WO2014055668A1 - Compositions and methods for immunotherapy - Google Patents

Compositions and methods for immunotherapy Download PDF

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Publication number
WO2014055668A1
WO2014055668A1 PCT/US2013/063097 US2013063097W WO2014055668A1 WO 2014055668 A1 WO2014055668 A1 WO 2014055668A1 US 2013063097 W US2013063097 W US 2013063097W WO 2014055668 A1 WO2014055668 A1 WO 2014055668A1
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WO
WIPO (PCT)
Prior art keywords
antigen
cell
receptor
immunoresponsive
tumor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2013/063097
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English (en)
French (fr)
Inventor
Christopher C. KLOSS
Michael Sadelain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Memorial Sloan Kettering Cancer Center
Original Assignee
Memorial Sloan Kettering Cancer Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50435409&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2014055668(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to ES13844468T priority Critical patent/ES2743738T3/es
Priority to EP13844468.2A priority patent/EP2903637B1/en
Priority to NZ706541A priority patent/NZ706541A/en
Priority to RU2015116901A priority patent/RU2729401C2/ru
Priority to JP2015534828A priority patent/JP6441802B2/ja
Priority to KR1020157011160A priority patent/KR102198058B1/ko
Priority to CN201380063036.8A priority patent/CN104853766A/zh
Priority to EP19179456.9A priority patent/EP3597215A1/en
Priority to CA2886859A priority patent/CA2886859C/en
Priority to AU2013327136A priority patent/AU2013327136A1/en
Priority to HK15109439.3A priority patent/HK1208631B/en
Priority to MX2015004287A priority patent/MX370148B/es
Priority to SG11201502598SA priority patent/SG11201502598SA/en
Application filed by Memorial Sloan Kettering Cancer Center filed Critical Memorial Sloan Kettering Cancer Center
Publication of WO2014055668A1 publication Critical patent/WO2014055668A1/en
Priority to IL238047A priority patent/IL238047B/en
Priority to US14/676,255 priority patent/US10654928B2/en
Anticipated expiration legal-status Critical
Priority to PH12015500747A priority patent/PH12015500747B1/en
Priority to ZA201502880A priority patent/ZA201502880B/en
Priority to AU2018204297A priority patent/AU2018204297B2/en
Priority to PH12019502424A priority patent/PH12019502424A1/en
Priority to IL272539A priority patent/IL272539B/en
Priority to US16/847,059 priority patent/US11712469B2/en
Priority to AU2020294287A priority patent/AU2020294287B2/en
Priority to US18/333,753 priority patent/US12263220B2/en
Priority to US19/063,828 priority patent/US20250186585A1/en
Ceased legal-status Critical Current

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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
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    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
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    • C12N2999/00—Further aspects of viruses or vectors not covered by groups C12N2710/00 - C12N2796/00 or C12N2800/00
    • C12N2999/002—Adverse teaching

Definitions

  • Immunotherapy is a targeted therapy that in principle provides for the treatment of such cancers .
  • Targeted T ceil therapies utilizing genetically modified autologous T cells are beginning to show evidence of therapeutic efficacy in melanoma and indolent B cell malignancies.
  • Current T ceil engineering strategies retarget patient T cells to tumor antigens through a transduced T cell receptor (TCR) or a chimeric antigen receptor (CAR).
  • TCR transduced T cell receptor
  • CAR chimeric antigen receptor
  • the present invention generally provides immunoresponsive cells, including T ceils and Natural Killer (NK) cells, expressing an antigen binding receptor (e.g., CAR or TCR) having immune cell activating actvity and a chimeric co-stimulating receptor (CCR), and methods of use therefore for the treatment of neoplasia, infectious disease, and other pathologies.
  • an antigen binding receptor e.g., CAR or TCR
  • CCR chimeric co-stimulating receptor
  • the invention provides an isolated immunoresponsive cell having an antigen recognizing receptor that binds a first antigen with low affinity, where the binding activates the immunoresponsive ceil, and a chimeric co stimulating receptor (CCR) that binds a second antigen and stimulates the immunoresponsive ceil.
  • CCR chimeric co stimulating receptor
  • the invention provides a method of inducing tumor cell death in a subject, the method comprising administering an effective amount of an immunoresponsive cell comprising an antigen recognizing receptor that binds a first antigen with low affinity, where the binding activates the immunoresponsive cell, and a chimeric co-stimulating receptor (CCR) that binds a second antigen and stimulates the immunoresponsive cell, thereby inducing tumor cell death in the subject.
  • an immunoresponsive cell comprising an antigen recognizing receptor that binds a first antigen with low affinity, where the binding activates the immunoresponsive cell, and a chimeric co-stimulating receptor (CCR) that binds a second antigen and stimulates the immunoresponsive cell, thereby inducing tumor cell death in the subject.
  • CCR chimeric co-stimulating receptor
  • the invention provides a method of treating or preventing a neoplasia in a subject, the method comprising administering an effective amount of an immunoresponsive cell comprising an antigen recognizing receptor that binds a first antigen with low affinity, where the binding activates the immunoresponsive ceil, and a chimeric co-stimulating receptor (CCR) that binds a second antigen and stimulates the immunoresponsive cell, thereby treating or preventing a neoplasia in the subject.
  • an immunoresponsive cell comprising an antigen recognizing receptor that binds a first antigen with low affinity, where the binding activates the immunoresponsive ceil, and a chimeric co-stimulating receptor (CCR) that binds a second antigen and stimulates the immunoresponsive cell, thereby treating or preventing a neoplasia in the subject.
  • CCR chimeric co-stimulating receptor
  • the invention provides a method of treating prostate cancer in a subject in need thereof, the method comprising
  • a T cell comprising an antigen recognizing receptor that binds PSCA or CD19 with low affinity, where the binding activates the immunoresponsive cell, and a chimeric co-stimulating receptor (CCR) that binds PSMA and stimulates the
  • the invention provides a method for producing an antigen- specific immunoresponsive ceil, the method involving introducing into the immunoresponsive cell a nucleic acid sequence that encodes a chimeric co- stimulating receptor (CCR), where the chimeric co-stimulating receptor has an antigen-binding domain coupled to an intracellular signaling domain that stimulates an immunoresponsive cell, where the immunoresponsive cell has an antigen recognizing receptor that binds a first antigen with low affinity, wherein the binding activates the immunoresponsive cell.
  • CCR chimeric co- stimulating receptor
  • the invention provides a pharmaceutical composition comprising an effective amount of an immunoresponsive ceil of the invention (e.g., a tumor antigen-specific T cell in a pharmaceutical composition for the treatment of neoplasia) in a pharmaceutically acceptable excipient.
  • an immunoresponsive ceil of the invention e.g., a tumor antigen-specific T cell in a pharmaceutical composition for the treatment of neoplasia
  • the invention provides a kit for treatment of a neoplasia, pathogen infection, an autoimmune disorder, or an allogeneic transplant, the kit containing an immunoresponsive cell having an antigen recognizing receptor that binds a first antigen and activates the
  • kits may further comprise written instructions for using the immunoresponsive cell for the treatment of a subject having a neoplasia, a pathogen infection, an autoimmune disorder, or an allogeneic transplant.
  • the immunoresponsive cell is selected as having an antigen recognizing receptor with low affinity. This may involve selecting the immunoresponsive cell as having an antigen recognizing receptor that binds a first antigen with low affinity, in various embodiments of any of the aspects delineated herein, the antigen recognizing receptor is selected as having low affinity for expression in the cell. This may involve introducing a second nucleic acid sequence that encodes a chimeric antigen receptor, where the chimeric antigen receptor comprises a second antigen-binding domain coupled to a second intracellular signaling domain that activates an immunoresponsive cell.
  • the antigen recognizing receptor is a T cell receptor (TCR) or chimeric antigen receptor (CAR).
  • TCR T cell receptor
  • CAR chimeric antigen receptor
  • the intracellular signaling domain of said antigen recognizing receptor is the CD3-chain signaling domain.
  • the intracellular signaling domain of the chimeric co-stimulating receptor (CCR) is a CD97, CD1 1a-CD18, CD2, ICOS, CD27, CD154, CD5, OX40, 4-1 BB or CD28 signaling domain.
  • the antigen recognizing receptor is exogenous or endogenous.
  • the antigen recognizing receptor is recombinantly expressed.
  • the antigen recognizing receptor is expressed from a vector.
  • the chimeric co-stimulating receptor (CCR) is expressed from a vector.
  • the immunoresponsive cell expresses a recombinant or an
  • endogenous antigen receptor that is 19z1 or Pz1.
  • the immunoresponsive cell is a T cell, a Natural Killer (NK) cell, a cytotoxic T
  • lymphocyte CTL
  • regulatory T cell a human embryonic stem ceil
  • human embryonic stem ceil a human embryonic stem ceil
  • the antigen is a tumor or pathogen antigen.
  • one or more antigen-binding domains are tumor antigen-binding domains.
  • the antigens or tumor antigens are selected from CAIX, CEA, CD5, CD7, CD10, CD19, CD20, CD22, CD30, CD33, CD34, CD38, CD41 , CD44, CD49f, CD56, CD74, CD133, CD138, a cytomegalovirus (CMV) infected ceil antigen, EGP-2, EGP-40, EpCAM, erb-B2,3,4, FBP, Fetal acetylcholine receptor, folate receptor-a, GD2, GD3, HER-2, hTERT, IL13R-a2, x-iight chain, KDR, LeY, Li cell adhesion molecule, MAGE-AI , MUC1 , Mesothelin, NKG2D iigands, NY- ES0-1 , oncofetal antigen (h5T4), PSCA, PSMA, ROR1 , TAG-72, VEGF-
  • CMV cytomegalovirus
  • the first and second antigens are selected from CD133, a cytomegalovirus (CMV) infected cell antigen, erbB2, KDR Mesothelin, NKG2D Iigands, NY-ES0-1 , oncofetal antigen (h5T4), PSCA, PSMA, CD19, VEGF-R2, and WT-1.
  • the first and second antigens are selected from HER2, MUC1 , CD44, CD49f, EpCAM, CEA, CD133, a
  • cytomegalovirus (CMV) infected cell antigen EGP-2, EGP-40, EpCAM, erb-B2,3,4, FBP, KDR, Mesothelin, NKG2D Iigands, NY-ES0-1 , oncofetal antigen (h5T4), PSCA, PSMA, VEGF-R2, or WT-1.
