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Purpose We conducted a cancer vaccine clinical trial with MAGE-A4 protein. Safety, clinical response, and antigen-specific immune responses were analyzed and the prognostic factors by vaccination were investigated. Experimental design Twenty patients with advanced esophageal, stomach or lung cancer were administered MAGE-A4 vaccine containing 300 μg protein subcutaneously once every 2 weeks in six doses. Primary endpoints of this study were safety and MAGE-A4 immune responses. Results The vaccine was well tolerated. Fifteen of 20 patients completed one cycle of vaccination and two patients showed SD. A MAGE-A4-specific humoral immune response was observed in four patients who had high expression of MAGE-A4 and MHC class I on tumor cells. These four patients showed significantly longer overall survival than patients without an antibody response after vaccination (p = 0.009). Patients with tumor cells expressing high MAGE-A4 or MHC class I antigen showed significantly longer overall survival than those with low expression. Induction of CD4 and CD8T cell responses was observed in three and six patients, respectively, and patients with induction of MAGE-A4-specific IFNγ-producing CD8T cells, but not CD4T cells, lived longer than those without induction. Conclusions The CHP-MAGE-A4 vaccine was safe. Expression of MAGE-A4 and MHC class I in tumor tissue and the induction of a MAGE-A4-specific immune response after vaccination would be feasible prognostic markers for patients vaccinated with MAGE-A4.

Background Since PD-1/PD-L1 blockade has displayed clinical efficacy in esophageal cancer patients, an immunological therapeutic approach such as a cancer vaccine will be realistic in clinics. NY-ESO-1, one of cancer-testis antigens, is expressed in approximately 30% esophageal squamous cell carcinoma (ESCC). Cholesteryl pullulan (CHP) is an antigen delivery system to antigen-presenting cells including macrophages. The complex of CHP and NY-ESO-1 protein (CHP-NY-ESO-1) is a vaccine that activates CD4+ and CD8+ T cells. We aimed to evaluate clinical efficacy of the CHP-NY-ESO-1 for esophageal cancer patients after radical surgery in a randomized phase II trial. Methods 54 NY-ESO-1-expressing ESCC patients who underwent radical surgery following neoadjuvant chemotherapy of cisplatin/5-FU were randomized to two arms, CHP-NY-ESO-1 vaccine and observation as a control arm. The vaccine was composed of 200 mg full-length NY-ESO-1 protein, which was subcutaneously given 15 doses with 2 or 4-week interval for 12 months. Primary endpoints were disease-free survival (DFS) and safety. Secondary endpoints were immune-responses and overall survival (OS). 49 patients were evaluated for DFS and OS. Results DFS in 2 years are 56.0% and 58.3% in the vaccine arm and in the control. OS in 2 years are 76.0% and 79.2%, respectively. No differences were seen between the vaccine and the control group. Subgroup analysis demonstrated that T-bet+ CD8+ T cell infiltration was significantly correlated to DFS and that PD-L1-expression in tumors showed unfavorable tendency for the vaccine group. Exploratory analysis of intra-cohort correlations among the vaccinated patients revealed that 5% or more expression of NY-ESO-1 and high polymeric immunoglobulin receptor (PIGR)-gene expression in tumors were favorable factors. Conclusions The clinical trial revealed that CHP-NY-ESO-1 vaccine alone did not display clinical efficacy compared to the control. It suggested that CHP-NY-ESO-1 vaccine would be indicated to > 5% NY-ESO-1 and/or high PIGR gene-expressing esophageal tumors that are infiltrated with activated T cells. Clinical trial identification UMIN000007905. Legal entity responsible for the study The authors. Funding Japan Agency for Medical Research and Development. Disclosure All authors have declared no conflicts of interest.

Background Adoptive transfer of TCR-redirected T cells has been reported to exhibit efficacy in some patients with melanoma and sarcoma. However, cytokine release syndrome (CRS) or its relations to tumor response has not been well documented. This study aimed to evaluate clinical responses in association with the cell kinetics and CRSs after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in cancer patients. Methods We developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1/TCR sequence was mutated for high affinity with replacements of G50A and A51E in CDR2 region. This is a first-in-human clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It was designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3 + 3 cohort design. Cyclophosphamide (1,500mg/m2) were administered prior to the TCR-T cell transfer as pre-conditioning. Results Nine patients were treated with the TCR-T cells that expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days after infusion. Three patients receiving 5x109 cells developed early-onset CRSs, with elevated levels of serum IL-6, IFN-γ. The CRSs on day1 or 2 were well managed with tocilizumab treatment. Three synovial sarcoma patients exhibited tumor shrinkage and partial responses, and they all had high-expression of NY-ESO-1 in the tumor samples, namely, 75% or more. Exploratory analysis revealed that multiple chemotactic cytokines including CCL2 and CCL7, and IL-3 increased in the serum from the patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development. Conclusions The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumor responses in the patients with high-NY-ESO-1-expressing synovial sarcoma. Clinical trial identification NCT02366546. Legal entity responsible for the study The authors. Funding Japan Agency for Medical Research and Development. Disclosure All authors have declared no conflicts of interest.

