immunoglobulin G (IgG) of prostate cancer patients and subsequently for the potential to induce peptide-specific cytotoxic T lymphocytes (CTLs) from HLA-A3 supertype+ prostate cancer patients. As a result, five SART3 peptides were frequently recognized by IgG, and two of them—SART3 511-19 and SART3 734-42—efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity toward prostate cancer cells was ascribed to peptide-specific and CD8+ T cells. These results indicate that these two SART3 peptides could be promising candidates for peptide-based immunotherapy for HLA-A3 supertype+ prostate cancer patients.

Transfection of poly(I:C) can induce reactive oxygen species-triggered apoptosis and interferon-β-mediated growth arrest in human renal cell carcinoma cells via innate adjuvant receptors and the 2-5A system.

BackgroundSynthetic double-stranded RNA poly(I:C) is a useful immune adjuvant and exhibits direct antitumor effects against several types of cancers. In this study, we elucidated the mechanisms underlying the effects induced in poly(I:C)-transfected human renal cell carcinoma (RCC) cells.ResultsIn contrast to the lack of an effect of adding poly(I:C), poly(I:C) transfection drastically decreased RCC cell viability. Poly(I:C) transfection induced reactive oxygen species (ROS)-dependent apoptosis in RCC cells and decreased the mitochondrial membrane potential (ΔΨm). Treatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, suppressed apoptosis and restored the ΔΨm. Although the levels of phosphorylated γH2A.X, an indicator of DNA damage, increased in poly(I:C)-transfected RCC cells, NAC treatment decreased their levels, suggesting ROS-mediated DNA damage. Furthermore, poly(I:C) transfection increased the levels of phosphorylated p53, NOXA, and tBid. Immunoblots and assays with a panel of caspase inhibitors revealed that poly(I:C) transfection-induced apoptosis was dependent on caspase-8 and -9, as well as caspase-2. Alternatively, poly(I:C) transfection increased mRNA expression of interferon (IFN)-β, and treatment with IFN-β suppressed growth of RCC cells without apoptosis. In addition, cyclinD1 and c-Myc expression decreased in poly(I:C)-transfected RCC cells. Moreover, RNA interference experiments revealed that poly(I:C) transfection exerted apoptotic effects on RCC cells through innate adjuvant receptors and the 2-5A system, the latter of which induces apoptosis in virus-infected cells.ConclusionsThese results suggest that poly(I:C) transfection induced two types of effects against RCC cells such as apoptosis, as a result of ROS-mediated DNA damage, and IFN-β-mediated growth arrest, both of which were exerted via innate adjuvant receptors and the 2-5A system.