  • the first and second antigens are selected from CD10 and CD19.
  • the first and second antigens are selected from CD56 and CD138.
  • the first and second antigens are selected from mesothelin, folate receptor-a, CD44, and CD133.
  • the neoplasia is selected from the group consisting of prostate cancer, breast cancer, B cell leukemia, multiple myeloma, and ovarian cancer.
  • the method reduces the number of tumor cells, reduces tumor size, and/or eradicates the tumor in the subject.
  • the neoplasia is prostate cancer and the first and second tumor antigens are distinct antigens selected from PSCA, PSMA, CD19, CD133, a cytomegalovirus (CMV) infected cell antigen, erb-B2, KDR
  • the neoplasia is breast cancer and the first and second tumor antigens are distinct antigens selected from HER2, MUC1 , CD44, CD49f, EpCAM, CEA, CD133, a cytomegalovirus (CMV) infected cell antigen, EGP-2, EGP-40, EpCAM, erb-B2,3,4, FBP, KDR, Mesothelin, NKG2D iigands, NY- ESO-1 , oncofetal antigen (h5T4), PSCA, PSMA, VEGF-R2, or WT-1 .
  • CMV cytomegalovirus
  • the neoplasia is B cell leukemia and the first and second tumor antigens are selected from CDIO and CD19.
  • the neoplasia is multiple myeloma and the first and second tumor antigens are selected from CD56 and CD138.
  • the neoplasia is ovarian cancer and the first and second tumor antigens are distinct antigens selected from mesothe!in, folate receptor-a, CD44, and CD133.
  • compositions and methods that provide for T ceil targeting of tumor cells.
  • Compositions and articles defined by the invention were isolated or otherwise manufactured in connection with the examples provided below. Other features and advantages of the invention will be apparent from the detailed description, and from the claims.
  • Figures 1A-C are graphics depicting chimeric antigen receptor (CAR) and chimeric costimulatory receptor (CCR) vector design and expression via transduction of primary human T cells.
  • CAR chimeric antigen receptor
  • CCR costimulatory receptor
  • CAR expression can be easily detected by correlation to dsRED fluorescence (data not shown).
  • the CCR was generated by fusing an scFv to a CD28 transmembrane and signaling domain 15 , fused to a 4-1 BB (aka CD137) cytosoiic signaling domain. 21 CCR expression can be correlated to the bicistronic expression of hrGFP (data not shown).
  • LTR Long Terminal Repeat
  • SD Splice Donor site
  • SA Splice Acceptor site
  • VH or V L -Variable Heavy or Light domains respectively
  • EC Extracellular domain
  • TM Transmembrane domain
  • C Cytosoiic domain
  • IRES Internal Ribosomal Entry Site
  • hrGFP Human
  • Recombinant Green Fluorescent Protein depicts representative transduction efficiencies of primary human T cells using these retroviral vectors.
  • C depicts transduction of CTLs with different and multiple CARs for the present studies.
  • Figures 2A-D show that dual-receptor, CAR/CCR-mediated activation of human T cells allowed for robust CTL function, long-term proliferation, and enhanced tumor eradication upon binding of two antigens.
  • A shows that T cells expressing chimeric receptors lysed cells positive for antigen when the
  • CAR specific to CD19 is expressed by T cells in CTL assays, compared to untransduced or P28BB transduced T cells.
  • Plots are representative of n > 4 experiments, with error bars representing standard deviation of the mean of 3 replicates.
  • (B) shows long-term proliferation of T cells by absolute T cell counts over 31 days of T cells expressing none, one, or both chimeric receptors that were co-cultured with human tumor cell lines expressing both or either antigen alone. Arrows indicate re-stimulation of T cells using freshly irradiated tumor cells. Only when dual-receptor expressing T ceils encounter both antigens is robust long-term proliferation observed.
  • Plots are representative of n > 4 experiments with error bars representing standard deviation of the mean of 3 replicates.
  • TTS tumor- sensing T
  • IV intravenously
  • (D) depicts selective eradication of DP tumors using a tri-tumor mouse model by subcutaneously injecting 1 x 10 6 PC3 tumors cells each of ceils positive for CD19 alone into the left flanks, cells positive for PSMA alone into the right flanks, and cells positive for both CD19 and PSMA into the backs of the mice.
  • T ceils expressing either 19z1 , P28BB, or both 19z1 + P28BB of the chimeric receptors were infused intravenously 7 days post tumor infusion. Representative images of 2 mice per group bearing these tumors are shown with luminescence of tumors represented in color. Tumors were quantitatively measured using calipers and tumor volumes were plotted versus time for each tumor. Error bars represent standard deviation from the mean of 6 mice.
  • Statistical significance was determined using two- tailed unpaired t tests to compare values obtained from 19z1 T cells and 19z1 + P28BB T cells and p values are represented as * for ⁇ 0.05 or ** for ⁇ 0.01.
  • FIGS 3A-E depict that tumor-sensing T (T TS ) ceils selectively eradicated human prostate tumors when targeting two prostate tumor antigens
  • T TS tumor-sensing T
  • A depicts the evaluation of three different scFvs specific to PSCA for their assembly into bispecific antibodies that contain specificity for CD3 as well. T ceils were co- cultured at ratio of 20:1 with PSCA + PC3 tumor cells and antibodies added at varying amounts and specific iysis was measured.
  • (B) depicts generation of CARs using the anti-PSCA scFvs that display varied efficacy in cytotoxicity assays.
  • Figures 4A-D depict enhanced cytokine secretion and Bd xL
  • TTS ceils when co-cultured on DP tumors.
  • A depicts multiplex cytokine analysis of untransduced T cells or T cells transduced with 19z1 , P28BB, or both 48 hours post first antigen stimulation using either untransduced PC3 cells (Empty) or CD19 + PSMA + PC3 ceils. Error bars represent standard deviation from the mean of 2 biological replicates.
  • B-D depict multiplex cytokine analysis of untransduced T cells or T cells transduced with Hz] (B), Mzl (C), and Lz1 (D) anti-PSCA CARs, P28BB CCRs, or both CAR + CCR is shown 48 hours post second antigen stimulation using either Empty or PSCA+PSMA+ PC3 cells.
  • E depicts Western blot analysis for BdxL performed using cellular lysates of untransduced T ceils or T ceils transduced with 19z1 , P28BB, or both after 24 hours post initial antigen stimulation. Total amount of Akt was used as a loading control.
  • FIG. 5 depicts generation of prostate tumor cells for the expression of fusion protein GFP-Firefiy Luciferase (GFP/Luc) and tumor antigens.
  • Untransduced PC3 cells (Empty) were transduced with GFP/Luc and either CD19, PSMA, PSCA, or a combination of two antigens using retroviral expression constructs. Cells were purified via double purity FACS for GFP/Luc, CD19, PSMA, and/or PSCA.
  • FIG. 6A-C illustrate the tumor-sensing T cell concept.
  • A depicts that TTS cells expressing an efficient CAR, become potently stimulated by A + 113 + cells to facilitate immune response against A + ceils.
  • CAR + CCR + cells can bind tumor antigen A + cells with a CAR that supplies CD3 activation signals. This can result in short-term cell lysis.
  • CAR + CCR + cells can bind tumor antigen B + cells with a CCR that supplies CD28 and CD137 signals. This signal alone is not sufficient to induce lysis or proliferation. Only when CAR + CCR + cells bind tumor antigen A + B + ceils with a CAR and CCR can both activation and stimulation be provided.
  • FIG. 6B depicts that by reducing the efficacy of the CAR, TTs celis can be functionally rescued by CCR binding when A + B + cells are encountered to selectively respond and eradicate A + 13 + ceils, while avoiding response to A+ cells.
  • (C) shows that by co-expressing one CAR that supplies a TCR activation signal upon binding a tumor antigen and a second CAR that supplies stimulation signals upon binding a different tumor antigen, T lymphocytes will only eradicate tumors expressing both antigens, but not tumors expressing either antigen alone.
  • an immunoresponsive ceil activates induction of signal transduction or changes in protein expression in the cell resulting in initiation of an immune response.
  • CD3 Chains cluster in response to ligand binding and immunoreceptor tyrosine-based inhibition motifs (ITAMs) a signal transduction cascade is produced.
  • ITAMs immunoreceptor tyrosine-based inhibition motifs
  • a formation of an immunologicai synapse occurs that includes clustering of many molecuies near the bound receptor (e.g. CD4 or CD8, CD3 / / / , etc.) This clustering of membrane bound signaling molecules allows for ITAM motifs contained within the CD3 chains to become phosphorylated.
  • T ceil activation pathway ultimately activating transcription factors, such as NF-KB and AP-1.
  • transcription factors induce global gene expression of the T cell to increase IL-2 production for proliferation and express master regulator T cell proteins in order to initiate a T ceil mediated immune response.
  • Stimulates an immunoresponsive cell is meant a signal that results in a robust and sustained immune response. In various embodiments, this occurs after immune cell (e.g., T-cell) activation or concomitantly mediated through receptors including, but not limited to, CD28, CD137 (4-1 BB), OX40, and ICOS.
  • receiving multiple stimulatory signals is important to mount a robust and long-term T cell mediated immune response.
  • T cells Without receiving these stimulatory signals, T cells quickly become inhibited and unresponsive to antigen. While the effects of these co-stimuiatory signals vary and remain partially understood, they generally result in increasing gene expression in order to generate long lived, proliferative, and anti-apoptotic T cells that robustly respond to antigen for complete and sustained eradication.
  • antigen recognizing receptor refers to a receptor that is capable of activating an immune cell (e.g., a T-cell) in response to antigen binding.
  • exemplary antigen recognizing receptors may be native or endogenous T cell receptors or chimeric antigen receptors in which a tumor antigen-binding domain is fused to an intracellular signaling domain capable of activating activating an immune cell (e.g., a T-cell).
  • an antigen recognizing receptor is selected to have low or minimal affinity or avidity for the antigen.
  • affinity is meant a measure of the binding strength between antibody and a simple hapten or antigen determinant. Without being bound to theory, affinity depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and on the distribution of charged and hydrophobic groups. Affinity also includes the term “avidity,” which refers to the strength of the antigen-antibody bond after formation of reversible complexes. Methods for calculating the affinity of an antibody for an antigen are known in the art, including use of binding experiments to calculate affinity. In the case of an antibody (Ab) binding to an antigen (Ag), the affinity constant is used (expressed as inverted dissociation constant).
