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41. 发明授权

US06632789B1 Methods for modulating T cell responses by manipulating intracellular signal transduction 失效
标题翻译：通过操纵细胞内信号转导来调节T细胞应答的方法
公开(公告)号：US06632789B1
公开(公告)日：2003-10-14
申请号：US08245282
申请日：1994-04-29
申请人： Carl H. June
发明人： Carl H. June
IPC分类号： A01N6100
CPC分类号： A61K31/365 , A61K31/00 , A61K31/35
摘要： Methods for modulating T cell responses by manipulating intracellular signals associated with T cell costimulation are disclosed. The methods involve inhibiting or stimulating the production of at least one D3-phosphoinositide in a T cell. Production of D3-phosphoinositides can be manipulated by contacting a T cell with an inhibitor or activator of phosphatidylinositol 3-kinase. Inhibitors of phosphatidylinositol 3-kinase for use in the methods of the invention include wortmannin and quercetin, or derivatives or analogues thereof. The methods of the invention can further comprise modulating other intracellular signals associated with costimulation, such as protein tyrosine phosphorylation, for example by modulating the activity of a protein tyrosine kinase or a protein tyrosine phosphatase in the T cell. Inhibition of a T cell response in accordance with the disclosed methods is useful therapeutically in situations where it is desirable to inhibit an immune response to an antigen(s), for example in organ or bone marrow transplantation and autoimmune diseases. Alternatively, stimulation of a T cell response in accordance with the disclosed methods is useful therapeutically to enhance an immune response to an antigen(s), for example to stimulate an anti-tumor response in a subject with a tumor, to stimulate a response against a pathogenic agent or increase the efficacy of vaccination. Novel screening assays for identifying inhibitors or activators of phosphatidylinositol 3-kinase, which can be used to inhibit or stimulate a T cell response, are also disclosed.
摘要翻译：公开了通过操作与T细胞共刺激相关的细胞内信号调节T细胞应答的方法。所述方法包括抑制或刺激T细胞中至少一种D3-磷酸肌醇的产生。可以通过使T细胞与磷脂酰肌醇3-激酶的抑制剂或活化剂接触来操作D3-磷酸肌醇的生产。用于本发明方法的磷脂酰肌醇3-激酶的抑制剂包括渥曼青霉素和槲皮素，或其衍生物或类似物。本发明的方法还可以包括调节与共刺激相关的其它细胞内信号，例如蛋白酪氨酸磷酸化，例如通过调节T细胞中的蛋白质酪氨酸激酶或蛋白质酪氨酸磷酸酶的活性。根据所公开的方法抑制T细胞应答在需要抑制对抗原的免疫应答（例如在器官或骨髓移植和自身免疫性疾病中）的情况下是有用的。或者，根据所公开的方法刺激T细胞应答在治疗上对于增强对抗原的免疫应答是有用的，例如用于刺激患有肿瘤的受试者的抗肿瘤反应，以刺激对抗致病剂或增加疫苗的功效。还公开了用于鉴定可用于抑制或刺激T细胞应答的磷脂酰肌醇3-激酶的抑制剂或活化剂的新型筛选试验。

42. 发明申请

US20180044424A1 CAR-EXPRESSING CELLS AGAINST MULTIPLE TUMOR ANTIGENS AND USES THEREOF 审中-公开
公开(公告)号：US20180044424A1
公开(公告)日：2018-02-15
申请号：US15548202
申请日：2016-02-01
申请人： Carl H. June , Daniel J. Powell, JR. , Novartis AG , The Trustees of the University of Pennsylvania
发明人： Carl H. June , Daniel J. Powell, Jr.
IPC分类号： C07K16/28 , C07K16/32 , C07K14/54 , C12N15/113 , C07K14/725 , C07K14/55
CPC分类号： C07K16/2863 , A61K35/17 , A61K38/00 , A61K39/39558 , A61K45/06 , A61K2039/505 , A61K2039/507 , C07K14/54 , C07K14/5418 , C07K14/5443 , C07K14/55 , C07K14/7051 , C07K14/70521 , C07K14/70578 , C07K16/28 , C07K16/2803 , C07K16/30 , C07K16/32 , C07K2317/22 , C07K2317/31 , C07K2317/55 , C07K2317/565 , C07K2317/569 , C07K2317/622 , C07K2317/76 , C07K2317/92 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C12N15/113 , C12N2310/14 , C12N2310/531 , A61K2300/00
摘要： The invention provides compositions and methods for treating cancer by using immune effector cells (e.g., T cells, NK cells) engineered to conditionally express an agent which enhances the immune effector response of an immune effector cell that expresses a Chimeric Antigen Receptor (CAR). The conditional agents described herein include agents that target a cancer associated antigen, e.g., a CAR, agents that inhibit one or more checkpoint inhibitors of the immune response, and a cytokine.

