Recent progress in cancer immunotherapy has been remarkable. Most striking are the clinical development and approval of immunomodulators, also known as immune checkpoint inhibitors. These monoclonal antibodies (mAb) are directed to immune checkpoint molecules, which are expressed on immune cells and mediate signals to attenuate excessive immune reactions. Although mAbs targeting tumor associated antigens, such as anti-CD20 mAb and anti-Her2 mAb, directly recognize tumor cells and induce cell death, immune checkpoint inhibitors restore and augment the antitumor immune activities of cytotoxic T cells by blocking immune checkpoint molecules on T cells or their ligands on antigen presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of immune checkpoint inhibitors in a variety of cancers. The first in class approved immune checkpoint inhibitor is ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) mAb. Two pivotal phase III randomized controlled trials demonstrated a survival benefit in patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved ipilimumab for metastatic melanoma. Several clinical trials have since investigated new agents, alone and in combination, for various cancers. In this review, we discuss the current development status of and future challenges in utilizing immune checkpoint inhibitors.

BackgroundNivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified.Case presentationWe report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8+ cells and T-bet expressing CD4+ cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases.ConclusionOur two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.

We retrospectively evaluated the outcome of administering low-dose rabbit anti-thymocyte globulin (thymoglobulin: ATG-T) to 219 patients (ATG-T group, n = 30; no-ATG-T group, n = 189) who received an initial unrelated hematopoietic stem cell transplantation (uHSCT). The median total dose of ATG-T was 1.5 mg/kg. There was no significant difference in the cumulative incidences of grade II-IV (42 vs. 38 %, P = 0.87) and grade III-IV (5 vs. 7 %, P = 0.52) acute GVHD. In patients who received uHSCT from a donor with at least one HLA allele mismatch, the cumulative incidence of extensive chronic GVHD was significantly lower in the ATG-T group than that in the no-ATG-T group (13 vs. 44 %, P = 0.02). No patient in the ATG-T group developed chronic lung dysfunction. The probabilities of 1-year, GVHD-free/relapse-free survival (GRFS) were 61 % in the ATG-T group and 35 % in the no-ATG-T group (P = 0.02). Patients in the ATG-T group discontinued immunosuppressive drugs significantly earlier than those in the no-ATG-T group (P < 0.01). The use of low-dose ATG-T did not increase the incidence of severe infectious disease. The use of low-dose ATG-T in patients who received uHSCT was associated with a superior GRFS, reflecting the reduced incidence of severe/persistent GVHD without compromising overall survival.

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The incidence of autoimmune hemolytic anemia (AIHA) is highest among the elderly, and thus it is frequently associated with co-morbidities such as diabetes mellitus (DM). However, there have been few reports on the impact of these co-morbidities on survival in patients with AIHA. Therefore, we retrospectively reviewed the records of 53 consecutive AIHA patients and assessed the impact of DM on survival. Eighteen of the 53 patients had DM. The estimated 4-year overall survival (4y-OS) for all patients was 84.9%. Infection was the most frequent cause of death, and fatal infections were exclusively observed in patients with DM. The deaths in DM patients occurred frequently within 1 year, to give significantly poor survival (4y-OS; 69.3% versus 93.6%, P=0.0064). The presence of DM was identified as the only significant risk factor for survival. A large prospective investigation is warranted to assess the impact of co-morbidities on survival in patients with AIHA.

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Recently, the prevalence of staphylococcal cassette chromosome mec (SCCmec) type IV isolates, which are the major community-acquired methicillin-resistant Staphylococcus aureus (MRSA), have increased in Japanese hospitals. The aim of this study was to elucidate the detailed molecular epidemiological features of the SCCmec type IV clones in Japanese hospitals. When 2589 MRSA isolated from four hospitals in Tokyo, Japan between 2010 and 2014 were analysed, the proportion of SCCmec type IV overtook that of type II, which was the major type of hospital-acquired MRSA in 2014. Multilocus sequence typing showed that CC1 was the most predominant clone in the SCCmec type IV isolates. The clinical departments that the patients belonged to, pulsed-field gel electrophoresis analysis and antimicrobial susceptibility profiles suggested that the origin of the CC1-SCCmec type IV (CC1-IV) clone was a community setting. Our data show that the CC1-IV clone is becoming a predominant MRSA clone in Japanese hospitals.

The prevalence of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) strains has become a serious problem worldwide. The aim of this study was to investigate the annual transitions of MRSA strains with the CA-MRSA feature, which were identified as SCCmec type IV or V, in a hospital setting in Japan. Between 2005 and 2012, MRSA strains were collected from a tertiary-care hospital in Tokyo, Japan, and SCCmec typing, detection of the virulence factors and antimicrobial susceptibility testing were conducted. The rate of detection of type II SCCmec, which is found mainly in healthcare-associated MRSA, significantly decreased from 90.0 (2005)(2006) [2005][2006] to 2.1 % (2011-2012) (P,0.01). The resistance rates of cefotaxime, levofloxacin, clarithromycin and minocycline decreased every year. The resistance rates of these antimicrobial agents for the SCCmec type IV or V strains were significantly lower than those for the SCCmec type I or II strains (P,0.01, respectively). Therefore, these results suggest that the annual transitions of the virulence factors and antibiograms in MRSA are closely related to the increase of SCCmec type IV/V strains.