Pazopanib for recurrent extraosseous Ewing's sarcoma of the retroperitoneum

ES represents the second most common primary osseous malignancy in adolescents and young adults, though ES can also occur as a primary soft tissue neoplasm, which is referred to as EES. ES, EES, PNET and Askin tumors are now considered part of the ESFT, as these neoplastic diseases share similar histological and immunohistochemical characteristics, and unique nonrandom chromosomal translocations. EES is a rare disease in the adult population, and is commonly treated with multimodality therapy including multidrug chemotherapy, radiation and/or surgery in the same way as ES. Recently, the Food and Drug Administration approved pazopanib for the treatment of patients with advanced STS including EES; however, there are no reports that describe the efficacy of pazopanib for the treatment of EES. Herein, we report a case of recurrent retroperitoneal EES treated with pazopanib. A 62-year-old Japanese man consulted Kinki University Hospital, Osakasayama, Japan, with the chief complaint of progressive abdominal distension in October 2012. CT showed a bulky mass with heterogeneous enhancement in the right retroperitoneum, which involved the right hepatic lobe and the inferior vena cava (Fig. 1a). Endocrinological examination, including levels of urine and serum catecholamines, and serum cortisol and androstenedione, were all within normal ranges. We excised the tumor with the right kidney, the right hepatic lobe and a part of the inferior vena cava. Histopathological examination showed round and hyperchromatic tumor cells with scanty cytoplasm and round nuclei, which were arranged in sheets and lobules. Immunohistochemical analysis showed the tumor cells strongly immunoreactive to vimentin and CD99. Genetic analysis by FISH showed t(11;22)(q24;q12), which forms a fusion transcription factor gene, EWSR1-FLI1. Based on these findings, the final diagnosis was confirmed to be EES. Follow-up CT 2 months after surgery showed local recurrence in the interaortacaval region and a minute liver metastasis (Fig. 1b). The patient refused both multiagent chemotherapy and radiation therapy because of protracted general fatigue. Ultimately, he received pazopanib (800 mg, daily), though off label use in a chemotherapy naïve setting. One month after treatment with pazopanib, the local lesion shrank markedly with 70% reduction in size, and liver metastasis was stabilized (Fig. 1c). However, pazopanib was discontinued 2 months later, because the liver lesion progressed and a new bone metastasis was observed, though the local recurrence continued to shrink. Grade 2 hypertension and fatigue were observed as adverse events during treatment with pazopanib. The patient died of the disseminated disease in June 2013. He died of disease 8 months after diagnosis and the survival duration after starting pazopanib was 5 months. EES is a rare soft tissue neoplasm first reported in 1969, further characterized by Angervall and Enzinger in 1975. Generally, multidrug chemotherapy, including vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and etoposide (collectively called VDC/IE), is usually carried out for recurrent or unresectable EES; however, severe adverse events are frequently observed. Furthermore, EES, which primarily occurs in the retroperitoneum, has a poorer prognosis than those occurring in other sites. Recently, pazopanib was approved worldwide for recurrent or unresectable soft tissue sarcoma including EES based on the results of the pazopanib explored in soft-tissue sarcoma, a phase 3 Abbreviations & Acronyms CT = computed tomography EES = extraosseous Ewing’s sarcoma ES = Ewing’s sarcoma ESFT = Ewing’s sarcoma family of tumors FISH = fluorescence in situ hybridization PNET = primitive neuroectodermal tumor STS = soft tissue sarcoma

Identification of erythropoietin receptor-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma☆

Molecular targeting therapy with anti-angiogenic agents, including sunitinib and sorafenib, has been proven to be the first- and second-line standard treatments for metastatic renal cell carcinoma (mRCC) worldwide. Despite their significant antitumor effects, most of the patients with mRCC have not been cured. Under such circumstances, anti-cancer immunotherapy has been considered as a promising treatment modality for mRCC, and cytotoxic T lymphocytes (CTLs) are the most powerful effectors among several immune cells and molecules. Therefore, we previously conducted anti-cancer vaccine therapy with peptides derived from carbonic anhydrase-9 and vascular endothelial growth factor receptor-1 as phase-I/II trials for mRCC patients and reported their clinical benefits. Alternatively, up-regulated expression of erythropoietin (Epo) and its receptor (EpoR) in RCC has been reported, and their co-expression is involved in tumorigenesis. In order to increase options for peptide-based vaccination therapy, we searched for novel EpoR-peptides for HLA-A24(+) RCC patients. Among 5 peptides derived from EpoR, which were prepared based on the binding motif to the HLA-A24 allele, EpoR52-60 peptide had the potential to induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24(+) RCC patients. Cytotoxicity toward HLA-A24(+) and EpoR-expressing RCC cells was ascribed to peptide-specific CD8(+) T cells. These results indicate that the EpoR52-60 peptide could be a promising candidate for a peptide-based anti-cancer vaccine for HLA-A24(+) mRCC patients.

Efficacy of Ramelteon in Patients with Insomnia and Nocturia.

Objectives: To study the efficacy of ramelteon for patients with insomnia and nocturia.

Survey on lower urinary tract symptoms and sleep disorders in patients treated at urology departments

Objectives This study examined the association between sleep disorders and lower urinary tract symptoms in patients who had visited urology departments. Methods This was an independent cross-sectional, observational study. Outpatients who had visited the urology departments at the Kinki University School of Medicine or the Sakai Hospital, Kinki University School of Medicine, between August 2011 and January 2012 were assessed using the Athens Insomnia Scale and the International Prostate Symptom Score. Results In total, 1174 patients (mean age, 65.7 ± 13.7 years), with 895 men (67.1 ± 13.2 years old) and 279 women (61.4 ± 14.6 years old), were included in the study. Approximately half of these patients were suspected of having a sleep disorder. With regard to the International Prostate Symptom Score subscores, a significant increase in the risk for suspected sleep disorders was observed among patients with a post-micturition symptom (the feeling of incomplete emptying) subscore of ≥1 (a 2.3-fold increase), a storage symptom (daytime frequency + urgency + nocturia) subscore of ≥5 (a 2.7-fold increase), a voiding symptom (intermittency + slow stream + hesitancy) subscore of ≥2 (a 2.6-fold increase), and a nocturia subscore of ≥2 (a 1.9-fold increase). Conclusion The results demonstrated that the risk factors for sleep disorders could also include voiding, post-micturition, and storage symptoms, in addition to nocturia.

