201U253U1#803U1#904U923U173U1#511U053U663U1#793UKA2#093UHT73U69U183U2#314U1#003U1#722U642U403U363U832U1#024U88U1#524U321U833U281U613U942U2#55U48U463UHK632U082U891U591U24U09U203U53U702U2#643U472U471U682U543U49U 1#144U252U391U1#903U492U151U202U421U401U 300nMFRAX597 30nM 300nMML141 30nM 300nMPonesimod 30nM 300nMReparixin 30nM 300nMSB225002 30nM 300nMNifuroxazide 30nM 300nMSuplatast 30nM 300nMA-205804 30nM 300nMAmiloride 30nM 300nMLY2584702 30nM 300nMIlomastat 30nM 300nMO6-BG 30nMU364U236U207U286U338U345U363U182U300U350AML > normal HSPCsTargeting BIRC2/4Targeting BCL2Targeting MCL1Targeting AURKBTargeting KIF10OutcomeComplexChromosome 5Chromosome 7Chromosome 17t(3;3)11q23t(6;9)50 µm10 µmChemical screening50 µm10 µm10010208030406050604070802090100IHCHEBACSIABNo treatment controlLow mag.High mag.IHCHE100%80%60%40%20%0%BIRC2/4 inhibition and BCL2 inhibitionLow mag.High mag.69with malignant diseases carry multiple somatic mutations in a patient-specific manner. The genetic complexity and heterogene-ity in cancer/leukemia patients complicates understanding of dis-ease initiation and relapse as well as drug development for human malignancies. In our acute myeloid leukemia (AML) research, we took a multiomics approach to find therapeutic targets in AML initiating cells as compared with normal hematopoietic stem and progenitor cells. By combining genetic and chemical screening, we found five critical vulnerabilities in AML: BIRC2/4, BCL2, MCL1, AURKB, and KIF10. In the presence of multiple somatic mutations and chromosomal abnormalities in patient AML cells, BIRC2/4 inhibition resulted in efficient killing of leukemic cells in vitro. Furthermore, we took advantage of patient-derived xeno-grafts to recapitulate patient leukemic status in mice followed by in vivo treatment experiments. By using two molecular targeting drugs to which individual patients showed the highest sensitiv-peutic potential in many areas, including regenerative medi-cine and immune therapy. On a collaborative basis with individ-ual IMS research laboratories, the core facility for iPS research is aiming to put cancer immunotherapy with iPS-derived NKT cells into clinical use.The facility has operated an IMS Cell Manufacturing Unit (CMU) to produce iPS-derived human invariant NKT (Vα24+iNKT) cells under GMP (Good Manufacturing Practice)/GCTP (Good Gene, Cellular, and Tissue-based Products Manu-facturing Practice) guidelines. The safety of these iPS-Vα24+iNKT cells was confirmed by preclinical studies. The facility has fin-ished PMDA (Pharmaceuticals and Medical Devices Agency) consultation for the clinical trial of iPS-Vα24+iNKT cell-mediated head and neck cancer immunotherapy and that is currently in progress.To assess the safety of clinical trials using allogeneic trans-plantation, the facility also needed to establish a cell tracking system to enable tracing of the transplanted cells in the patient. To accomplish this, the facility focused this year on AkaBLI, an ity, we confirmed profound therapeutic efficacy, as evidenced by complete elimination of patient-derived leukemic cells in the bone marrow and spleen as well as recovery of normal hematopoietic cells. Integrative analyses of somatic mutational profiling, gene expression profiling, transcription factor binding to promoter re-gions of target genes, and drug sensitivity experiments has enabled us to identify the optimal compounds for each patient. We hope to bring this precision medicine into clinical practice in the future.all-engineered bioluminescence in vivo imaging system, and they generated human iPSCs containing the Akaluc gene by using the CRISPR/Cas9 system. Akaluc-expressing human iPS cells were further differentiated into iPS-Vα24+iNKT cells and then injected intravenously into human cytokine knock-in NSG mice. By using the IVIS imaging system, strong bioluminescence signals derived from the transplanted cells were clearly observed in the recipient mice (Figure). These results suggest that Akaluc-expressing iPS-Vα24+iNKT cells will be useful to determine residence time of transplanted cells in the patient and to establish future therapeu-tic planning.Figure: A. a whole mount bone marrow section after immunohistochemical staining with anti-human CD45 antibody. Left: no treatment control, Right: treatment with AZD5582 and ABT199.B. Lower and higher magnification images of immunohistochemical staining with anti-hCD45 antibody and HE staining. Upper: IHC CD45, Lower: HE staining.Figure: Analysis of Akaluc-expressing iPS-Vα24+iNKT cells in the mouse(A) Flow cytometry analysis of Venus-Akaluc expressing cells by comparing wild type iPS-Vα24+iNKT cells and Venus-Akaluc knock-in iPS-Vα24+iNKT cells. (B) Biolumines-cence images of mice 1 month after intravenous injection of Venus-Akaluc expressing iPS-Vα24+iNKT cells. Pictures were kindly provided by Dr. Shin-ichiro Fujii in the Labo-ratory for Immunotherapy.Humanized mouseIn the past decade, DNA sequencing revealed that patients iPS projectInduced pluripotent stem (iPS) cells possess tremendous thera-
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