  • the chemical equilibrium of antibody binding is also the ratio of the on-rate (k forward) and off-rate (kback) constants.
  • Two antibodies can have the same affinity, but one may have both a high on- and off-rate constant, while the other may have both a low on- and off-rate constant.
  • Antibody activity in functionai assays is also reflective of antibody affinity.
  • the antigen recognizing receptor has low affinity.
  • Low affinity includes micromolar and nanomolar affinities (e.g. IfJ 5 , 50 "6 , I0 “6 , 5x 1fJ 7 , 10 "7 , 5x 10 "8 , 10 “8 , 5x1 fJ 9 , iO "9 M).
  • Anitbody and affinities can be phenotypically characterized and compared using functional assay (e.g., cell lysis assay).
  • chimeric co-stimulatory receptor refers to a specific type of chimeric antigen receptor (CAR) that mediates costimulation independently of activation.
  • CAR chimeric antigen receptor
  • the CCR When expressed on immunoresponsive cells in combination with an antigen recognizing receptor (e.g., CAR or TCR that activates the cell), the CCR is targeted to a second antigen.
  • the CCR has mid or high affinity for its target antigen.
  • chimeric antigen receptor refers to a tumor antigen-binding domain that is fused to an intracellular signaling domain capable of activating or stimulating T ceils. Most commonly, the CAR'S
  • extracellular binding domain is composed of a single chain variable fragment (scFv) derived from fusing the variable heavy and light regions of a murine or humanized monoclonal antibody.
  • scFv's may be used that are derived from Fab's (instead of from an antibody, e.g., obtained from Fab libraries).
  • this scFv is fused to a transmembrane domain and then to intracellular signaling domain.
  • “First-generation” CARs include those that solely provide CD3 signals upon antigen binding
  • “Second-generation” CARs include those that provide both costimulation (e.g. CD28 or CD137) and activation (CD3 ).
  • “Third-generation” CARs include those that provide multiple
  • CD3 polypeptide is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to NCBI Reference No: NP_932170 or a fragment thereof that has activating or stimulatory activity.
  • An exemplary CD3 is provided in Table 1 below.
  • CD3 nucleic acid molecule is meant a polynucleotide encoding a CD3 polypeptide.
  • CD8 polypeptide is meant a protein having at least 85, 90, 95, 96, 97, 98, 99or 100% identity to NCBI Reference No: NP_001759 or a fragment thereof that has stimulatory activity.
  • An exemplary CD8 is provided in Table 1 below.
  • CD8 nucleic acid molecule is meant a polynucleotide encoding a CD8 polypeptide.
  • CD28 polypeptide is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to NCBI Reference No: NP_006130 or a fragment thereof that has stimulatory activity.
  • An exemplary CD28 is provided in Table 1 below.
  • CD28 nucleic acid molecule is meant a polynucleotide encoding a CD28 polypeptide.
  • 4-1 BB polypeptide is meant a protein having at least 85, 90, 95,
  • 4-1 BBL nucleic acid molecule is meant a polynucleotide encoding a 4-1 BBL polypeptide.
  • CD80 polypeptide is meant a protein having at least 85, 90, 95, 96,
  • CD80 polypeptide is provided in Table 1 below.
  • CD80 nucleic acid molecule any polynucleotide encoding a CD80 polypeptide.
  • An exemplary CD80 nucleic acid molecule is NM_005191 .
  • OX40L polypeptide is meant a protein having at least 85, 90, 95, 96,
  • OX40L nucleic acid molecule is meant a polynucleotide encoding a OX40L polypeptide.
  • 19z1 polypeptide is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to the sequence provided below and having activating activity when bound to CD19.
  • P28z polypeptide is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to the sequence provided below.
  • CD19 is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to the sequence provided below and is able to bind CD19.
  • PSMA is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to the sequence provided below and is able to bind PSMA.
  • P28BB is meant a protein having at least 85, 90, 95, 96, 97, 98, 99 or 100% identity to the sequence provided below and having stimulatory activity when bound to PSMA.
  • CD3 ⁇ mkwkalftaa ilqaqlpite aqsfglldpk lcylldgilf iygviltalf Irvkfsrsad apayqqgqnq lynelnlgrr eeydvldkrr grdpemggkp qrrknpqegl ynelqkdkma eayseigmkg errrgkghdg lyqglsta tkdtydalhm qalppr
  • CD80 evkevatlsc ghnvsveela qtriywqkek kmvltmmsgd mni peyknr tifditnnls ivilalrpsd egtyecvvlk yekdafkreh laevtlsvka dfptpsisdf eiptsnirri icstsggfpe phlswlenge elnainttvs qdpetelyav sskldfnmtt nhsfmcliky ghlrvnqtfn wnttkqehfp dnllpswait lisvngif i ccltycfapr crerrrnerl rresvrov mervqpleen vgnaarprfe rnklllvasv iqglgl ll
  • GYAFSSYWMNWKQRPGQGLE IGQIYPGDGDTNYNGKFKGQA TLTADKSSSTAYMQLSGLTSEDSAVYECARKTISSWDFYFDY WGQGTTVTVSSGGGGSGGGGSGGGGSDIELTQSPKFMSTSVGD RVSVTCKASQ VGT VAWYQQKPGQSPKPLIYSATYRNSGVPD RFTGSGSGTDFTLTITNVQSKDLADYFCQQYNRYPYTSGGGTK LEIKRAAAPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGA VHTRGLDFACDIYI APLAGTCGVLLLSLVITLYCNHRVKFSR SAEPPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKP RRK PQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQG LSTATKDTYDALHMQALPPR
  • Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having "substantial identity" to an endogenous
  • hybridize is meant pair to form a double- stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency.
  • complementary polynucleotide sequences e.g., a gene described herein
  • stringent salt concentration will ordinarily be less than about 750 mM NaCI and 75 mM trisodium citrate, preferably less than about 500 mM NaC1 and 50 mM trisodium citrate, and more preferably less than about 250 mM NaC1 and 25 mM trisodium citrate.
  • Low stringency hybridization can be obtained in the absence of organic solvent, e.g., formamide, while high
  • stringency hybridization can be obtained in the presence of at least about 35% formamide, and more preferably at least about 50% formamide.
  • Stringent temperature conditions wiil ordinarily inciude temperatures of at least about 30° C, more preferably of at least about 37° C, and most preferably of at least about 42° C.
  • Varying additional parameters, such as hybridization time, the concentration of detergent, e.g., sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA are well known to those skilled in the art.
  • Various levels of stringency are accomplished by combining these various conditions as needed. In a preferred: embodiment, hybridization will occur at 30° C in 750 mM NaCI, 75 mM trisodium citrate, and 1% SDS.
  • hybridization will occur at 37° C in 500 mM NaCI, 50 mM trisodium citrate, 1 % SDS, 35% formamide, and 1001.1 g/m1 denatured salmon sperm DNA (ssDNA).
  • hybridization wiil occur at 42° C C. in 250 mM NaCI, 25 mM trisodium citrate, 1 % SDS, 50% formamide, and 200 p.g/ml ssDNA. Useful variations on these conditions will be readily apparent to those skilled in the art.
  • wash stringency conditions can be defined by salt concentration and by temperature. As above, wash stringency can be increased by decreasing salt concentration or by increasing temperature.
  • stringent salt concentration for the wash steps will preferably be less than about 30 mM NaC1 and 3 mM trisodium citrate, and most preferably less than about 15 mM NaCI and 1.5 mM trisodium citrate.
  • Stringent temperature conditions for the wash steps wiil ordinarily inciude a temperature of at least about 25° C, more preferably of at least about 42° C, and even more preferably of at least about 68° C.
  • wash steps wiil occur at 25°C in 30 mM NaCI, 3 mM trisodium citrate, and 0.1% SDS.
  • wash steps will occur at
  • wash steps wiil occur at 68° C in 15 mM NaC1 , 1.5 mM trisodium citrate, and 0.1% SDS. Additional variations on these conditions will be readily apparent to those skilled in the art.
  • Hybridization techniques are well known to those skilled in the art and are described, for example, in Benton and Davis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad.Sci., USA 72:3961 , 1975); Ausubel et al. (Current Protocols in Molecular Biology, Wiley Interscience, New York, 2001 ); Berger and Kimmei (Guide to Molecular Cloning Techniques, 1987, Academic Press, New York); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York.
  • substantially identical is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein).
  • a reference amino acid sequence for example, any one of the amino acid sequences described herein
  • nucleic acid sequence for example, any one of the nucleic acid sequences described herein.
  • such a sequence is at least 60%, more preferably 80% or 85%, and more preferably 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison.
  • Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and/or other modifications.
  • sequence analysis software for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs.
  • Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, g!utamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.
  • a BLAST program may be used, with a probability score between e-3 and e-100 indicating a closely related sequence.
  • analog is meant a structurally related polypeptide or nucleic acid molecule having the function of a reference polypeptide or nucleic acid molecule.
  • iigand refers to a molecule that binds to a receptor.
  • the iigand binds a receptor on another cell, allowing for cell-to-cel! recognition.
  • disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • diseases include neoplasia or pathogen infection of cell.
  • effective amount is meant an amount sufficient to arrest, ameliorate, or inhibit the continued proiiferation, growth, or metastasis (e.g., invasion, or migration) of a neoplasia.
  • enforcing tolerance is meant preventing the activity of self-reactive cells or immunoresponsive cells that target transplanted organs or tissues.
  • exogenous is meant a nucleic acid molecule or polypeptide that is not endogenously present in the cell, or not present at a level sufficient to achieve the functional effects obtained when over-expressed.
  • exogenous would therefore encompass any recombinant nucleic acid molecule or polypeptide expressed in a cell, such as foreign, heterologous, and over- expressed nucleic acid molecules and polypeptides.
  • nucleic acid molecule or polypeptide a nucleic acid molecule (e.g., a cDNA, DNA or RNA molecule) or polypeptide that is not normally present in a cell or sample obtained from a cell.
  • This nucleic acid may be from another organism, or it may be, for example, an mRNA molecule that is not normally expressed in a cell or sample.
  • immunoresponsive cell is meant a cell that functions in an immune response or a progenitor, or progeny thereof.
  • isolated cell is meant a ceil that is separated from the molecular and/or cellular components that naturally accompany the cell.
  • isolated refers to material that is free to varying degrees from components which normally accompany it as found in its native state.
  • Isolate denotes a degree of separation from original source or surroundings.
  • Purify denotes a degree of separation that is higher than isolation.
