Renpei Kato

Phase I clinical trial of cell division associated 1 (CDCA1) peptide vaccination for castration resistant prostate cancer

Cell division associated 1 (CDCA1) was screened as an oncogene that is overexpressed on several cancers, including prostate cancer. A highly immunogenic HLA‐A*2402‐restricted epitope peptide corresponding to part of the CDCA1 protein was also identified. A phase I clinical trial was conducted for patients with castration resistant prostate cancer (CRPC) using a CDCA1 peptide vaccination. Twelve patients having HLA‐A*2402 with CRPC after failure of docetaxel chemotherapy were enrolled. They received subcutaneous administration of the CDCA1 peptide as an emulsion with Montanide ISA51VG once a week in a dose‐escalation manner (doses of 1.0 or 3.0 mg/body, six patients received each dose). The primary endpoint was safety, and the secondary endpoints were the immunological and clinical responses. Vaccination with CDCA1 peptide was well tolerated without any serious adverse events. Peptide‐specific cytotoxic T lymphocyte (CTL) responses using ELISPOT assay and dextramer assay were observed in three patients receiving the 1.0 mg dose and five patients receiving the 3.0 mg dose. The median overall survival time was 11.0 months and specific CTL reacting to CDCA1 peptide were recognized in long‐surviving patients. CDCA1‐derived peptide vaccine treatment was tolerable and might effectively induce peptide‐specific CTLs for CRPC patients. This novel peptide vaccine therapy for CRPC appears promising. (ClinicalTrials.gov number, NCT01225471).

Recent progress in immunotherapy for urological cancer

Cancer immunotherapy for urological tumors had made progress for several decades, but recent advances in immunotherapy, as therapeutic vaccines or immune checkpoint inhibitors, have drastically changed the present treatment strategy. Recently, nivolumab and atezolizumab have been approved by the Food and Drug Administration for treatment of urological cancers. Additional immune checkpoint inhibitors and vaccines are being tested in clinical trials. Despite advances in these therapeutic modalities, benefits are limited to a subset of patients. New agents and novel combinations will also continue to create new immunotherapy strategies. Further development of biomarkers for predicting response is required to achieve optimal efficacy with these therapeutic interventions.

Efficacy of Everolimus in Patients with Advanced Renal Cell Carcinoma Refractory or Intolerant to VEGFR-TKIs and Safety Compared with Prior VEGFR-TKI Treatment

OBJECTIVE Everolimus is positioned as second-line treatment for metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated retrospectively the efficacy and safety of everolimus in Japanese patients with advanced renal cell carcinoma in the clinical setting. METHODS Nineteen patients who discontinued treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors because of disease progression or adverse events were administered everolimus. We evaluated progression-free survival, overall survival and tumor response rate of everolimus treatment. We also compared laboratory abnormalities and adverse events of everolimus treatment with those of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors therapy. RESULTS In all patients, median progression-free survival was 8.4 months and median overall survival was not reached at 25 months. The best objective response was complete response in 1 patient and stable disease in 15 patients. Eleven patients (58%) were intolerant and 8 (42%) were refractory to prior vascular endothelial growth factor receptor-tyrosine kinase inhibitors treatment. Median overall survival was significantly longer (P < 0.01) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (>25 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (4.3 months), and median progression-free survival tended to be better (P= 0.06) in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant (10.0 months) than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects (2.5 months). Two patients discontinued everolimus treatment because of adverse events. CONCLUSIONS In this study, the overall survival and progression-free survival were better in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-intolerant than in vascular endothelial growth factor receptor-tyrosine kinase inhibitor-refractory subjects. The adverse event profiles of everolimus and vascular endothelial growth factor receptor-tyrosine kinase inhibitors were different. Patients intolerant to vascular endothelial growth factor receptor-tyrosine kinase inhibitors may tolerate everolimus well and have greater survival benefit from switching to everolimus than those refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitors.

Present status and future perspective of peptide‐based vaccine therapy for urological cancer

Use of peptide‐based vaccines as therapeutics aims to elicit immune responses through antigenic epitopes derived from tumor antigens. Peptide‐based vaccines are easily synthesized and lack significant side‐effects when given in vivo. Peptide‐based vaccine therapy against several cancers including urological cancers has made progress for several decades, but there is no worldwide approved peptide vaccine. Peptide vaccines were also shown to induce a high frequency of immune response in patients accompanied by clinical efficacy. These data are discussed in light of the recent progression of immunotherapy caused by the addition of immune checkpoint inhibitors thus providing a general picture of the potential therapeutic efficacy of peptide‐based vaccines and their combination with other biological agents. In this review, we discuss the mechanism of the antitumor effect of peptide‐based vaccine therapy, development of our peptide vaccine, recent clinical trials using peptide vaccines for urological cancers, and perspectives of peptide‐based vaccine therapy.