Combination vaccines of the NY-ESO-1 protein complexed with cholesteryl pullulan (CHP), CHP-NY-ESO-1, and the truncated 146HER2 protein with CHP, CHP-HER2, were subcutaneously administered with the immuno-adjuvant OK-432 to eight esophageal cancer patients. Vaccination was well-tolerated. NY-ESO-1- and HER2-specific antibody responses were analyzed using the patients' sera and samples from previous single CHP-NY-ESO-1 or CHP-HER2 vaccine trial. The responses to NY-ESO-1 in the combination vaccine study were comparable to the single vaccine. For responses to HER2, there were fewer antibody responses in the combination vaccines. Although there were marked individual variations in the antibody responses to the NY-ESO-1 and HER2 antigens, the reaction patterns to these antigens were comparable within each patient. Antibodies to OK-432 were not augmented. Protein cancer vaccines targeting multiple antigens are feasible.

Patients with acute leukemia are at high risk of fungal infection, suggesting that a preventive strategy is required. Fourteen patients receiving intensive chemotherapy for acute leukemia were studied to evaluate antifungal prophylaxis using itraconazole, and the plasma concentration of the drug was measured to determine its relationship to clinical efficacy. The median age of the patients was 50 years (range, 25 to 79 years), and all patients had neutropenia (less than 500 neutrophils/mgr;l) which had lasted a median of 16 days (range, 4 to 30 days). Itraconazole was given orally at a dose of 200 mg (four capsules of 50 mg) once daily for at least 14 days. An H2-receptor antagonist was also given to prevent chemotherapy-induced gastrointestinal toxicity. Trough plasma concentrations of itraconazole and its metabolite, hydroxyitraconazole, were determined by reverse-phase high-performance liquid chromatography. The mean concentrations of itraconazole and hydroxyitraconazole on day 10 were 300 +/- 96 ng/ml (range, 131-428 ng/ml) and 776 +/- 369 ng/ml (range, 320-1582 ng/ml), respectively. There were marked inter-patient variations in both concentrations. No side effects were observed in the patients, and there was no definite fungal infection episode during this study. Daily oral administration of 200 mg of itraconazole appears to be effective as prophylaxis against fungal infection in neutropenic patients with acute leukemia. However, there were marked individual variations in the itraconazole plasma concentrations, which suggests that the plasma concentration should be monitored in patients with a risk of low absorption of this drug to adjust the dose given to an adequate level.

To clarify the clinical and hematologic features of a rare numerical chromosome abnormality, we searched for trisomy 10 in acute myelogenous leukemias (AMLs) using the database of the Japan Adult Leukemia Study Group (JALSG) AML 92 and 95. Among the sequentially registered patients of JALSG-AML 92 (655 patients) and JALSG-AML 95 (531 patients), chromosome results were obtained in 1,074 patients (90.6%), and we found 3 patients with trisomy 10 as a sole abnormality. The first patient had an AML-M1 morphology with CD7 antigen; the patient obtained complete remission (CR) with the first course of chemotherapy. The second patient had an AML-M1 morphology without expressing CD7 antigen; this patient obtained CR, but relapsed 3 months later, and underwent allogeneic bone marrow transplantation. He suffered from chronic graft-versus-host disease and expired 38 months after the AML diagnosis. The third patient had AML-M0 with CD7 positivity. He obtained CR; however, brain abscess and cerebral hemorrhage occurred. In the literature, the mean age of patients with trisomy 10 AML is 57.8 years, the gender ratio is M/F = 1.5, and the frequency of M0/M1/M2 is 85.7%. A high incidence (81.8%) of CD7 expression of leukemia cells is notable. About 73% of patients survived for greater than 12 months.

Background For the prevention of nausea/vomiting during anthracyline/cyclophosphamide (CPA) therapy for breast cancer, the use of aprepitant (AP) combined with serotonin antagonist and dexamethasone is recommended. It has been reported that AP does not influence AUC's of 4-hydro-cyclophosphamide, an active metabolite of CPA and DCE, a CPA-metabolite causing nephrotoxicity. Although, in the previous clinical reports for anthracyline/CPA, the toxicities were not significant in patients who were given AP, compared with those without AP, we have experienced several cases of severe hyponatremia probably caused by AP. Occurrence of hyponatremia during chemotherapy might be an issue to be cautious. Methods We investigated serum levels of Na in 67 breast cancer patients who received CPA-combined therapy with the use of AP or not. They all received 600 mg/m2 of CPA combined with either of doxorubicine, epirubicin, or docetaxel. Their prior electrolytes were to be within the normal range. In the first cycle, we evaluated serum Na levels before the CPA start and those of 24 h after. We defined a serum Na level lower than 135 mEq/l as ‘hyponatremia’. Results The background between the two groups, with AP and without AP, was comparable, in whom the prior Na levels were 140.0 ± 1.97 and 140.1 ± 1.88 mEq/l, in the AP group and in the non-AP group, respectively. The chemotherapies including CPA, the clinical stages, the uses of serotonin-receptor antagonist and dexamethasone were comparable between the two groups. Hyponatremia occurred in 11 of 42 (26.2%) patients in the AP group, whereas 2 of 25 patients (8.0%) in the non-AP group. Since the rate in the non-AP group was comparable with the previous reports, hyponetremia seemed to occur frequently in the AP group. The average Na level at 24 h after chemotherapy was 136.429 ± 3.94 mEq/L in the AP group and 138.68 ± 3.05 mEq/l in the non-AP group, respectively. Among 11 patients who developed hyponateremia, they were resolved within 48 h without any treatments in 10 patients and only one needed the Na replacement. The patient did not develop hyponatremia without using AP in the third cycle. Conclusions According to our cohort study, AP might frequently cause hyponatremia in the CPA-combined chemotherapy.

