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CAR T cell design:approaching the elusive AND-gate

细胞研究（英文版） 2023年第10期33卷 739-740页

作者： Zeguo Zhao Michel Sadelain Center for Cell Engineering and Immunology Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA

Logic gating is a strategy for chimeric antigen receptor(CAR)T cell therapy to target tumor cells that lack tumor-specific antigens and prevent on-target/off-tumor *** a recent Nature article,Tousley et *** an elegant CAR T cell AND-gate design to enhance CAR T cell safety without compromising efficacy. Chimeric antigen receptor(CAR)T cells are powerful immune effectors that engage cell surface *** relative scarcity of broadly expressed,tumor-associated CAR targets has led many to investigate combinatorial antigen recognition patterns to address and reconcile the challenges of tumor heterogeneity and on-target/off-tumor toxicity.

关键词： Cancer immunotherapy immunology

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Harnessing novel engineered feeder cells expressing activating molecules for optimal expansion of NK cells with potent antitumor activity

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cellular & Molecular immunology 2022年第2期19卷 296-298页

作者： Bokyung Min Bitna Yang You-Sun Kim Gyeong Min Park HyunAh Kim Hyojin Kim Eun-Ji Kim Yu Kyeong Hwang Eui-Cheol Shin Sungyoo Cho BioMedical Science and Engineering Interdisciplinary Program KAISTDaejeonKorea Cell Therapy Research Center GC LabCellYonginKorea Laboratory of Immunology and Infectious Diseases Graduate School of Medical Science and EngineeringKAISTDaejeonKorea

Natural killer(NK)cells play an important role in the antitumor immune response as the major cytotoxic lymphocytes in the innate immune *** cells without any genetic modifications have been used for both autologous and allogeneic ***,many reports have suggested that allogeneic NK cells can reduce the recurrence of disease and improve survival through a graft-versus-leukemia effect without GVHD[1,2].

关键词： killer expressing optimal

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Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

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Nucleic Acids Research 2024年第11期52卷 6472-6489页

作者： Marie Gaela, Venus Hsia, Hsuan-Yu Joseph, Nithila A. Tzeng, Wan-Yi Ting, Pin-Chao Shen, Yi-Ling Tsai, Chia-Tsen Boudier, Thomas Chen, Liuh-Yow Molecular and Cell Biology Taiwan International Graduate Program Academia Sinica Graduate Institute of Life Sciences National Defense Medical Center Taipei 11529 Taiwan Institute of Molecular Biology Academia Sinica Taipei 11529 Taiwan Insitute of Molecular and Cellular Biology National Taiwan University Taipei 106319 Taiwan Department and Graduate Institute of Microbiology and Immunology National Defense Medical Center Taipei 11490 Taiwan CENTURI multi-engineering platform Aix-Marseille Université Marseille 13288 France

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers. © The Author(s) 2024.

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Interleukin-10 production by innate lymphoid cells restricts intestinal inflammation in mice

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Mucosal immunology 2025年第3期18卷 643-655页

作者： Li, Jing Jacobse, Justin Pilat, Jennifer M. Kaur, Harsimran Gu, Weihong Kang, Seung Woo Rusznak, Mark Huang, Hsin-I Barrera, Julio Oloo, Pauline A. Roland, Joseph T. Hawkins, Caroline V. Pahnke, Andrew P. Khalil, Marian Washington, M.Kay Wilson, Keith T. Williams, Christopher S. Peebles, R.Stokes Konnikova, Liza Choksi, Yash A. Hammer, Gianna Elena Lau, Ken S. Goettel, Jeremy A. Department of Pathology Microbiology and Immunology Vanderbilt University Medical Center Nashville TN United States Department of Medicine Division of Gastroenterology Hepatology and Nutrition Vanderbilt University Medical Center Nashville TN United States Willem-Alexander Children's Hospital Department of Pediatrics Leiden University Medical Center Leiden Netherlands Veterans Affairs Tennessee Valley Healthcare System Nashville 37212 TN United States Program in Cancer Biology Vanderbilt University School of Medicine Nashville TN United States Program in Chemical and Physical Biology Vanderbilt University School of Medicine Nashville TN United States Department of Pediatrics Yale Medical School New Haven 06520 CT United States Department of Cell and Developmental Biology Vanderbilt University School of Medicine Nashville TN United States Department of Internal Medicine Vanderbilt University Medical Center Nashville TN United States Department of Pathology Division of Microbiology and Immunology University of Utah Salt Lake City 84112 UT United States Department of Surgery Vanderbilt University Medical Center Nashville TN United States Epithelial Biology Center Vanderbilt University Medical Center Nashville TN United States Center for Mucosal Inflammation and Cancer Vanderbilt University Medical Center Nashville TN United States Department of Immunobiology Yale School of Medicine New Haven 06520 CT United States Center for Systems and Engineering Immunology Yale School of Medicine New Haven 06520 CT United States Human and Translational Immunology Program Yale School of Medicine New Haven 06520 CT United States Program in Translational Biomedicine Yale School of Medicine New Haven 06520 CT United States Department of Obstetrics Gynecology and Reproductive Sciences Yale School of Medicine New Haven 06520 CT United States Center for Computational Systems Biology Vanderbilt University Nashville TN United States Vanderbilt Institut