Immunotherapy with cancer peptides in combination with intravesical bacillus Calmette–Guerin for patients with non-muscle invasive bladder cancer

PurposeA phase I study using two peptide vaccines derived from M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1) demonstrated promising results for the treatment of advanced bladder cancer. Therefore, we further tested the ability of these peptides to prevent recurrence after transurethral resection of the bladder tumor in patients with non-muscle invasive bladder cancer (NMIBC).Materials and methods127 patients were enrolled in a multicenter, non-randomized phase II clinical trial. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoints were safety and immunological response. HLA-A24-restricted peptides were subcutaneously administered in addition to intravesical BCG therapy. The exploratory endpoint evaluated differences of RFS rate between HLA-A*2402-positive (A24(+)) and -negative (A24(−)) groups.ResultsA 2-year RFS rate in all patients was 74.0%. The RFS rate in the A24(+) group (n = 75) and in the A24(−) group (n = 52) were 76.0 and 71.2%, respectively. This vaccine therapy was well-tolerated and feasible. MPHOSPH1 and DEPDC1 peptide-specific cytotoxic T lymphocyte responses were observed in 75.8 and 77.5% of the A24(+) group, respectively. Patients having both peptide-specific CTL responses showed significantly better RFS than patients without CTL response (P = 0.014). In the A24(+) group, patients who had positive reaction at the injection sites (RAI) had significantly lower rates of recurrence than RAI-negative patients (P = 0.0019).ConclusionsCancer peptide vaccines in combination with intravesical BCG therapy demonstrated good immunogenicity and safety, and may provide benefit for preventing recurrence of NMIBC.

A prospective study to examine the accuracies and efficacies of prediction systems for response to neoadjuvant chemotherapy for muscle invasive bladder cancer

The present study established systems to predict the chemo-sensitivity of muscle invasive bladder cancer (MIBC) for neoadjuvant chemotherapy (NAC) with methotrexate, vinblastine, doxorubicin plus cisplatin (M-VAC) and carboplatin plus gemcitabine (CaG) by analyzing microarray data. The primary aim of the study was to investigate whether the clinical response would increase by combining these prediction systems. Treatment of each MIBC case was allocated into M-VAC NAC, CaG NAC, surgery, or radiation therapy groups by their prediction score (PS), which was calculated using the designed chemo-sensitivity prediction system. The therapeutic effect of the present study was compared with the results of historical controls (n=76 patients) whose treatments were not allocated using the chemo-sensitivity prediction system. In addition, the overall survival between the predicted to be responder (positive PS) group and predicted to be non-responder (negative PS) group was investigated in the present study. Of the 33 patients with MIBC, 25 cases were positive PS and 8 were negative PS. Among the 25 positive PS cases, 7 were allocated to receive M-VAC NAC and 18 were allocated to receive CaG NAC according to the results of the prediction systems. Of the 8 negative PS cases, 3 received CaG NAC, 1 received surgery without NAC and 4 received radiation therapy. The total clinical response to NAC was 88.0% (22/25), which was significantly increased compared with the historical controls [56.6% (43/76) P=0.0041]. Overall survival of the positive PS group in the study was significantly increased compared with the negative PS group (P=0.027). In conclusion, the combination of the two prediction systems may increase the treatment efficacy for patients with MIBC by proposing the optimal NAC regimen. In addition, the positive PS group would have a better prognosis compared with the negative PS group. These results suggest that the two prediction systems may lead to the achievement of ‘precision medicine’.

Laparoscopic nephrectomy in a patient with severe scoliosis: A case report: Nephrectomy in a case of scoliosis

Although the role of laparoscopic nephrectomy (LN) has been established, few studies have reported cases of LN in individuals with scoliosis. Here we report a case of right LN in a patient with severe right convex scoliosis. A 26‐year‐old man presented with a fever. His medical history comprised severe right convex lumbar scoliosis. CT revealed right hydronephrosis and right kidney stones. Pyelonephritis requiring nephrectomy was diagnosed. Right LN was feasible with elaborate perioperative care. The postoperative course was uneventful with no relapse of urinary tract infection.