  • A"purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by
  • purified can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel.
  • modifications for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified.
  • tumor antigen-binding domain refers to a domain capable of specifically binding a particular antigenic determinant or set of antigenic determinants present on a tumor.
  • modulate is meant to alter positively or negatively.
  • exemplary modulations include a 1%, 2%, 5%, 10%, 25%, 50%, 75%, or 100% change.
  • Neoplasia is meant a disease characterized by the pathological proliferation of a cell or tissue and its subsequent migration to or invasion of other issues or organs. Neoplasia growth is typically uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells.
  • Neoplasias can affect a variety of cell types, tissues, or organs, including but not limited to an organ selected from the group consisting of bladder, bone, brain, breast, cartilage, glia, esophagus, fallopian tube, gallbladder, heart, intestines, kidney, liver, lung, lymph node, nervous tissue, ovaries, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urogenital tract, ureter, urethra, uterus, and vagina, or a tissue or cell type thereof.
  • an organ selected from the group consisting of bladder, bone, brain, breast, cartilage, glia, esophagus, fallopian tube, gallbladder, heart, intestines, kidney, liver, lung, lymph node, nervous tissue, ovaries, pancreas, prostate, skeletal muscle, skin, spinal cord, spleen, stomach, teste
  • Neoplasias include cancers, such as sarcomas, carcinomas, or plasmacytomas ⁇ malignant tumor of the plasma cells).
  • Illustrative neoplasms for which the invention can be used include, but are not limited to leukemias (e.g., acute Ieukemia, acute lymphocytic Ieukemia, acute myelocytic leukemi a, acute myeloblasts Ieukemia, acute promyelocytic ieukemia, acute myelomonocytic ieukemia, acute monocytic Ieukemia, acute erythroieukemia, chronic Ieukemia, chronic myelocytic Ieukemia, chronic lymphocytic Ieukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease),
  • leukemias e.g., acute Ieukemia, acute lymphocytic Ieukemia, acute myelocy
  • Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas ⁇ e.g., fibrosarcoma, myxosarcoma,
  • liposarcoma chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma,iymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous giand carcinoma, papillary carcinoma, papillary
  • adenocarcinomas cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal ceil carcinoma, hepatoma, nile duct carcinoma,
  • choriocarcinoma seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small ceil lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medullobiastoma, craniopharyngioma, ependymoma, pinealoma,
  • screening methods of the invention identify compositions that are useful for treating breast or lung cancer.
  • receptor is meant a polypeptide, or portion thereof, present on a cell membrane that selectively binds one or more ligands.
  • a T cell that recognizes a virus typically expresses a receptor that binds an antigen expressed by the virus.
  • Retroviridae e.g. human immunodeficiency viruses, such as HIV-1 (also referred to as HDTV-ill, LAVE or HTLV-III/LAV, or HIV-III; and other isolates, such as HIV- LP; Picornaviridae (e.g. polio viruses, hepatitis A virus; enteroviruses, human Coxsackie viruses, rhinoviruses, echoviruses); Calciviridae (e.g. strains that cause gastroenteritis); Togaviridae (e.g. equine encephalitis viruses, rubella viruses); Flaviridae (e.g. dengue viruses, encephalitis viruses, yellow fever viruses);
  • Retroviridae e.g. human immunodeficiency viruses, such as HIV-1 (also referred to as HDTV-ill, LAVE or HTLV-III/LAV, or HIV-III; and other isolates, such as HIV- LP; Picornaviridae (e.g.
  • Coronoviridae e.g. coronaviruses
  • Rhabdoviridae e.g. vesicular stomatitis viruses, rabies viruses
  • Filoviridae e.g. ebola viruses
  • Paramyxoviridae e.g. parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus
  • Orthomyxoviridae e.g . influenza viruses
  • Bungaviridae e.g. Hantaan viruses, bunga viruses, phieboviruses and Nairo viruses
  • Arena Viridae hemorrhagic fever viruses
  • Reoviridae e.g. reoviruses, orbiviurses and
  • rotaviruses rotaviruses
  • S/ ' ma r/ ' c/ae Hepadnaviridae (Hepatitis B virus); Parvovihda ⁇ parvov ⁇ ruses);Papovaviridae (papilloma viruses, polyoma viruses);
  • Adenoviridae most adenoviruses
  • Herpesviridae herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus
  • Poxviridae variola viruses, vaccinia viruses, pox viruses
  • Iridoviridae e.g. African swine fever virus
  • Exemplary bacteria include, but are not limited to, Pasteurella, Staphylococci, Streptococcus, Escherichia coli, Pseudomonas species, and Salmonella species.
  • Specific examples of infectious bacteria include but are not limited to, Helicobacter pyloris, Borelia burgdoiferi, Legionella
  • pneumophilia e.g. M. tuberculosis, M. avium, M.
  • M. kansaii M. gordonae
  • Staphylococcus aureus Staphylococcus aureus
  • Neisseria gonorrhoeae Neisseria meningitidis
  • Listeria monocytogenes Listeria monocytogenes
  • Streptococcus pyo genes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Streptococcus (viridans group), Streptococcus faecalis, Streptococcus bovis, Streptococcus (anaerobic sps.), Streptococcus pneumoniae, pathogen cCampylobacter sp.,
  • corynebacterium diphtheriae corynebacterium sp., Erysipelothrix rhusiopathiae, Clostridium perfringers, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides sp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidium, Treponema peramba, Leptospira, Rickettsia, and Actinomyces israelii.
  • polypeptide or fragment thereof that recognizes and binds a polypeptide of interest, but which does not
  • a sample for example, a biological sample, which naturally includes a polypeptide of the invention.
  • tumor antigen refers to any polypeptide expressed by a tumor that is capable of inducing an immune response.
  • virus antigen is meant a polypeptide expressed by a virus that is capable of inducing an immune response.
  • treatment refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • a treatment can prevent deterioration due to a disorder in an affected or diagnosed subject or a subject suspected of having the disorder, but also a treatment may prevent the onset of the disorder or a symptom of the disorder in a subject at risk for the disorder or suspected of having the disorder.
  • subject refers to a vertebrate, preferably a mammal, more preferably a human.
  • immunocompromised refers to a subject who has an immunodeficiency.
  • the subject is very vulnerable to opportunistic infections, infections caused by organisms that usually do not cause disease in a person with a healthy immune system, but can affect people with a poorly functioning or suppressed immune system.
  • the present invention generally provides cells, including genetically modified immunoresponsive cells (e.g., T cells, Natural Killer (NK) cells, cytotoxic T lymphocytes (CTL) ceils) expressing at least a combination of an antigen- recognizing receptor (e.g., TCR or CAR) and a chimeric co-stimulating receptor (CCR), and methods of use therefore for the treatment of neoplasia and other pathologies where an increase in an antigen-specific immune response is desired.
  • genetically modified immunoresponsive cells e.g., T cells, Natural Killer (NK) cells, cytotoxic T lymphocytes (CTL) ceils
  • an antigen- recognizing receptor e.g., TCR or CAR
  • CTL chimeric co-stimulating receptor
  • the invention is based, at least in part, on the discovery that the simultaneous engagement of two antigens co-expressed by a tumor cell by an antigen-recognizing receptor and chimeric co-stimulating receptor is useful for activating and stimulating an immunoreactive cell without systemic effects.
  • the reactivity against tissues expressing either antigen alone is preferably minimal, inducing T cell activaiion in the presence of both antigens but not either one alone.
  • T ceil activation is mediated by a TCR or a CAR targeted to an antigen (e.g., CD19 or prostate stem cell antigen, PSCA).
  • Costimulation is independently mediated by a "chimeric costimulatory receptor" (CCR), 2 ' 3 which is targeted to a second antigen (e.g., prostate-specific membrane antigen, PSMA).
  • CCR chimeric costimulatory receptor
  • PSMA prostate-specific membrane antigen
  • this approach is not limited to the treatment of neoplasias, but is amenable to a wide range of applications where an increase in an antigen-specific immune response is desired, such applications include not only the treatment of neoplasias, but also for the enhancement of an immune response against a pathogen infection or an infectious disease and to reinforce immune tolerance in regulatory T ceils in the context of autoimmunity or allogeneic transplantation.
  • lymphoid lineage comprising B, T and natural killer (NK) cells, provides for the production of antibodies, regulation of the cellular immune system, detection of foreign agents in the blood, detection of cells foreign to the host, and the iike.
  • T cells refers to lymphocytes that mature in the thymus and are chiefly responsible for cell- mediated immunity. T cells are involved in the adaptive immune system.
  • NK ceils refers to lymphocytes that are part of cell-mediated immunity and act during the innate immune response. They do not require prior activation in order to perform their cytotoxic effect on target ceils. Cytotoxic T cells (CTL or killer T ceils) are a subset of T TTL or killer T ceils.
  • lymphocytes capable of inducing the death of infected somatic or tumor cells.
  • the present invention provides cells expressing a combination of an antigen-recognizing receptor that activates an immunoresponsive ceil (e.g., TCR, CAR) and a chimeric co-stimulating receptor (CCR), and methods of using such cells for the treaiment of a disease that requires an enhanced immune response.
  • an immunoresponsive ceil e.g., TCR, CAR
  • CCR chimeric co-stimulating receptor
  • tumor antigen-specific T cells, NK cells, CTL ceils or other immunoresponsive cells are used as shuttles for the selective enrichment of one or more co-stimulatory ligands for the treaiment or prevention of neoplasia.
  • a T cell expressing a chimeric antigen receptor 19z1 that recognizes CD19 is co-expressed in a T cell that expresses a chimeric co- stimuiatory receptor P28BB that recognizes and binds Prostate Specific
  • PSMA Membrane Antigen
  • T cells NK cells
  • CTL cells can be used for the treatment of viral diseases.
  • a chimeric co-stimuiatory antigen receptor that recognizes a first CMV antigen and a chimeric antigen receptor that recognizes and binds a second CMV antigen are co-expressed in cytotoxic T lymphocytes for the treatment of CMV.
  • Types of tumor antigen-specific human lymphocytes that can be used in the methods of the invention include, without limitation, peripheral donor lymphocytes genetically modified to express chimeric antigen receptors (CARs) (Sadelain, M., et al. 2003 Nat Rev Cancer 3:35-45), peripheral donor
  • CARs chimeric antigen receptors
  • lymphocytes genetically modified to express a full-length tumor antigen- recognizing T cell receptor complex comprising the a and p heterodimer (Morgan, R.A., et al. 2006 Science 314:126-129), lymphocyte cultures derived from tumor infiltrating lymphocytes (TILs) in tumor biopsies (Panelii, M.C., et al. 2000 J Immunol 164:495-504; Panelii, M.C., et al.