Interleukin-10 (IL-10) is an immunomodulatory cytokine critical for intestinal immune homeostasis. IL-10 is produced by various immune cells but IL-10 receptor signaling in intestinal CX₃CR1⁺ mononuclear phagocytes is necessary to prevent spontaneous colitis in mice. Here, we utilized fluorescent protein reporters and cell-specific targeting and found that Rorc-expressing innate lymphoid cells (ILCs) produce IL-10 in response to anti-CD40-mediated intestinal inflammation. Deletion of Il10 specifically in Rorc-expressing ILCs led to phenotypic changes in intestinal macrophages and exacerbated both innate and adaptive immune-mediated models of experimental colitis. The population of IL-10⁺ producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of the NCR⁺ subtype. Interestingly, Ccl26 was enriched in IL-10⁺ ILCs and was markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX₃CR1, we employed RNA in situ hybridization and observed increased numbers of ILCs in close proximity to Cx3cr1-expressing cells under inflammatory conditions. Finally, we generated transgenic Rorc^tdTomato reporter mice that faithfully marked RORγt⁺ cells that could rescue disease pathology and aberrant macrophage phenotype following adoptive transfer into mice with selective Il10 deficiency in ILC3s. These results demonstrate that IL-10 production by a population of ILCs functions to promote immune homeostasis in the intestine possibly via direct effects on intestinal macrophages. © 2025 The Author(s)

关键词： CCL26 CX3CR1 IBD IL-10 ILC3

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Derivation of totipotent-like stem cells with blastocyst-like structure forming potential

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细胞研究（英文版） 2022年第6期32卷 513-529页

作者： Yaxing Xu Jingru Zhao Yixuan Ren Xuyang Wang Yulin Lyu Bingqing Xie Yiming Sun Xiandun Yuan Haiyin Liu Weifeng Yang Yenan Fu Yu Yu Yinan Liu Rong Mu Cheng Li Jun Xu Hongkui Deng MOE Engineering Research Center of Regenerative Medicine School of Basic Medical SciencesState Key Laboratory of Natural and Biomimetic DrugsPeking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and DifferentiationCollege of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijingChina School of Life Sciences Center for BioinformaticsCenter for Statistical SciencePeking UniversityBeijingChina Department of Rheumatology and Immunology Peking University Third HospitalBeijingChina Beijing Vitalstar Biotechnology Co. LtdBeijingChina Program for Cancer and Cell Biology Department of Human AnatomyHistology and EmbryologySchool of Basic Medical SciencesPKU International Cancer Institute MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs Peking University Health Science CenterBeijingChina Department of Cell Biology School of Basic Medical SciencesPeking University Stem Cell Research CenterPeking University Health Science CenterPeking UniversityBeijingChina

It is challenging to derive totipotent stem cells in vitro that functionally and molecularly resemble cells from totipotent ***,we report that a chemical cocktail enables the derivation of totipotent-like stem cells,designated as totipotent potential stem(TPS)cells,from 2-cell mouse embryos and extended pluripotent stem cells,and that these TPS cells can be stably maintained long term in *** cells shared features with 2-cell mouse embryos in terms of totipotency markers,transcriptome,chromatin accessibility and DNA methylation *** vivo chimera formation assays show that these cells have embryonic and extraembryonic developmental potentials at the single-cell ***,TPS cells can be induced into blastocyst-like structures resembling preimplantation mouse ***,inhibition of HDAC1/2 and DOT1L activity and activation of RARγ signaling are important for inducing and maintaining totipotent features of TPS *** study opens up a new path toward fully capturing totipotent stem cells in vitro.