Therapeutic efficacy and anti-inflammatory effect of ramelteon in patients with insomnia associated with lower urinary tract symptoms

Objectives This study was conducted to examine the therapeutic efficacy and anti-inflammatory effect of ramelteon in elderly patients with insomnia associated with lower urinary tract symptoms (LUTS), who visited our urology department. Methods The study included 115 patients (102 men, 13 women) who scored ≥4 on the Athens Insomnia Scale and who wished to receive treatment. The assessment scales for therapeutic efficacy included the International Prostate Symptom Score (IPSS) for LUTS and the Insomnia Severity Index (ISI) for sleep disorders. The high-sensitivity C-reactive protein (hs-CRP) test was used to an objective assessment. The patients were treated with ramelteon (8 mg/day) for an average of 10 weeks and were then reexamined using the questionnaires and hs-CRP test to evaluate therapeutic efficacy. Results IPSS total scores declined significantly from 11.39 ± 8.78 to 9.4 ± 7.72. ISI total scores improved significantly from 11.6 ± 5.2 to 9.2 ± 5.3 (P < 0.0001). The levels of hs-CRP decreased significantly from 0.082 (standard deviation [SD] upper limit, 0.222; SD lower limit, −0.059) to 0.06 (SD upper limit, 0.152; SD lower limit, −0.032). The ISI scores ≥ 10 (n = 51) showed a weak correlation with the hs-CRP levels. Conclusion Ramelteon had a systemic anti-inflammatory effect and improved sleep disorders and LUTS, suggesting that it may be a useful treatment for patients with LUTS-associated insomnia.

Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma

&NA; Hypoxic tumor microenvironment makes cancer cells to be therapy‐resistant and hypoxia‐inducing factors (HIFs) play a central role in hypoxic adaptation. Especially, renal cell carcinoma (RCC) is often associated with von Hippel‐Lindau (VHL) gene mutations, leading to up‐regulation of HIFs. However, from a different point of view, this suggests the possibility that HIFs could be promising targets in anti‐cancer therapy. In this study, we searched for HIF‐1&agr;‐derived peptides that are able to induce RCC‐reactive cytotoxic T lymphocytes (CTLs) from HLA‐A24+ RCC patients. Among five peptides derived from HIF‐1&agr;, which were prepared based on the binding motif to the HLA‐A24 allele, a HIF‐1&agr;278–287 peptide induced peptide‐specific CTLs from peripheral blood mononuclear cells of HLA‐A24+ RCC patients most effectively. In immunoblot assays, the expression of HIF‐1&agr; was lowly detected in whole and nuclear lysates of RCC cell lines even under normoxia (20% O2), and their expression in whole lysates was increased under hypoxia (1% O2). Additionally, HIF‐1&agr;278–287 peptide‐stimulated T cells showed a higher cytotoxicity against HLA‐A24+ HIF‐1&agr;‐expressing RCC cells than against HLA‐A24− HIF‐1&agr;‐expressing RCC cells. The cytotoxicity was inhibited by the addition of HIF‐1&agr;278–287 peptide‐pulsed cold target cells. Altogether, these results indicate that the HIF‐1&agr;278–287 peptide could be a candidate for peptide‐based anti‐cancer vaccines for HLA‐A24+ RCC patients. HighlightsRenal cell carcinoma (RCC) is often associated with von Hippel‐Lindau (VHL) gene mutations, leading to up‐regulation of HIFs.From a different point of view, this suggests the possibility that HIFs could be promising targets in anti‐cancer therapy.We identified a HIF‐1&agr; 278‐287 peptide as a candidate of anti‐cancer vaccine for HLA‐A24+ RCC patients.