  • TILs tumor infiltrating lymphocytes
  • T ceils may be autologous, allogeneic, or derived in vitro from engineered progenitor or stem cells.
  • any suitable tumor antigen is suitable for use in the tumor-related embodiments described herein.
  • Sources of antigen include, but are not limited to cancer proteins.
  • the antigen can be expressed as a peptide or as an intact protein or portion thereof.
  • the intact protein or a portion thereof can be native or mutagenized.
  • Suitable antigens include prostate specific membrane antigen (PSMA) and prostate stem cell antigen (PCSA).
  • Viral antigen-specific T lymphocytes and NK cells
  • Suitable antigens for use in the treatment of pathogen infection or other infectious disease, for example, in an immunocompromised subject include, without limitation, viral antigens present in Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Human Immunodeficiency Virus (HIV), and influenza virus.
  • CMV Cytomegalovirus
  • EBV Epstein Barr Virus
  • HAV Human Immunodeficiency Virus
  • the unpurified source of CTLs may be any known in the art, such as the bone marrow, fetal, neonate or adult or other hematopoietic ceil source, e.g. , fetal liver, peripheral blood or umbilical cord blood.
  • hematopoietic ceil source e.g. , fetal liver, peripheral blood or umbilical cord blood.
  • Various techniques can be employed to separate the cells. For instance, negative selection methods can remove non-CTLs initially. mAbs are particularly useful for identifying markers associated with particular cell lineages and/or stages of differentiation for both positive and negative selections.
  • a large proportion of terminally differentiated cells can be initially removed by a relatively crude separation.
  • magnetic bead separations can be used initially to remove large numbers of irrelevant ceils.
  • at least about 80%, usually at least 70% of the total hematopoietic cells will be removed prior to cell isolation.
  • Procedures for separation include, but are not limited to, density gradient centrifugation; resetting; coupling to particles that modify cell density; magnetic separation with antibody-coated magnetic beads; affinity
  • cytotoxic agents joined to or used in conjunction with a mAb including, but not limited to, complement and cytotoxins; and panning with antibody attached to a solid matrix, e.g. plate, chip, elutriation or any other convenient technique.
  • Techniques for separation and analysis include, but are not limited to, flow cytometry, which can have varying degrees of sophistication, e.g., a plurality of color channels, low angle and obtuse light scattering detecting channels, impedance channels.
  • the cells can be selected against dead cells, by employing dyes associated with dead cells such as propidium iodide (PI).
  • PI propidium iodide
  • the ceils are coi!ected in a medium comprising 2% fetal calf serum (FCS) or 0.2% bovine serum albumin (BSA) or any other suitable, preferably sterile, isotonic medium.
  • FCS fetal calf serum
  • BSA bovine serum albumin
  • the invention generally provides an immunoresponsive celi, such as a virus specific or tumor specific T cell comprising a receptor that binds a first antigen and activates the immunresponsive celi and a receptor that binds a second antigen and stimulates the immunresponsive cell.
  • an immunoresponsive celi such as a virus specific or tumor specific T cell comprising a receptor that binds a first antigen and activates the immunresponsive celi and a receptor that binds a second antigen and stimulates the immunresponsive cell.
  • immunoresponsive ceils e.g., T cells, CTL cells, NK cells
  • Genetic modification of immunoresponsive ceils can be accomplished by transducing a substantially homogeneous cell composition with a recombinant DNA construct.
  • a retroviral vector (either gamma-retroviral or lentiviral) is employed for the introduction of the DNA construct into the ceil.
  • a polynucleotide encoding a receptor that binds an antigen can be cloned into a retroviral vector and expression can be driven from its endogenous promoter, from the retroviral long terminal repeat, or from a promoter specific for a target cell type of interest.
  • an antigen e.g., a tumor antigen, or a variant, or a fragment thereof
  • Non-viral vectors may be used as well.
  • a retroviral vector is generally employed for transduction, however any other suitable viral vector or non-viral delivery system can be used.
  • retroviral gene transfer for subsequent genetic modification of the cells to provide ceils comprising an antigen presenting complex comprising at least two co- stimulatory ligands, retroviral gene transfer (transduction) likewise proves effective.
  • Combinations of retroviral vector and an appropriate packaging line are also suitable, where the capsid proteins will be functional for infecting human cells.
  • Various amphotropic virus-producing cell lines are known, including, but not limited to, PA12 (Miller, et ai. (1985) Mol. Cell. Biol.
  • Non- amphotropic particles are suitable too, e.g., particles pseudotyped with VSVG, RD114 or GALV envelope and any other known in the art.
  • Possible methods of transduction also include direct co-culture of the cells with producer cells, e.g., by the method of Bregni, et al. (1992) Blood 80:1418- 1422, or culturing with viral supernatant alone or concentrated vector stocks with or without appropriate growth factors and poiycations, e.g., by the method of Xu, et al. (1994) Exp. Hemat. 22:223-230; and Hughes, et al. (1992) J. Clin. Invest. 89:1817.
  • transducing viral vectors can be used to express a co-stimulatory ligand of the invention in an immunoresponsive ceil.
  • the chosen vector exhibits high efficiency of infection and stable integration and expression (see, e.g., Cayouette et ai., Human Gene Therapy 8:423-430, 1997; Kido et al., Current Eye Research 15:833-844, 1996; Bloomer et al., Journal of Virology 71 :6641-6649, 1997; Naldini et al., Science 272:263-267, 1996; and Miyoshi et al., Proc. Natl. Acad. Sci. U.S.A. 94:10319, 1997).
  • viral vectors that can be used include, for example, adenoviral, lentiviral, and adeno-associated viral vectors, vaccinia virus, a bovine papilloma virus, or a herpes virus, such as Epstein-Barr Virus (also see, for example, the vectors of Miller, Human Gene Therapy 15-14, 1990; Friedman, Science 244:1275-1281 , 1989; Eglitis et al., BioTechniques 6:608-614, 1988;
  • Epstein-Barr Virus also see, for example, the vectors of Miller, Human Gene Therapy 15-14, 1990; Friedman, Science 244:1275-1281 , 1989; Eglitis et al., BioTechniques 6:608-614, 1988;
  • Retroviral vectors are particularly well developed and have been used in clinical settings (Rosenberg et al., N. Engl. J . Med 323:370, 1990; Anderson et al., U.S. Pat. No. 5,399,346).
  • Non-viral approaches can also be employed for the expression of a protein in ceil.
  • a nucleic acid molecule can be introduced into a cell by administering the nucleic acid in the presence of lipofection (Feigner et al., Proc. Natl. Acad. Sci. U.S.A. 84:741 3, 1987; Ono et a!., Neuroscience Letters 17:259, 1990; Brigham et al., Am. J. Med. Sci. 298:278, 1989;
  • RNA molecules can also be potentially beneficial for delivery of DNA into a ceil.
  • Transplantation of normal genes into the affected tissues of a subject can also be accomplished by transferring a normal nucleic acid into a cuitivatable ceil type ex vivo (e.g., an autologous or heterologous primary cell or progeny thereof), after which the cell (or its descendants) are injected into a targeted tissue or are injected systemically.
  • Recombinant receptors can also be derived or obtained using transposases or targeted nucleases (e.g. Zinc finger nucleases, meganucleases, or TALE nucleases).
  • Transient expression may be obtained by RNA
  • cDNA expression for use in polynucleotide therapy methods can be directed from any suitable promoter (e.g., the human cytomegalovirus (CMV), simian virus 40 (SV40), or metailothionein promoters), and regulated by any appropriate mammalian regulatory element or intron (e.g. the elongation factor 1c enhancer/promoter/intron structure).
  • CMV human cytomegalovirus
  • SV40 simian virus 40
  • metailothionein promoters regulated by any appropriate mammalian regulatory element or intron (e.g. the elongation factor 1c enhancer/promoter/intron structure).
  • enhancers known to preferentially direct gene expression in specific cell types can be used to direct the expression of a nucleic acid.
  • the enhancers used can include, without limitation, those that are characterized as tissue- or cell-specific enhancers.
  • regulation can be mediated by the cognate regulatory sequences or, if desired, by regulatory sequences derived from a heterologous source, including any of the promoters or regulatory elements described above.
  • the resulting cells can then be grown under conditions similar to those for unmodified cells, whereby the modified ceils can be expanded and used for a variety of purposes.
  • Also included in the invention are 19z1 , CD19, CD8, CD3 , dsRed, P28BB, PSMA, CD28, 4-1 BB, GFP polypeptides or fragments thereof that are modified in ways that enhance their anti-neopiastic activity when expressed in an immunoresponsive cell.
  • the invention provides methods for optimizing an amino acid sequence or nucleic acid sequence by producing an alteration in the sequence. Such alterations may include certain mutations, deletions, insertions, or post-translational modifications.
  • the invention further includes analogs of any naturally-occurring polypeptide of the invention. Analogs can differ from a naturally-occurring polypeptide of the invention by amino acid sequence differences, by post-translational modifications, or by both.
  • Analogs of the invention will generally exhibit at least 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity with all or part of a naturally-occurring amino, acid sequence of the invention.
  • the length of sequence comparison is at least 5, 10, 15 or 20 amino acid residues, preferably at least 25, 50, or 75 amino acid residues, and more preferably more than 100 amino acid residues.
  • a BLAST program may be used, with a probability score between e 3 and e " 00 indicating a closely related sequence.
  • Modifications include in vivo and in vitro chemical derivatization of polypeptides, e.g., acetylation, carboxyiation, phosphorylation, or giycosylation; such modifications may occur during polypeptide synthesis or processing or following treatment with isolated modifying enzymes.
  • Analogs can also differ from the naturally-occurring polypeptides of the invention by alterations in primary sequence.
  • the invention also provides fragments of any one of the polypeptides or peptide domains of the invention.
  • a fragment means at least 5, 10, 13, or 15 amino acids.
  • a fragment is at least 20 contiguous amino acids, at least 30 contiguous amino acids, or at least 50 contiguous amino acids, and in other embodiments at least 60 to 80, 100, 200, 300 or more contiguous amino acids.