关键词： Self-renewal Totipotent stem cells

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Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates

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Biophysical Journal 2025年第10期124卷 1562-1586页

作者： Choe, Mangyu Einav, Tal Phillips, Rob Titov, Denis V. Department of Nutritional Sciences and Toxicology University of California Berkeley Berkeley California United States Department of Molecular and Cell Biology University of California Berkeley Berkeley California United States Center for Computational Biology University of California Berkeley Berkeley California United States Division of Biology and Biological Engineering California Institute of Technology Pasadena California United States Department of Physics California Institute of Technology Pasadena California United States Basic Sciences Division and Computational Biology Program Fred Hutchinson Cancer Research Center Seattle WA United States Center for Vaccine Innovation La Jolla Institute for Immunology La Jolla California United States

Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase and phosphofructokinase by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining hexokinase and phosphofructokinase enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes. © 2025 Biophysical Society

关键词： allosteric feedback glycolysis metabolism modeling

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Function and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors

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Immuno-Oncology and Technology 2020年 8卷 2-11页

作者： Feucht, J. Sadelain, M. Center for Cell Engineering and Immunology Program Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York United States

T cells engineered to express chimeric antigen receptors (CARs) specific for CD19 have yielded remarkable clinical outcomes in patients with refractory B-cell malignancies. The first CARs to be approved by the US Food and Drug Administration and the European Medicines Agency are CD19 CARs that comprise either CD28/CD3ζ or 4-1BB/CD3ζ dual-signalling domains. While their efficacy and safety profiles in patients with B-cell malignancies are comparable overall, the functional properties these two CAR designs impart upon engineered T cells differ significantly. Remarkably, alternative costimulatory domains have not, to date, superseded these foundational designs. Rather, recent CAR advances have focused on perfecting the original CD28- and 4-1BB-based CD19 CARs by calibrating strength of activation, pre-empting T-cell exhaustion and increasing the functional persistence of CAR T cells. This article reviews the essential biological properties of these first-in-class prototypes and their recent evolution. © 2020 The Authors

关键词： 4-1BB cancer immunotherapy CAR therapy CD19 CD28 chimeric antigen receptors immune-oncology

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NOTCH and CAR Signaling Control T cell Lineage Commitment from Pluripotent Stem cells

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BLOOD 2020年 136卷 30-30页

作者： Van der Stegen, Sjoukje Lindenbergh, Pieter Petrovic, Roseanna Whitlock, Benjamin Clarke, Raedun Valamehr, Bahram Riviere, Isabelle Sadelain, Michel Center for Cell Engineering Memorial Sloan Kettering Cancer Center New York NY Fate Therapeutics Inc. San Diego CA Fate Therapeutics Inc. San Diego CA Cell Therapy and Cell Engineering Facility Memorial Sloan Kettering Cancer Center New York NY Center for Cell Engineering and Immunology Program Memorial Sloan Kettering Cancer Center New York City NY

Chimeric Antigen Receptor (CAR) T cells are a new treatment paradigm for relapsed/refractory hematopoietic malignancies. However, their autologous nature imposes manufacturing constraints that can delay CAR T cell availability and increase their cost. We previously established proof of principle that αβ T cell-derived induced pluripotent stem cells (TiPSCs) can provide a self-renewing source for in vitro CAR T cell production (Themeli, Nat Biotechnol, 2013). The use of cloned TiPSC further enhances the feasibility of verifying genome integrity of the genetically engineered stem cells and should in principle yield highly homogenous cell products. Using αβ T cell-derived TiPSCs transduced with a well-defined CD19-specific CAR (1928z; Park, NEJM, 2018), we previously demonstrated that TiPSCs can be differentiated into CAR T cells. These T cells retained their endogenous T cell receptor (TCR) and also displayed characteristics of innate lymphoid cells. We have now examined how the timing of CAR expression as well as the CAR signaling strength influence T cell lineage commitment, enabling better control towards αβ T cell lineage commitment. αβ T cell lineage development depends in part on a precisely orchestrated interactions between NOTCH and (pre)TCR signaling, the timing and strength of which are crucial for αβ lineage commitment. Because TiPSCs harbor rearranged TCRα and TCRβ genes, mature TCR expression occurs earlier than if it required VDJ recombination, skewing differentiation towards acquiring innate features including CD4 - CD8 - double-negative or CD8αα single-positive phenotypes. We show that providing strong NOTCH stimulation counteracts the effects of early antigen receptor expression, facilitating CD4 + CD8αβ + double positive (DP) formation. We hypothesized that CAR signaling in the absence of ligand binding (tonic signaling) may mimic a TCR signal, the strength and timing of which could re-direct lineage commitment. We therefore investigated CARs providi

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Targeted Integration of a CAR at a Novel Genomic Safe Harbor Directs Potent Therapeutic Outcomes

