73CreationofinvivomodelsHSCsImmune cellsLeukemic cellsUnderstanding how leukemia initiatesand relapse occurs.In vivo validation of efficacy and safety using xenograft for leukemia and normalhuman immunityMulti-omicsfortargetexplorationHSCsLeukemiaT cellsSmall molecules, CAR-T cellsMembraneInvivo/invitrovalidationoftherapeuticsCD25FLT3HCKBCL2MCLMitochondriaCytosolBIRC/IAPChr.７3q2111q2311q23IDH1FLT3FLT3TP53CBL, NRASNucleus1with normal human hematopoiesis and immunity to study the differentiation and function of immature human stem and pro-genitor cells. We have also recapitulated patients’ leukemic status in immune-deficient mice using patient samples. In each patient, there must be specific reasons why immune surveillance has failed. Nevertheless, the mystery of suppressed human immunity by leukemic cells has yet to be addressed.In this project, our first step has been to functionally iden-tify normal and malignant human stem cells via xenogeneic transplantation. Then we perform multi-omics to determine the distinction between the two stem cell types. This approach has enabled us to find therapeutic molecules expressed by malignant antigen-specific tumor rejection under certain conditions, however the tumors often evade the immune network. To ac-complish this escape, tumors may mediate immunosuppression through various soluble and cellular mechanisms. Understanding the role of the immune system in the tumor microenvironment (TME) will lead to a variety of specific approaches designed to initiate or enhance antitumor immunity (Figure). The groups in cancer immunology are using both murine models and human clinical samples from a variety of cancers to find crucial mol-ecules for therapy. Tsunoda’s group (Lab for Medical Science Mathematics) proposed a novel method of scientific discovery from omics data with deep learning. After conducting multi-omics analyses of colorectal and renal cancers, they discovered novel immunological classifications and association with poor prognoses. Nakagawa’s group (Lab for Cancer Genomics) ana-lyzed whole genome and RNAseq data from biopsy specimens of esophageal cancers before chemotherapy and demonstrated that a subfraction of immune cells and copy number alterations were as-sociated with the response to chemotherapy. Ishikawa’s group (Lab for Human Disease Models) published a new precision medicine approach targeting non-mutated survival molecules in AML. To strengthen the therapeutic effect of these small molecules, they set out to engineer T cells that could target the AML cells. Con-sidering that there is little expression of CD25 in normal HSPCs, stem cells but not by normal hematopoietic stem cells. During the last few years, we have identified therapeutic targets in different cellular organelles. Humanized mice reconstituted with normal hematopoiesis and immunity are used to assess potential adverse effects of new treatment modalities, while leukemia xenografts are essential in evaluating the treatment efficacy in multiple or-gans. We are currently trying to maximize the therapeutic impact on aggressive types of myeloid and lymphocytic leukemia by inhibiting two different molecules in different locations of patient malignant cells. Through understanding the genetic and biologi-cal heterogeneity of hematologic malignancies, we hope to trans-late curative precision medicine into the clinic in the future.they chose it as the first target. Using NSG xenograft mice, they found nice therapeutic efficacy of CD25-targeted CAR-T cells against AML, especially in presence of CXCR4. Fujii’s group (Lab for Immunotherapy) promoted their aAVC project for cancer. NY-ESO-1 is an esophageal squamous cell carcinoma antigen and WT1 is a Wilms’ tumor antigen. They established an NY-ESO-1-expressing aAVC (aAVC-NY-ESO-1) and showed immunologi-cal and anti-tumor effect using NOG mice in a preclinical study. For the aAVC-WT1, they started a Phase II clinical study as mul-ticenter joint research. In addition, Koseki’s group (Lab for Devel-opmental Genetics) has started an iPS-NKT cell clinical trial for head and neck cancer. These TR projects have been supported by an interaction between IMS and the Drug Discovery and Medical Technology Platforms (DMP).Figure: We have created an in vivo system for human immunity and leukemia. Using this system, we have identified cells responsible for disease initiation and relapse, which were then subjected to mutational and gene expression profil-ing for target exploration. As therapeutic targets, we have discovered mutated proteins, over-expressed proteins, key survival molecules in the membranes of different organelles, non-mutated vulnerabilities in mitochondria or cytosol. Distinct therapeutic targets in different patients appear to be determined by the leukemogenic events that have occurred in the nucleus. We hope that this step-wise effort, from the creation of in vivo systems to the development of therapeu-tics, will be applied not only to leukemias, but also to non-leukemic hematologic tumors and even solid tumors.Humanized mouseIn the Humanized Mice project, we have reconstituted mice Cancer ImmunologyThe immune system recognizes tumor cells and can mediate
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