  • Fragments of the invention can be generated by methods known to those skilled in the art or may result from normal protein processing (e.g., removal of amino acids from the nascent polypeptide that are not required for biological activity or removal of amino acids by alternative mRNA splicing or alternative protein processing events).
  • Non-protein analogs have a chemical structure designed to mimic the functional activity of a protein of the invention. Such analogs are administered according to methods of the invention. Such analogs may exceed the
  • Co- stimulatory ligands include, without limitation, tumor necrosis factor (TNF) ligands, cytokines (such as IL-2, IL-12, !L-15 or IL21 ), and immunoglobulin (ig) superfamily ligands.
  • TNF tumor necrosis factor
  • cytokines such as IL-2, IL-12, !L-15 or IL21
  • immunoglobulin (ig) superfamily ligands include, without limitation, tumor necrosis factor (TNF) ligands, cytokines (such as IL-2, IL-12, !L-15 or IL21 ), and immunoglobulin (ig) superfamily ligands.
  • ig immunoglobulin
  • Tumor necrosis factor is a cytokine involved in systemic inflammation and stimulates the acute phase reaction, its primary role is in the regulation of immune cells.
  • Tumor necrosis factor (TNF) ligands share a number of common features. The majority of the ligands are synthesized as type II transmembrane proteins (extracelluiarC-terminus) containing a short cytoplasmic segment and a relatively long extracellular region.
  • TNF ligands include, without limitation, nerve growth factor (NGF), CD40L (CD40L)/CD154, CD137L/4- 1 BBL, tumor necrosis factor alpha (TNFa), CD134L/OX40L/CD252, CD27L/CD70, Fas ligand (FasL), CD30L/CD153, tumor necrosis factor beta (TNF(3)/iymphotoxin- aipha (LTa), lymphotoxin-beta (ur(3), CD257/B cell-activating factor
  • immunoglobulin (Ig) superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. These proteins share structural features with immunoglobulins - they possess an immunoglobulin domain (fold). Immunoglobulin superfamily ligands include, without limitation, CD80 and CD86, both ligands for CD28.
  • compositions comprising genetically modified immunoresponsive ceils of the invention can be provided systemically or directly to a subject for the treatment of a neoplasia, pathogen infection, or infectious disease.
  • ceils of the invention are directly injected into an organ of interest (e.g., an organ affected by a neoplasia).
  • compositions comprising genetically modified immunoresponsive cells are provided indirectly to the organ of interest, for example, by administration into the circulatory system (e.g. , the tumor vasculature).
  • Expansion and differentiation agents can be provided prior to, during or after administration of the cells to increase production of T cells, NK cells, or CTL cells in vitro or in vivo.
  • the modified cells can be administered in any physiologically acceptable vehicle, normaily intravascuiarly, although they may also be introduced into bone or other convenient site where the cells may find an appropriate site for regeneration and differentiation (e.g., thymus). Usuaily, at least 1x10 5 cells will be administered, eventually reaching 1x10 10 , or more.
  • Genetically modified immunoresponsive cells of the invention can comprise a purified population of celis. Those skilled in the art can readily determine the percentage of genetically modified immunoresponsive cells in a population using various well-known methods, such as fluorescence activated cell sorting (FACS). Preferable ranges of purity in populations comprising genetically modified immunoresponsive ceils are about 50 to about 55%, about 55 to about 60%, and about 65 to about 70%.
  • the purity is about 70 to about 75%, about 75 to about 80%, about 80 to about 85%; and still more preferably the purity is about 85 to about 90%, about 90 to about 95%, and about 95 to about 100%. Dosages can be readily adjusted by those skilled in the art (e.g., a decrease in purity may require an increase in dosage).
  • the cells can be introduced by injection, catheter, or the like, if desired, factors can also be included, including, but not limited to, interleukins, e.g. IL-2, IL- 3, IL-6, and IL-1 1 , as well as the other interleukins, the colony stimulating factors, such as G-, M- and GM-CSF, interferons, e.g. .gamma. -interferon and erythropoietin.
  • interleukins e.g. IL-2, IL- 3, IL-6, and IL-1 1
  • the colony stimulating factors such as G-, M- and GM-C
  • compositions of the invention include pharmaceutical compositions comprising genetically modified immunoresponsive celis or their progenitors and a pharmaceutically acceptable carrier.
  • Administration can be autologous or heterologous.
  • immunoresponsive ceils, or progenitors can be obtained from one subject, and administered to the same subject or a different, compatible subject.
  • Peripheral blood derived immunoresponsive cells of the invention or their progeny e.g., in vivo, ex vivo or in vitro derived
  • a therapeutic composition of the present invention e.g., a pharmaceutical composition containing a genetically modified immunoresponsive cell
  • it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion).
  • compositions of the invention comprising genetically modified immunoresponsive cells can be conveniently provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may be buffered to a selected pH.
  • sterile liquid preparations e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may be buffered to a selected pH.
  • Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues.
  • Liquid or viscous compositions can comprise carriers, which can be a solvent or dispersing medium containing, for example, water, saline, phosphate buffered saline, polyoi (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like) and suitable mixtures thereof.
  • carriers can be a solvent or dispersing medium containing, for example, water, saline, phosphate buffered saline, polyoi (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like) and suitable mixtures thereof.
  • Sterile injectable solutions can be prepared by incorporating the genetically modified immunoresponsive cells utilized in practicing the present invention in the required amount of the appropriate solvent with various amounts of the other ingredients, as desired.
  • Such compositions may be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physioiogical saline, glucose, dextrose, or the like.
  • a suitable carrier diluent, or excipient
  • the compositions can also be lyophiiized.
  • compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcelluiose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
  • auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcelluiose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
  • Standard texts such as "REMINGTON'S PHARMACEUTICAL SCIENCE", 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.
  • compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the genetically modified
  • compositions can be isotonic, i.e., they can have the same osmotic pressure as blood and lacrimal fluid.
  • the desired isotonicity of the compositions of this invention may be accomplished using sodium chloride, or other
  • Sodium chloride is preferred particularly for buffers containing sodium ions.
  • Viscosity of the compositions can be maintained at the selected level using a pharmaceutically acceptable thickening agent.
  • Methyiceiluiose is preferred because it is readily and economically available and is easy to work with.
  • suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like.
  • concentration of the thickener will depend upon the agent selected. The important point is to use an amount that will achieve the selected viscosity.
  • suitable carriers and other additives will depend on the exact route of administration and the nature of the particular dosage form, e.g., liquid dosage form (e.g., whether the composition is to be formulated into a solution, a suspension, gel or another liquid form, such as a time release form or liquid-filled form).
  • compositions should be selected to be chemically inert and will not affect the viability or efficacy of the genetically modified immunoresponsive cells as described in the present invention. This will present no problem to those skilled in chemical and pharmaceutical principies,or problems can be readily avoided by reference to standard texts or by simple experiments (not involving undue experimentation), from this disclosure and the documents cited herein.
  • One consideration concerning the therapeutic use of genetically modified immunoresponsive cells of the invention is the quantity of ceils necessary to achieve an optimal effect. The quantity of ceils to be administered will vary for the subject being treated.
  • between 10 4 to 10 10 , between 10 5 to 10 9 , or between 10 6 and 10 s genetically modified immunoresponsive cells of the invention are administered to a human subject. More effective ceils may be administered in even smaller numbers. In some embodiments, at least about 1 x 10 8 , 2 x 10 8 , 3 x 10 8 , 4 x 10 8 , and 5 x 10 8 genetically modified immunoresponsive cells of the invention are administered to a human subject. The precise determination of what would be considered an effective dose may be based on factors individual to each subject, including their size, age, sex, weight, and condition of the particular subject. Dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art.
  • any additives in addition to the active ceil(s) and/or agent(s) are present in an amount of 0.001 to 50 % (weight) solution in phosphate buffered saline, and the active ingredient is present in the order of micrograms to milligrams, such as about 0.0001 to about 5 wt %, preferably about 0.0001 to about 1 wt %, still more preferably about 0.0001 to about 0.05 wt % or about 0.001 to about 20 wt %, preferably about 0.01 to about 10 wt %, and still more preferably about 0.05 to about 5 wt %.
  • any composition to be administered to an animal or human, and for any particular method of
  • toxicity such as by determining the lethal dose (LD) and LD50 in a suitable animal model e.g., rodent such as mouse; and, the dosage of the composition(s), concentration of components therein and timing of administering the composition(s), which elicit a suitable response.
  • kits for treating neoplasia in a subject are also contemplated herein.
  • methods for treating a pathogen infection or other infectious disease in a subject comprise administering a T cell, NK cell, or CTL cell of the invention in an amount effective to achieve the desired effect, be it palliation of an existing condition or prevention of recurrence.
  • the amount administered is an amount effective in producing the desired effect.
  • An effective amount can be provided in one or a series of administrations.
  • An effective amount can be provided in a bolus or by continuous perfusion.
  • an “effective amount” is an amount sufficient to effect a beneficial or desired clinicai result upon treatment.
  • An effective amount can be administered to a subject in one or more doses.
  • an effective amount is an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of the disease, or otherwise reduce the pathological consequences of the disease.
  • the effective amount is generally determined by the physician on a case-by-case basis and is within the skill of one in the art. Several factors are typically taken into account when
  • determining an appropriate dosage to achieve an effective amount include age, sex and weight of the subject, the condition being treated, the severity of the condition and the form and effective concentration of the antigen-binding fragment administered.
  • ceil doses in the range of 10 6 — 10 10 are typically infused.
  • T cells are induced that are specifically directed against the specific antigen.
  • "Induction" of T cells can include inactivation of antigen-specific T ceils such as by deletion or anergy. inactivation is particularly useful to establish or reestablish tolerance such as in autoimmune disorders.
  • the modified cells can be administered by any method known in the art including, but not limited to, intravenous, subcutaneous, intranodal, intratumorai, intrathecal, intrapleural, intraperitoneal and directly to the thymus.
  • the invention provides methods for increasing an immune response in a subject in need thereof.
  • the invention provides methods for treating or preventing a neoplasia in a subject.
  • the invention provides therapies that are particularly useful for the treatment of subjects having prostate cancer, or metastatic prostate cancer that is not amenable to conventional therapeutic interventions.
  • Suitabiehuman subjects for therapy typically comprise two treatment groups that can be distinguished by clinical criteria. Subjects with "advanced disease” or "high tumor burden” are those who bear a clinically measurable tumor.