Efficacy of Everolimus for Treating Renal Angiomyolipoma with Inferior Vena Cava Thrombus Associated with Tuberous Sclerosis: A Case Report

Here we report a case of 57-year-old woman with renal angiomyolipoma associated with tuberous sclerosis complex involving inferior vena cava thrombus. We could perform less invasive nephrectomy with thrombectomy because everolimus administration reduced the inferior vena cava thrombus. To the best of our knowledge, this is the first report the use of everolimus before performing surgery to treat renal angiomyolipoma with inferior vena cava thrombus.

MP49-13 SELECTIVE NEOADJUVANT CHEMOTHERAPY BY PREDICTION SYSTEMS IMPROVES THE CHEMO-SENSITIVITY OF THE MUSCLE INVASIVE BLADDER CANCERS

INTRODUCTION AND OBJECTIVES: To compare the rate of chemo-sensitivity in neoadjuvant chemotherapy for muscle invasive bladder cancer between historical control and this interventional prospective study by using our M-VAC and CaG prediction systems. METHODS: Muscle invasive bladder cancer patients (Stage II-III) were engaged in this study. They were assigned to M-VAC, CaG, operation or radiation therapy according to the result of the prediction system which we had already established. According to their responses to the neoadjuvant chemotherapy, we categorized the patients into two groups: 0responders0 who achieved significant tumor shrinking (>60%), and 0non-responders0 ( 60%). Patients were evaluated either 0accurate0 or 0 inaccurate0 according to a tumor shrinkage rate cut off line of a 60% decrease after chemotherapies. The primary endpoint of this study was comparison with the historical controls in terms of the rate of chemo-sensitivity and efficacy. The secondary endpoint was down staging ( pT1) and the overall survival. RESULTS: From March 2011 to July 2013, an intention-to-treat 35 cancer samples from patients were entered in this study. Seven patients M-VAC, 22 CaG, 2 operation and 4 radiation therapy were received respectively. The predicted responder rate for M-VAC was 42.9% (15/35) and for CaG was 57.1% (20/35). Moreover, 74.3% (26/35) of all patients could be expected to respond to both or either of these two regimens by applying our two prediction systems. While, in previous historical control studies (M-VAC 39, CaG 37, total 76 cases), the total predicted response rate of the 76 cases was 57.9% (44/76) (p1⁄40.09). And in the predicted 0responder0 cases, the response rate of M-VAC neoadjuvant chemotherapy was 85.7% (6/7) and CaG was 89.5% (17/19). Therefore, the combined response rate in this group was 88.5% (23/26). In the historical control cases, the observed response rate of M-VAC/CaG therapy was 59.0% (23/39)/54.1% (20/37), and combined observed response rate was 56.6% (43/76) (p1⁄40.004). Down staging and overall survival between this prospective study and the historical control were not significant statistical differences, however in overall survival this prospective study was better tendency than that of the historical control (p1⁄40.233). CONCLUSIONS: Combining the M-VAC and CaG prediction systems would improve the chemo-sensitivity for muscle invasive bladder cancers.

Neural cell adhesion molecule (CD56)-positive B cell lymphoma of the urinary bladder

CD56, the neural cell adhesion molecule (NCAM), is a member of the immunoglobulin superfamily and is associated with cell-to-cell adhesion and migration.1 Among haematological malignancies, CD56 expression has been described mainly in NK/T cell lymphoma, plasma cell myeloma and acute myeloid leukaemia, and rarely in B cell lymphomas, accounting for no more than 0.5% of all B lymphomas.2–8 Malignant lymphoma constitutes <1% of bladder neoplasms and low-grade mucosa-associated lymphoid tissue (MALT) type is most frequent.9 Herein, we describe the first case of primary CD56-positive B cell lymphoma (diffuse large B cell lymphoma, DLBCL) of the urinary system. The patient, a 60-year-old Japanese woman, presented with recurrent cystitis. Cystoscopy revealed a mass lesion in the urinary bladder. On MRI, this lesion appeared as a sessile tumour protruding into the bladder lumen at the posterior wall, with destruction of the muscularis propria. These images suggested an invasive urothelial carcinoma. Systemic CT, especially of lymph nodes, detected no other suspicious lesions. We performed transurethral biopsy of the bladder tumour after obtaining informed consent. Histologically, medium to large neoplastic cells with high nuclear/cytoplasmic ratios showed diffuse and/or relatively cohesive proliferations (figure 1A, B). Centrally located, ovoid or irregular-shaped nuclei had a finely dispersed chromatin pattern, occasionally with prominent nucleoli (centroblastic variant). Mitotic figures were numerous (98 per 10 high-power fields). …