43. 发明申请

US20160185861A1 METHODS OF MAKING CHIMERIC ANTIGEN RECEPTOR -EXPRESSING CELLS 审中-公开
标题翻译：制备抗原抗体接种细胞的方法
公开(公告)号：US20160185861A1
公开(公告)日：2016-06-30
申请号：US14981142
申请日：2015-12-28
申请人： Felipe Bedoya , Saba Ghassemi , Carl H. June , Bruce L. Levine , Jan J. Melenhorst , Michael C. Milone , Daniel J. Powell, JR. , Zoe Zheng
发明人： Felipe Bedoya , Saba Ghassemi , Carl H. June , Bruce L. Levine , Jan J. Melenhorst , Michael C. Milone , Daniel J. Powell, JR. , Zoe Zheng
IPC分类号： C07K16/28 , A61K35/17 , C07K14/725 , C12N5/0783 , C12N9/12 , C07K14/705
CPC分类号： C07K16/2803 , A61K35/17 , A61K2039/5156 , A61K2039/5158 , C07K14/7051 , C07K14/70517 , C07K14/70578 , C07K16/28 , C07K2317/14 , C07K2317/622 , C07K2319/03 , C07K2319/74 , C12N5/0087 , C12N5/0636 , C12N5/0638 , C12N9/1276 , C12N2501/2302 , C12N2501/2307 , C12N2501/2315 , C12N2501/51 , C12N2501/515 , C12N2510/00 , C12Y207/07049
摘要： The invention provides methods of making immune effector cells (e.g., T cells, NK cells) that can be engineered to express a chimeric antigen receptor (CAR), and compositions and reaction mixtures comprising the same.
摘要翻译：本发明提供了可以进行工程化以表达嵌合抗原受体（CAR）的免疫效应细胞（例如，T细胞，NK细胞）的制备方法，以及包含其的组合物和反应混合物的方法。

44. 发明申请

US20130101567A1 Methods to Expand a T Regulatory Cell Master Cell Bank 审中-公开
标题翻译：扩展T调节细胞主细胞库的方法
公开(公告)号：US20130101567A1
公开(公告)日：2013-04-25
申请号：US13639927
申请日：2011-03-28
申请人： James L. Riley , Carl H. June , Bruce R. Blazar , Keli Hippen
发明人： James L. Riley , Carl H. June , Bruce R. Blazar , Keli Hippen
IPC分类号： C12N5/0783
CPC分类号： C12N5/0637 , C12N2500/32 , C12N2501/04 , C12N2501/2302 , C12N2501/51 , C12N2501/515
摘要： Compositions and methods for expanding natural T regulatory cells (nTregs) without substantially sacrificing suppressive function of the cells are disclosed. Also provided are uses of the expanded nTregs for cellular therapy.
摘要翻译：公开了用于扩增天然T调节细胞（nTreg）而不显着牺牲细胞抑制功能的组合物和方法。还提供了扩大的nTregs用于细胞治疗的用途。

45. 发明申请

US20110268752A1 Inducible Regulatory T-Cell Generation for Hematopoietic Transplants 有权
标题翻译：造血移植的诱导性调节性T细胞产生
公开(公告)号：US20110268752A1
公开(公告)日：2011-11-03
申请号：US12999926
申请日：2009-06-19
申请人： James L. Riley , Carl H. June , Bruce R. Blazar , Keli Hippen
发明人： James L. Riley , Carl H. June , Bruce R. Blazar , Keli Hippen
IPC分类号： A61K35/14 , A61P37/06 , C12N5/0783
CPC分类号： A61K39/0008 , A61K39/001 , A61K2035/122 , A61K2039/5158 , C12N5/0636 , C12N5/0638 , C12N2501/065 , C12N2501/70 , C12N2501/999
摘要： The present invention provides methods and compositions for converting non-Tregs into Tregs. The converted Tregs are referred to as inducible Tregs (iTregs). The iTregs are useful for preventing, suppressing, blocking or inhibiting an immune response. For example the iTregs are useful for preventing rejection of a transplanted tissue in a human or other animal host, or protecting against graft vs host disease. The iTregs can also be used to treat autoimmune diseases.
摘要翻译：本发明提供了将非Treg转化为Treg的方法和组合物。转化的Treg被称为可诱导Treg（iTreg）。 iTregs可用于预防，抑制，阻断或抑制免疫应答。例如，iTreg可用于防止人或其他动物宿主中移植组织的排斥，或防止移植物抗宿主病。 iTreg也可用于治疗自身免疫性疾病。