  • a clinically measurable tumor is one that can be detected on the basis of tumor mass (e.g., by palpation, CAT scan, sonogram, mammogram or X-ray; positive biochemical or histopathologic markers on their own are insufficient to identify this population).
  • composition embodied in this invention is administered to these subjects to elicit an anti-tumor response, with the objective of palliating their condition.
  • reduction in tumor mass occurs as a result, but any clinical improvement constitutes a benefit.
  • Clinical improvement includes decreased risk or rate of progression or reduction in pathological
  • adjuvant group are individuals who have had a history of neoplasia, but have been responsive to another mode of therapy.
  • the prior therapy can have included, but is not restricted to, surgical resection, radiotherapy, and traditional chemotherapy. As a result, these individuals have no clinically measurable tumor. However, they are suspected of being at risk for
  • This group can be further subdivided into high-risk and iow-risk individuals. The subdivision is made on the basis of features observed before or after the initial treatment. These features are known in the clinical arts, and are suitably defined for each different neoplasia. Features typical of high-risk subgroups are those in which the tumor has invaded neighboring tissues, or who show involvement of lymph nodes.
  • Another group have a genetic predisposition to neoplasia but have not yet evidenced clinical signs of neoplasia. For instance, women testing positive for a genetic mutation associated with breast cancer, but still of childbearing age, can wish to receive one or more of the antigen-binding fragments described herein in treatment prophylacticaliy to prevent the occurrence of neoplasia until it is suitable to perform preventive surgery.
  • glioblastoma melanoma
  • neuroblastoma adenocarcinoma
  • glioma soft tissue sarcoma
  • various carcinomas including prostate and small cell lung cancer
  • Suitable carcinomas further include any known in the field of oncology, including, but not limited to, astrocytoma,
  • fibrosarcoma myxosarcoma, liposarcoma, oligodendroglioma, ependymoma, medullobiastoma, primitive neural ectodermal tumor (PNET), chondrosarcoma, osteogenic sarcoma, pancreatic ductal adenocarcinoma, small and large cell lung adenocarcinomas, chordoma, angiosarcoma, endotheliosarcoma, squamous cell carcinoma, bronchoalveolarcarcinoma, epithelial adenocarcinoma, and liver metastases thereof, lymphangiosarcoma, iymphangioendotheliosarcoma, hepatoma, cholangiocarcinoma, synovioma, mesothelioma, Ewing's tumor, rhabdomyosarcoma, colon carcinoma, basal cell carcinoma, sweat gland carcinoma, papillar
  • craniopharyngioma ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, leukemia, multiple myeloma, Waldenstrom's macroglobuiinemia, and heavy chain disease
  • breast tumors such as ductal and lobular adenocarcinoma, squamous and adenocarcinomas of the uterine cervix, uterine and ovarian epithelial carcinomas, prostatic adenocarcinomas, transitional squamous cell carcinoma of the bladder, B and T cell lymphomas (nodular and diffuse) plasmacytoma, acute and chronic leukemias, malignant melanoma, soft tissue sarcomas and leiomyosarcomas.
  • the subjects can have an advanced form of disease, in which case the treatment objective can include mitigation or reversal of disease progression, and/or amelioration of side effects.
  • the subjects can have a history of the condition, for which they have already been treated, in which case the therapeutic objective will typically include a decrease or delay in the risk of recurrence.
  • the invention provides a method of treating or preventing a neoplasia in a subject, the method comprising administering an effective amount of an immunoresponsive cell comprising a receptor that binds a tumor antigen and activates the immunoresponsive ceil (e.g., TCR, CAR) and a vector encoding a receptor that binds another tumor antigen and stimulates the immunoresponsive cell, in one embodiment, the neoplasia is selected from the group consisting of prostate cancer, breast cancer, blood cancers (e.g.
  • leukemias lymphomas, and myelomas
  • ovarian cancer bladder cancer, brain cancer, colon cancer, intestinal cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, glioblastoma, and throat cancer.
  • the tumor antigen is one or more of carbonic anhydrase IX (CAIX), carcinoembryonic antigen (CEA), CD5, CD7, CD10, CD19, CD20, CD22, CD30, CD33, CD34, CD38, CD41 , CD44, CD49f, CD56, CD74, CD133, CD138, an antigen of a cytomegalovirus (CMV) infected cell (e.g., a cell surface antigen), epithelial giycoprotein-2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), receptor tyrosine-protein kinases erb-B2,3,4, foiate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-a, Gangiioside G2 (GD2), Gangiioside G3 (GD3), human Epidermal Growth Factor Receptor 2 (HER-2
  • adoptively transferred human T or NK cells are endowed with augmented and selective cytolytic activity at the tumor site.
  • a receptor that binds a tumor antigen and activates the immunoresponsive ceil e.g., TCR, CAR
  • a vector encoding a receptor that binds another tumor antigen and stimulates the immunoresponsive cell e.g. CCR
  • adoptively transferred human T or NK cells are endowed with augmented and selective cytolytic activity at the tumor site.
  • co-stimulatory ligandexpressing T ceils turn the tumor or viral infection site into a highly conductive environment for a wide range of immune ceils involved in the physiological anti-tumor or antiviral response (tumor infiltrating lymphocytes, NK-, NKT- cells, dendritic cells, and macrophages).
  • the invention provides methods for treating subjects with a pathogen infection (e.g., viral infection, bacterial infection, fungal infection, parasite infection, or protozoa! infection).
  • a pathogen infection e.g., viral infection, bacterial infection, fungal infection, parasite infection, or protozoa! infection.
  • the invention is particularly useful for enhancing an immune response in an
  • Exemplary viral infections susceptible to treatment using a method of the invention include, but are not limited to, Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Human Immunodeficiency Virus (HIV), and influenza virus infections.
  • CMV Cytomegalovirus
  • EBV Epstein Barr Virus
  • HAV Human Immunodeficiency Virus
  • influenza virus infections include, but are not limited to, influenza virus infections.
  • the invention provides a method of treating or preventing a pathogen infection in a subject, the method comprising administering an effective amount of an immunoresponsive cell as described herein.
  • kits for the treatment or prevention of a neoplasia, pathogen infection, immune disorder or allogeneic transplant includes a therapeutic or prophylactic composition containing an effective amount of an immunoresponsive cell comprising an activating antigen receptor and a co-stimulatory antigen receptor in unit dosage form.
  • the kit further comprise a co-stimulatory ligand.
  • the kit comprises a sterile container which contains a
  • Such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding
  • the immunoresponsive cell is provided together with instructions for administering the ceil to a subject having or at risk of developing a neoplasia, pathogen infection, immune disorder or allogeneic transplant.
  • the instructions will generally include information about the use of the composition for the treatment or prevention of neoplasia, pathogen infection, immune disorder or allogeneic transplant.
  • the instructions include at least one of the foliowing: description of the therapeutic agent; dosage schedule and administration for treatment or prevention of a neoplasia, pathogen infection, immune disorder or allogeneic transplant or symptoms thereof; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references.
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • Example 1 T cells co-expressing a chimeric antigen receptor (CAR) and a chimeric co-stimulating receptor (CCR) eradicated established tumors.
  • CAR chimeric antigen receptor
  • CCR chimeric co-stimulating receptor
  • the invention provides "tumor-sensing T ceils" that simultaneously engage two antigens co-expressed by a tumor ceil. Importantly, it has been found that the reactivity against tissues expressing either antigen alone should be negligible, only unleashing T cell activation in the presence of both antigens but not either one alone.
  • the invention is at least based in part on the discoveries that in combination provide selective T ceil immunoreactivity, and, thus, make this approach clinically relevant.
  • the first is to assign T cell activation to one antigen (e.g., CD19 or prostate stem cell antigen, PSCA), which may be mediated by a T cell receptor (TCR) or a chimeric antigen receptor (CAR). Costimulation is independently mediated by a "chimeric costimuiatory receptor" (CCR ), 2,13 which is targeted to a second antigen (e.g., prostate-specific membrane antigen, PSMA).
  • TCR T cell receptor
  • CAR chimeric antigen receptor
  • mice were systemicaily engrafted with 2.0 x 10 6 firefly-!uciferase expressing PC3 tumor cells that expressed both CD19 and PSMA ( Figure 5) and treated 19 days later with a single intravenous infusion of 1 .0 x 10 6 19z1 , 19z1 +P28BB, P28BB or control T cells. Thirty-five days later, mice that received P28BB T cells or control T cells were sacrificed due to tumor burden.
  • mice treated with 19z1 T cells had a marked reduction of tumor burden.
  • mice treated with 19z1 +P28BB T cells had undetectable tumor burden (Figure 2C).
  • the CD19 + tumors eventually relapsed in mice that received 19z1 T cells, while complete remission persisted in ail mice that received 19z1 +P28BB T cells ( Figure 2C). This result strongly indicated that tumor eradication had been achieved.
  • mice were administered one of 19z1 , P28BB, or 19z1 +P28BB T cells (1 .0 x 10 6 cells) intravenously. Mice that received P28BB T cells had progression of all three tumors and needed to be sacrificed within 35 days ( Figure 2D).
  • the CD19 + PSMA ⁇ and CD19 + PSMA + tumors underwent a substantial reduction compared to their progression in recipients of P28BB T cells, before eventually progressing. Consistent with prior results, mice treated with 19z1 +P28BB T cells showed complete eradication of CD19 + PSMA + tumors.
  • mice were inoculated intravenously with 2 x 106 FFLuc-expressing PC3 cells positive for PSMA, PSCA, or both (Figure 5).
  • one set of mice received 1 x 106 Mzl+P28BB CAR+ T cells infused intravenously, and another set of received 1 x 106 Lz1 +P28BB CARP T cells.
  • Mice bearing PSCA+PSMA tumor cells that were treated with the more efficient Mzl+P28BB T cells exhibited greater tumor regression than mice treated with Lz1 +PBB T cells (Figure 3C). Similar to the CD19 experiment ( Figure 2C), these tumors eventually relapsed and progressed.
  • mice bearing PSCA+PSMA+ tumor celis Mzl+P28BB T ceils induced robust and long-term tumor eradication. Consistent with the lesser potency of Lzl+P28BB T ceils, tumor eradication in mice bearing PSCA+PSMA+ tumor cells treated with Lz1 +P28BB T cells was slower but nonetheless equally successful, resulting in strong tumor eradication and long-term survival of ail treated mice ( Figure 3C). Tumor eradication was not enhanced in control mice bearing either PSCAVSMA- or PSCA-PSMA+ tumors ( Figure 3C). A more stringent evaluation of background activity against PSCAVSMA.- tumors was tested in the context of animals also bearing PSCA+PSMA+ and PSCAPSMA+ tumors. Lz1 +P28BB T cells mediated eradication of PSCA+PSMA+ tumors without increasing eradication of PSCA+PSMA tumors ( Figure 3E), which was not different from that induced by Lzl T celis.
