Clinical Applications of Natural Killer Cells

Natural killer (NK) cells are an essential component of the innate immune system, and they play a crucial role in immunity against malignancies. Recent advances in our understanding of NK cell biology have paved the way for new therapeutic strategies based on NK cells for the treatment of various cancers. In this section, we will focus on NK cell immunotherapy, including the enhancement of antibody‐dependent cellular cytotoxicity, the manipulation of receptor‐mediated activation, inclusion criteria based on killer cell immunoglobulin‐like receptor (KIR) ligand mismatches, and adoptive immunotherapy with ex vivo expanded chimeric antigen receptor (CAR)‐engineered or engager‐modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack any recipient tissues based on allogeneic human leukocyte antigens (HLAs), suggesting that NK‐mediated antitumor effects may be achieved without the risk of graft‐versus‐host disease (GvHD). Despite reports of clinical efficacy, the application of NK cell immunotherapy is limited. Developing strategies for manipulating NK cell products, host factors, and tumor targets are thus current subjects of diligent study. Research into the biology of NK cells has indicated that NK cell immunotherapy has the potential to become the forefront of cancer immunotherapy in the coming years

Integrated analysis of the oral and intestinal microbiome and metabolome of elderly people with more than 26 original teeth: a pilot study

Elderly subjects with more than 20 natural teeth have a higher healthy life expectancy than those with few or no teeth. The oral microbiome and its metabolome are associated with oral health, and they are also associated with systemic health via the oral-gut axis. Here, we analyzed the oral and gut microbiome and metabolome profiles of elderly subjects with more than 26 natural teeth. Salivary samples collected as mouth-rinsed water and fecal samples were obtained from 22 healthy individuals, 10 elderly individuals with more than 26 natural teeth and 24 subjects with periodontal disease. The oral microbiome and metabolome profiles of elderly individuals resembled those of subjects with periodontal disease, with the metabolome showing a more substantial differential abundance of components. Despite the distinct oral metabolome profiles, there was no differential abundance of components in the gut microbiome and metabolomes, except for enrichment of short-chain fatty acids in elderly subjects. Finally, to investigate the relationship between the oral and gut microbiome and metabolome, we analyzed bacterial coexistence in the oral cavity and gut and analyzed the correlation of metabolite levels between the oral cavity and gut. However, there were few associations between oral and gut for bacteria and metabolites in either elderly or healthy subjects. Overall, these results indicate distinct oral microbiome and metabolome profiles, as well as the lack of an oral-gut axis in elderly subjects with a high number of natural teeth

Living with a double A-Bomb surviving parent

日本語版は関連リンクhttp://hdl.handle.net/10069/33732参照のこと。平和講座アーカイブは関連リンクhttp://hdl.handle.net/10069/25531を参照のこと

Chondroitin Sulfate-Based pH-Sensitive Polymer-Modified Liposomes for Intracellular Antigen Delivery and Induction of Cancer Immunity.

Bioconjugate Chemistry. 2019, 30 (5), P.1518-152

Restrictions on monetary payments for human biological substances in Japan: The mu-shou principle and its ethical implications for stem cell research

Introduction: Restrictions on financial gains from the sale of human body parts is a leading policy issue surrounding the use of human tissues and cells. However, discrepancies exist between regulations and reality. In stem cell research, in which diverse sources of tissues and cells can be used, unclear regulations can impede research. Thus, using the Japanese system as a case study, we examined the challenges in the implementation of the “no payment” or the mu-shou principle in stem-cell research over the years. Methods: We reviewed 28 Japanese laws and governmental guidelines and summarized the scope of restrictions on payments for the donation and supply of human biological samples (HBS). Results: As part of restrictions on financial rewards, the mu-shou principle emerged in Japanese laws and administrative documents in the 1990s. Although the Japanese mu-shou generally means “free” or “gratis” in English, its interpretation in research and development settings remains ambiguous. Traditionally, this principle was used to deny remuneration to donors. However, it is also inconsistently applied while processing and transferring human tissue after donation, which creates confusion among the various stakeholders. Recent policies have interpreted the principle in multiple ways: (1) treating the use of HBS for cell-processing as a non-profit activity; (2) a flexible interpretation of the principle to broaden the scope of user payments; and (3) removal of the principle itself to allow for commercial use. Conclusions: The inconsistencies in the monetary payment requirements for HBS could hinder research and development. After scrutinizing the principle's background, an effective approach is needed that considers the concerns of the providers, users, and society alike

Fc-Binding Antibody-Recruiting Molecules for Cancer Therapy: Exploiting Endogenous IgG Without antigen–Fab Interactions

Small molecules emulating the effector functions of antibodies have potential clinical benefits because of their low immunogenicity. Antibody-recruiting molecules (ARMs) are bispecific molecules designed to redirect endogenous antibodies to targets. However, endogenous antibodies show intra/inter-patient differences regarding their concentrations and affinities, limiting the potential of ARMs. We sought to address this issue using a Fc-binding peptide instead of an antigen for antibody redirection. Fc-binding ARM (Fc-ARM) targeting folate receptor-α (FR-α) expressed on cancer cells, formed a ternary complex of Fc-ARM, FR-α, and antibody on cancer cells. The ability of this ternary complex to activate natural killer cells was positively correlated with its Fc affinity, and did not require the Fab region. Fc-ARM hitchhiked on pooled human IgG to enhance its blood retention, and suppressed tumor growth in a mouse xenograft model of human cancer. Thus, Fc-ARM has the potential to be employed as a less immunogenic alternative to therapeutic antibodies.</div

Fc-Binding Antibody-Recruiting Molecules Targeting Prostate-Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement

Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing cancer cell elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate membrane-specific antigen but did so with lower efficiency compared with Fc-ARMs targeting folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy. </div

Acute myeloid leukemia and myelodysplastic syndrome associated with a combination of immune checkpoint inhibitor and platinum‐based chemotherapy

Abstract Therapy related‐acute myeloid leukemia (t‐AML) and myelodysplastic syndrome (t‐MDS) are complications of chemotherapy and/or radiation therapy for malignant diseases. In this report, we describe a patient with advanced lung adenocarcinoma who developed autoimmune hemolytic anemia and MDS associated with a combination of atezolizumab and platinum‐based chemotherapy. The patient showed progression from t‐MDS to t‐AML 20 months after the treatment was initiated. A combination of immune checkpoint inhibitor (ICI) and chemotherapy may increase the risk of developing therapy‐related myeloid neoplasms. As the prognosis of t‐AML and t‐MDS is poorer than that of de novo AML and MDS, proper surveillance, follow‐up, and treatment are needed throughout the course of immunotherapy