46. 发明授权

US06905681B1 Methods for selectively stimulating proliferation of T cells 失效
标题翻译：选择性刺激T细胞增殖的方法
公开(公告)号：US06905681B1
公开(公告)日：2005-06-14
申请号：US09349915
申请日：1999-07-08
申请人： Carl H. June , Craig B. Thompson , Gary J. Nabel , Gary S. Gray , Paul D. Rennert
发明人： Carl H. June , Craig B. Thompson , Gary J. Nabel , Gary S. Gray , Paul D. Rennert
IPC分类号： A61K35/14 , A61K35/17 , A61K35/28 , A61K38/00 , A61K38/17 , A61K38/46 , A61K39/00 , A61K39/02 , A61K39/12 , A61K48/00 , C07K14/705 , C07K16/00 , C07K16/28 , C12N5/0783 , A61K35/26
CPC分类号： C12N5/0636 , A61K35/17 , A61K38/00 , A61K48/00 , A61K2039/505 , A61K2039/5158 , C07K14/705 , C07K14/70521 , C07K14/70532 , C07K16/00 , C07K16/2806 , C07K16/2809 , C07K16/2812 , C07K16/2815 , C07K16/2818 , C07K16/2833 , C07K16/2866 , C07K16/289 , C07K16/2896 , C07K2317/24 , C07K2317/34 , C07K2317/54 , C07K2317/55 , C07K2317/73 , C07K2317/74 , C07K2319/00 , C07K2319/30 , C12N2501/51 , C12N2501/515 , C12N2501/599 , C12N2740/16011 , C12N2795/00011
摘要： Methods for inducing a population of T cells to proliferate by activating the population of T cells and stimulating an accessory molecule on the surface of the T cells with a ligand which binds the accessory molecule are described. T cell proliferation occurs in the absence of exogenous growth factors or accessory cells. T cell activation is accomplished by stimulating the T cell receptor (TCR)/CD3 complex or the CD2 surface protein. To induce proliferation of an activated population T cells, an accessory molecule on the surface of the T cells, such as CD28, is stimulated with a ligand which binds the accessory molecule. The T cell population expanded by the method of the invention can be genetically transduced and used for immunotherapy or can be used in methods of diagnosis.
摘要翻译：描述了通过激活T细胞群并用结合辅助分子的配体刺激T细胞表面上的辅助分子来诱导T细胞群体增殖的方法。 T细胞增殖发生在没有外源生长因子或附属细胞的情况下。通过刺激T细胞受体（TCR）/ CD3复合物或CD2表面蛋白来完成T细胞活化。为了诱导活化的群体T细胞的增殖，T细胞表面上的辅助分子如CD28被与配合分子结合的配体刺激。通过本发明的方法扩增的T细胞群体可以被遗传转导并用于免疫治疗，或可用于诊断方法。

