Kazuhiro Yoshimura

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.

Phase I clinical trial of human vascular endothelial growth factor receptor 1 peptide vaccines for patients with metastatic renal cell carcinoma

Background:It is well known that renal cell carcinoma (RCC) represents one of the most immune-responsive cancers. Although the lack of defined antigens in RCC has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of RCC for more than 30 years.Methods:To evaluate the safety of the vascular endothelial growth factor receptor 1 (VEGFR1) peptide vaccination and its clinical outcomes, data from 18 metastatic RCC (mRCC) patients treated with VEGFR1 vaccine were collected. Toxicity assessments were performed. Clinical outcomes included assessment using CT scanning, magnetic resonance imaging or X-ray examination in accordance with the WHO Response Evaluation Criteria in Solid Tumors.Results:No patient showed any toxicities of grade 3 or greater. Of the 18 patients, 2 patients showed a partial response during treatment. Stable disease for more than 5 months was observed in eight patients with a median duration of 16.5 months (4–32 months). At the time of the analysis in this study, six patients were alive with a median follow-up of 30 months (26–36 months).Conclusion:These results suggest that VEGFR1 peptide vaccine is safe and is recommended for further trials for patients with mRCC.

Identification of Programmed Death Ligand 1-derived Peptides Capable of Inducing Cancer-reactive Cytotoxic T Lymphocytes From HLA-A24+ Patients With Renal Cell Carcinoma.

Molecular therapy targeting tumor angiogenesis has been the standard treatment for metastatic renal cell carcinoma (mRCC). However, despite their significant antitumor effects, most of patients with mRCC have not been cured. Under such circumstances, anticancer immunotherapy has been considered a promising treatment modality for mRCC, and cancer-reactive cytotoxic T lymphocytes (CTLs) are the most powerful effectors among several immune cells. However, anticancer CTLs can be inhibited by several immune inhibitory mechanisms, including the interaction between programmed death 1 (PD-1) and its ligand PD-L1, on T cells and cancer cells, respectively. Alternatively, this also means that PD-L1 could be a promising target for anticancer immunotherapy. Therefore, we searched for PD-L1-derived peptides that are applicable for anticancer vaccine for HLA-A24+ RCC patients. Among 5 peptides derived from PD-L1, which were prepared based on the binding motif to the HLA-A24 allele, both PD-L111-19 and PD-L141-50 peptides induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24+ RCC patients. Such PD-L1 peptide-stimulated CD8+ T cells showed cytotoxicity against HLA-A24+ and PD-L1-expressing RCC cells. Although IFN-&ggr; treatment increased PD-L1 expression on PD-L1low RCC cells, their sensitivity to cytotoxicity of PD-L1 peptide-stimulated CD8+ T cells varied between patients. Altogether, these results indicate that both PD-L111-19 and PD-L141-50 peptides could be candidates for peptide-based anticancer vaccines for HLA-A24+ mRCC patients.

Role of vaccine therapy for renal cell carcinoma in the era of targeted therapy

Renal cell carcinoma is the most common malignant tumor originating from the kidney. Compared with other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiotherapy. However, it is well known that renal cell carcinoma represents one of the most immune‐responsive cancers and several immunotherapeutic strategies have been investigated in the management of renal cell carcinoma with variable degrees of success. The development of immunotherapy with α‐interferon or high‐dose interleukin‐2 is the best established treatment, and is associated with durable disease control. Although the lack of defined antigens in renal cell carcinoma has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of renal cell carcinoma for more than 30 years. At present, there are three types of cell‐based vaccines in renal cell carcinoma treatment: autologous tumor‐cell vaccines, genetically modified tumor vaccines and dendritic cell‐based vaccines. A further type is peptide‐based vaccination with tumor‐associated antigens as possible targets, such as carbonic anhydrase IX, survivin and telomerase that are overexpressed in renal cell carcinoma. In the present article, we review data from completed clinical trials of vaccine therapy, and discuss future trials to assess the current knowledge and future role of vaccine therapy for renal cell carcinoma in the era of recently developed targeted therapy.

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

Pharmacotherapies for renal cell carcinoma in Japan

The standard treatment for advanced renal cell carcinoma has changed dramatically in the past decade, from cytokine therapy to targeted therapy. Since sorafenib was approved in April 2008, four tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors have become available in Japan. Most Japanese renal cell carcinoma patients are treated by urologists who are involved in not only kidney surgeries, but also targeted therapy using tyrosine kinase inhibitors, as well as mammalian target of rapamycin inhibitors. Optimal treatment methods are selected from theoretically‐based global recommendations, such as the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines; however, real‐world clinical practice might be different from that in non‐Asian countries. This might be because of different practical conditions; for example, different adverse events and efficacy profiles, different healthcare system, and so on. In the present review, we examine current pharmacotherapy for renal cell carcinoma from evidence‐based global data, and compare the reality of Japanese clinical practice to explore the importance of individualized patient therapy.

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.