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BLOOD 2020年 136卷 28-28页

作者： Odak, Ashlesha Yuan, Han Feucht, Judith Mansilla-Soto, Jorge Eyquem, Justin Leslie, Christina Sadelain, Michel Weill Cornell Graduate School Weill Cornell Medicine New York NY Center for Cell Engineering Memorial Sloan Kettering Cancer Center New York NY Computational Biology Program Memorial Sloan Kettering Cancer Center New York NY Calico Life Sciences San Francisco CA Center for Cell Engineering and Immunology Program Memorial Sloan Kettering Cancer Center New York City NY University of California San Francisco San Francisco CA

Chimeric receptor antigen (CAR)-T cell therapy using CARs specific for CD19 have been remarkably successful for treating chemo-refractory/relapsed B cell malignancies. These successes not withstanding, therapeutic outcomes between patients are variable and occasional cases of clonal expansion of the transduced T cells have been observed, albeit without leukemic transformation. These issues are cause for concern and need to be addressed to achieve better and safer therapeutic outcomes. Clonal expansion due to insertional mutagenesis and variegated transgene expression due to position effects are well established to be the consequence of the semi-random integration pattern afforded by gamma-retroviral and lentiviral vectors. We previously established that integration of a CAR cDNA in the TCR alpha locus ( TRAC ) provides consistent, regulated expression of CD19 CARs and superior CAR T cell efficacy in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). Here, we identify a novel extragenic site devoid of any known function and remote from endogenous genes, i.e. a ‘genomic safe harbor’ (GSH), that can be efficiently targeted in human T cells and drives potent CAR T cell therapy in the B-ALL mouse model. To identify GSHs that could be efficiently targeted in T cells by CRISPR-Cas9 and that could also support durable transgene expression, we screened for genomic regions meeting both, GSH criteria and high chromatin accessibility in T cells as measured by ATAC-seq. In human primary T cells, we identified 379 such sites. Ten of the highest accessible sites were investigated. All showed high (>90%) cleavage efficiency and allowed for CAR cDNA targeted integration and expression which also translated into effective cytolytic activity of the CARs within a few days after transduction. However, thereafter CAR expression diminished over the course of a week at most but not all of these sites. In order to prevent possible heterochromatinization, we incorporated chromatin

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A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T cells in Adult Patients with Relapsed or Refractory B-cell Malignancies

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BLOOD 2020年 136卷 43-44页

作者： Park, Jae H. Riviere, Isabelle Sikder, Devanjan S. Bermudez, Vladimir P. Senechal, Brigitte Wang, Xiuyan Auchincloss, Thomas H. Diamonte, Claudia Halton, Elizabeth Palomba, M. Lia Brentjens, Renier J. Sadelain, Michel Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Cell Therapy and Cell Engineering Facility Memorial Sloan Kettering Cancer Center New York NY Cellular Therapeutics Center Memorial Sloan Kettering Cancer Center New York NY Lymphoma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY Center for Cell Engineering and Immunology Program Memorial Sloan Kettering Cancer Center New York City NY

Background: Autologous CAR T cell therapy targeting the B-cell specific surface antigen CD19 has demonstrated favorable clinical responses in relapsed or refractory (R/B) B-cell lymphomas (BCL). However, despite 40-60% initial complete response (CR) rates, only a subset of patients experience durable remissions, and there is a need to further improve the efficacy of CAR therapies by preventing relapse and attaining a deeper CR. We hypothesized that the redundancy of CD28 and CD3V signaling in a CAR design incorporating all 3 CD3Vimmunoreceptor tyrosine-based activation motifs (ITAMs) might foster counterproductive T cell differentiation and exhaustion, and therefore created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX. In systemic ALL mouse models, 19-28z1XX CAR induced effective tumor eradication at low CAR T cell doses with improved survival compared to conventional 19-28z CAR. Further preclinical studies demonstrated that the enhanced therapeutic benefit resulted from the reduced strength of activation mediated by the 19-28z1XX CAR, achieving a favorable balance of effector and memory functions, thereby enhancing persistence of functional CAR T cells and promoting effective elimination of CD19+ leukemia at lower T cell doses than needed with 19-28z CAR T cells (Feucht J et al . Nat Med 2019). To further improve the persistence of functional CAR T cells, we screened different humanized CD19-directed scFv in the context of a 19-28z1XX CAR design and proved high specificity and functionality of 19-28z1XX CARs containing a novel humanized scFv T2 - termed 19(T2)28z1XX. Study Design and Methods: This study is a single center Phase I clinical trial of 19(T2)28z1XX in patients with R/R B-cell malignancies at Memorial Sloan Kettering Cancer center (NCT04464200). Key disease eligibility criteria include R/R diffuse large B cell lymphoma (DLBCL), high grade BCL, primary mediastinal BCL, indolent BCL and chronic

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