Background The skeleton is one of the most frequent sites for metastases in patients with advanced cancer. Several guidelines have been proposed covering diagnosis and management of skeletal metastases in patients with breast and prostate cancer. As skeletal metastases in gastric cancer are less frequent events, there have been limited reports that evaluated the incidence, influence on survival of skeletal metastases and the role of bisphosphonate in the treatment of advanced gastric cancer. Material and methods Between 2002 and 2011, we retrospectively reviewed the medical records of 138 patients with metastatic gastric cancer in our institute. We investigated incidence of skeletal metastases, percentage of patients who developed skeletal-related events (SREs) and differences in the therapeutic outcome between patients with and without skeletal metastases. Results Of the 138 patients, 23 patients (median age: 59.5 years; ranged from 29 to 76) were found to have skeletal metastases during their clinical course. Almost all patients have multiple sites of disease that appeared osteoblastic on radiography. Among them, only three (13%) patients experienced SREs (two had spinal cord compression and one had pathological fracture), because most of the patients died of systemic disease progression before the clinical development of SREs. Of the 23 patients, 18 patients (78.3%) had skeletal metastases at the time of initial diagnosis, and 5 patients (21.7%) developed skeletal metastases later in the course of their disease. For 18 patients who presented skeletal metastases at the diagnosis, the median survival time (MST) was 7.4 months, whereas it was 11 months for those without such metastases. Hematological complications, including microangiopathic hemolytic anemia (MAHA) and disseminated intravascular coagulation (DIC), occurred more often with skeletal metastases than with non-skeletal metastases (44 versus 0.9%, respectively), which may relate to the shorter survival of patients with skeletal metastases. Conclusions Our study suggests that the prognosis of gastric cancer with skeletal metastases is poor. Earlier identification and the novel treatment of skeletal metastases would be crucial for improving survival in this patient group.

Background For prevention of emesis during anthracyline (A)/cyclophosphamide(CPA) therapy for breast cancer, use of aprepitant(AP) combined with serotonin receptor antagonist(5HT3) and dexamethasone(DEX) is recommended. AP, known to function as a CYP3A4 inhibitor, has been reported to interfere with metabolism of chemotherapeutic drugs. It has been also reported that AP does not influence the AUC's of 4-OH and DCE. Although, in the previous clinical reports for AC, the toxicities were not significant in patients who were given AP, compared to those without AP, we have experienced a cases of severe hyponatremia probably related to AP. Thus, we investigated an impact of AP on Na metabolism during chemotherapy using CPA for breast cancer. Material and methods We investigated serum levels of Na in primary breast cancer patients who received CPA-combined therapy with the use of AP as anti-emesis, or not. They all received 600mg/m2 of CPA combined with either of anthracycline or docetaxel. Their ages were to be less than 65 years, and their GFR's were more than 60 ml/min/1.73m2. Their prior electrolytes were to be within normal range. In the first cycle, we evaluated serum Na levels before the CPA start and that at 24 hours after. We defined serum Na level lower than 135 mEq/L as “hyponatremia” based on previous study. We enrolled 81 patients, in whom 52 were given AP and 29 were without AP, between December 2010 and April 2012. Results The background between the two groups, with AP and without AP, were comparable, in whom the median ages were 53.0(33-64) and 53.2(38-65), and the prior Na levels were139.84 ± 1.89 mEq/L, and 140.25 ± 1.82 mEq/L, in the AP-group and in non-AP-group, respectively. The uses of 5HT3 and DEX were similar between the two groups. The incidence of CPA-induced hyponatremia was significantly higher in AP-group than in non-AP-group (26.9% v 6.9%; P =0.04). The average Na level at 24 hours after chemotherapy was 136.32 ± 3.73 mEq/L in AP-group, and 138.60 ± 2.92 mEq/L in non-AP-group. Among 14 patients who developed hyponateremia in AP-group, they were resolved without any intervention in 13, and one needed Na replacement. The patient did not develop hyponatremia without AP in the third cycle. Conclusions According to our cohort study, AP cause hyponatremia more frequently in the CPA-combined chemotherapy. Disclosure All authors have declared no conflicts of interest.