47. 发明授权

US09499629B2 Use of chimeric antigen receptor-modified T-cells to treat cancer 有权
标题翻译：使用嵌合抗原受体修饰的T细胞治疗癌症
公开(公告)号：US09499629B2
公开(公告)日：2016-11-22
申请号：US13992622
申请日：2011-12-09
申请人： Carl H. June , Bruce L. Levine , David L. Porter , Michael D. Kalos , Michael C. Milone
发明人： Carl H. June , Bruce L. Levine , David L. Porter , Michael D. Kalos , Michael C. Milone
IPC分类号： C12N5/071 , C12N5/0783 , C12N5/22 , C07K16/28 , A61K35/17 , A61K39/00 , A61K39/395 , C12N15/85 , C07K14/705 , A61K48/00 , C07K14/525 , C07K14/725 , C07K16/30 , C12N7/00 , A61K38/17 , A61K45/06
CPC分类号： C12N5/0636 , A61K35/17 , A61K38/177 , A61K38/1774 , A61K39/0011 , A61K39/39558 , A61K45/06 , A61K48/005 , A61K2039/505 , A61K2039/5156 , A61K2039/5158 , A61K2039/5256 , A61K2039/585 , C07K14/075 , C07K14/525 , C07K14/7051 , C07K14/70517 , C07K14/70521 , C07K14/70578 , C07K14/70596 , C07K16/2803 , C07K16/2896 , C07K16/30 , C07K16/3061 , C07K2317/53 , C07K2317/622 , C07K2317/76 , C07K2317/80 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/30 , C07K2319/33 , C07K2319/74 , C12N7/00 , C12N15/85 , C12N15/861 , C12N2501/51 , C12N2501/515 , C12N2510/00 , C12N2740/15034 , C12N2740/15043 , C12N2740/15071 , A61K2300/00
摘要： The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain.
摘要翻译：本发明提供了治疗人类癌症的组合物和方法。本发明涉及施用经遗传修饰的T细胞以表达CAR，其中CAR包含抗原结合结构域，跨膜结构域，共刺激信号传导区和CD3ζ信号结构域。

48. 发明授权

US09133436B2 ICOS critically regulates the expansion and function of inflammatory human Th17 cells 有权
标题翻译： ICOS严格控制炎症性人Th17细胞的扩增和功能
公开(公告)号：US09133436B2
公开(公告)日：2015-09-15
申请号：US13576249
申请日：2011-02-04
申请人： James L. Riley , Chrystal Paulos , Carl H. June , Bruce Levine
发明人： James L. Riley , Chrystal Paulos , Carl H. June , Bruce Levine
IPC分类号： C12N5/10 , A61K38/19 , A61K39/395 , C12N5/0783 , A61K35/17 , A61K39/00
CPC分类号： C12N5/0637 , A61K35/17 , A61K2039/5158 , A61K2039/57 , C12N5/0636 , C12N2501/2301 , C12N2501/2302 , C12N2501/2306 , C12N2501/2321 , C12N2501/2323 , C12N2501/51 , C12N2501/515 , C12N2501/599
摘要： The invention includes compositions and methods for generating and expanding therapeutic Th17 cells. The invention includes contacting T cells with a composition comprising a first agent that is capable of providing a primary activation signal to T cells and a second agent that is capable of activating ICOS on T cells in the presence of Th-17 polarizing agents.
摘要翻译：本发明包括用于产生和扩大治疗性Th17细胞的组合物和方法。本发明包括使T细胞与包含能够向T细胞提供主要激活信号的第一药剂和能够在Th-17偏振剂存在下在T细胞上活化ICOS的第二药剂的组合物接触。

49. 发明授权

US08415150B2 Methods for treating progressive multifocal leukoencephalopathy (PML) 有权
标题翻译：治疗进行性多灶性脑白质病（PML）的方法
公开(公告)号：US08415150B2
公开(公告)日：2013-04-09
申请号：US13201829
申请日：2010-02-24
申请人： Carl H. June , Bruce Levine , Anne Chew , Stephen J. Schuster
发明人： Carl H. June , Bruce Levine , Anne Chew , Stephen J. Schuster
IPC分类号： C12N5/00
CPC分类号： A61K35/17 , A61K39/0008 , A61K2035/122 , A61K2039/5158 , C12N5/0636 , C12N2501/51 , C12N2501/515
摘要： The present invention relates generally to the treatment of PML by infusion of activated and expanded autologous lymphocytes.
摘要翻译：本发明一般涉及通过输注活化和扩增的自体淋巴细胞来治疗PML。

50. 发明申请

US20120263693A1 Methods for Treating Progressive Multifocal Leukoencephalopathy (PML) 审中-公开
公开(公告)号：US20120263693A1
公开(公告)日：2012-10-18
申请号：US13537330
申请日：2012-06-29
申请人： Carl H. June , Bruce Levine , Anne Chew , Stephen J. Schuster
发明人： Carl H. June , Bruce Levine , Anne Chew , Stephen J. Schuster
IPC分类号： A61K35/14 , A61P35/02
CPC分类号： A61K35/17 , A61K39/0008 , A61K2035/122 , A61K2039/5158 , C12N5/0636 , C12N2501/51 , C12N2501/515
摘要： The present invention relates generally to the treatment of PML by infusion of activated and expanded autologous lymphocytes.

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