  • Targeted T ceil therapies have the potential to provide curative treatments but their applicability is limited by the paucity of validated tumor-specific targets. Extra- tumoral expression results indeed in "on-target, off-tumor” effects that 2-4" may be sometimes tolerable but are eventually lethal 11.
  • the method described herein provides improved targeting by supplying titrated activation and
  • T ceils are primed in lymph nodes by receiving activating and costimuiatory signals and migrate to peripheral sites, where effector functions of the T cells are not as dependent on costimuiation.
  • T cells engaged through an antigen receptor and a CCR may recirculate to other peripheral sites and display heightened cytolytic activity against tissues expressing only one of the targeted antigens (Figure 6A). Therefore, the present strategy was developed to address this problem of a potential systemic effect in order to spare cells singly positive for the antigen, including non-tumor cells (Figure 6B).
  • PSCA and PSMA are promising targets for the treatment of metastatic prostate cancer 26 ' 27 , although neither is absolutely prostate-specific.
  • PSCA expression is found in prostate cancer and within the renal pelvis, ureter, urinary bladder, and urethra.
  • Expression of PSMA strongly correlates with primary prostate cancer, metastases, as well as in astrocytes type II, the kidney proximal tubule and the intestinal brush border.
  • Dual PSCA/PSMA targeting is thus expected to increase prostate cancer targeting and reduce reactivity against these normal tissues. It is appreciated that this principle can be extended to other tumor types which express a pair of antigens, especially those that confer true tumor-specificity.
  • HER2, MUC1 , CD44, CD49f, and/or EpCAM could be used in this manner to treat breast cancer.
  • mesothelin, folate receptor-a, CD44, and/or CD133 could be used to treat ovarian cancer.
  • 32 ' 33 The targeting of tumor initiating cells or cancer stem cells, for which unique target antigens/structures have not yet been clearly identified34.3s would be particularly attractive using this approach.
  • An important aspect of this approach is to constrain and nearly abolish T cell activation in response to a single antigen. CARs with low affinity or low avidity that only provide a poor activation signal were found to be usefui for achieving this effect.
  • an endogenous TCR with low affinity or low avidity may be used in combination with a CCR to provide antigen-specific costimulation.
  • This backbone construct was used to exchange scFvs to generate SFG-Hzl, SFG-Mzl, and SFG-Lzl by directional cloning utilizing a Ncol site located 5' of the scFv and a Nod site located 3' of the scFv.
  • SFG- P28BB the fused CD28 and CD137 domains were PCR amplified from SFG- P28BBz1 and iigated 3' of the PSMA scFv using a 5' Ncol site and a 3' BamHI site to include a stop codon 3' of the BB domain, while the CD3 domain was removed.
  • VH variabie heavy
  • VL variabie light
  • Hzl, Mzl, and Lzl were generated byampiifying the variabie heavy (VH) and variabie light (VL) domains conferring PSCA antigen specificity of non-overlapping epitopes using degenerate primers from hybridomas as previously described. 36 These VH and V
  • Peripherai blood leukocytes were isolated using Ficoli gradients and transduced as previously described. Briefly, after 48-hour activation with 2 &g/ml_ phytohemagglutinin, cells were transduced twice via spinocuiation for 1 hour on retronectin coated plates over the next 48 hours and 20 U/mL of lL-2 was added. After allowing 3 days for vector expression, transduction efficiencies were determined via flow cytometry and bulk unsorted ceils were used for various assays or adoptive transfers.
  • PC3 human prostate tumor line was obtained from ATCC and retrovirally 16 transduced in order to generate PC3 -GFP/Luc, which was subsequently used to create 10 PC3-CD19, PC3-PSMA, PC3-CD19-PSMA, PC3- PSCA, and PC3-PSCA-PSMA via retroviral transduction.
  • Target cells expressing desired antigen were labeled with 5 Cr and co- cultured with T cells at decreasing effector : target ratio's. After 4 hours of culture, supernatant was removed and used to measure radioactivity released from chromium. Specific lysis was determined by subtracting background radioactivity of target celis not cultured with T cells and dividing by the radioactivity measured from target cells completely Iysed by using 0.2% Triton X-100.
  • Tumor celis expressing desired antigen were irradiated with 30 Gy prior to co-culture with 1.0 x 10 6 T cells at a 5:1 effector : target ratio. T cells were counted weekly using an Invitrogen Countess cell counter and then re-stimuiated with irradiated tumor celis. No exogenous cytokines were added to these co- cultures.
  • PC3 tumor cells were infused into NOD/SCID-IL2Ry mice obtained from either Jackson Laboratories or from in-house breeding under the protocol 04-10- 024 approved by the MSKCC Institutional Animal Care and Use Committee.
  • 1.0 x 10 6 tumor cells were injected per tumor site, established for 7 days upon which 1.0 x 10 6 chimeric positive T ceils were infused IV.
  • tumor burden quantitativeiy measure tumor burden by correlating the amount of tumor burden to luminescence using an S 100 system (Caliper Life Sciences) as previously described.
  • S 100 system Caliper Life Sciences
  • Tumor volume was calculated by multiplying the length, width, and height of each tumor.
  • Bispecific antibodies containing a PSCA specific scFv fused to a CD3 specific scFv were added at various amounts to untransduced T cells co-cultured with PSCA + PC3 at a 20:1 ratio, respectively in standard 4hr chromium release assay assays.
  • Cells were analyzed using an LSRII flow cytometer or sorted using a FACSAria cell sorter (BD Biosciences) as previously described. 16 Detection of chimeric receptor at the cell surface could be achieved directly by using AF647 conjugated goat-anti-mouse antibody (invitrogen). Antibodies for CD4-PE-Cy7, CD8-Pacific Blue, and CD19-APC were obtained from Invitrogen while PSCA antibodies were purified from hybridoma supernatants and PSMA antibodies were obtained from MBL Interantional.
  • Ciinicai cancer research an official journal of the American Association for Cancer Research 16, 3533-3538 (2010).
  • Ciinicai cancer research an official journal of the American Association for Cancer Research 11 , 2591-2596 (2005).
  • Ciinicai cancer research :

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Cited By (313)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014134165A1 (en) * 2013-02-26 2014-09-04 Memorial Sloan-Kettering Cancer Center Compositions and methods for immunotherapy
WO2015188141A2 (en) 2014-06-06 2015-12-10 Memorial Sloan-Kettering Cancer Ceneter Mesothelin-targeted chimeric antigen receptors and uses thereof
WO2015188119A1 (en) * 2014-06-06 2015-12-10 Bluebird Bio, Inc. Improved t cell compositions
WO2016033570A1 (en) 2014-08-28 2016-03-03 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for cd19
WO2016064929A1 (en) 2014-10-20 2016-04-28 Juno Therapeutics, Inc. Methods and compositions for dosing in adoptive cell therapy
WO2016073602A2 (en) 2014-11-05 2016-05-12 Juno Therapeutics, Inc. Methods for transduction and cell processing
WO2016090190A1 (en) 2014-12-03 2016-06-09 Juno Therapeutics, Inc. Methods and compositions for adoptive cell therapy
WO2016115177A1 (en) 2015-01-12 2016-07-21 Juno Therapeutics, Inc. Modified hepatitis post-transcriptional regulatory elements
WO2016115559A1 (en) 2015-01-16 2016-07-21 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for ror1
WO2016138034A1 (en) * 2015-02-24 2016-09-01 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
WO2016168493A1 (en) * 2015-04-15 2016-10-20 Prospect CharterCare RWMC, LLC d/b/a Roger Williams Medical Center Hepatic arterial infusion of car-t cells
WO2016166568A1 (en) 2015-04-16 2016-10-20 Juno Therapeutics Gmbh Methods, kits and apparatus for expanding a population of cells
WO2016172606A1 (en) * 2015-04-23 2016-10-27 Baylor College Of Medicine Cd5 chimeric antigen receptor for adoptive t cell therapy
WO2016196388A1 (en) 2015-05-29 2016-12-08 Juno Therapeutics, Inc. Composition and methods for regulating inhibitory interactions in genetically engineered cells
US9546206B2 (en) 2014-08-08 2017-01-17 The Board Of Trustees Of The Leland Stanford Junior University High affinity PD-1 agents and methods of use
WO2017021701A1 (en) * 2015-07-31 2017-02-09 King's College London Therapeutic agents
WO2017040945A1 (en) 2015-09-04 2017-03-09 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use
WO2017053906A1 (en) 2015-09-24 2017-03-30 Abvitro Llc Hiv antibody compositions and methods of use
CN106574272A (zh) * 2014-08-29 2017-04-19 哥莫阿波单克隆有限责任公司 靶向多样的多种抗原的通用嵌合抗原受体表达性免疫细胞及其制造方法及其在癌症、感染和自身免疫病的治疗中的应用
WO2017068419A2 (en) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Methods, kits, agents and apparatuses for transduction
WO2017068425A1 (en) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
WO2017068421A1 (en) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
WO2017079705A1 (en) 2015-11-05 2017-05-11 Juno Therapeutics, Inc. Chimeric receptors containing traf-inducing domains and related compositions and methods
WO2017079703A1 (en) 2015-11-05 2017-05-11 Juno Therapeutics, Inc. Vectors and genetically engineered immune cells expressing metabolic pathway modulators and uses in adoptive cell therapy
WO2017096329A1 (en) 2015-12-03 2017-06-08 Juno Therapeutics, Inc. Modified chimeric receptors and related compositions and methods
WO2017096327A2 (en) 2015-12-03 2017-06-08 Juno Therapeutics, Inc. Compositions and methods for reducing immune responses against cell therapies
WO2017120501A1 (en) 2016-01-07 2017-07-13 Mayo Foundation For Medical Education And Research Methods of treating cancer with interferon
CN107002045A (zh) * 2014-12-24 2017-08-01 Ucl商务股份有限公司 细胞
WO2017161212A1 (en) 2016-03-16 2017-09-21 Juno Therapeutics, Inc. Methods for adaptive design of a treatment regimen and related treatments
WO2017161208A1 (en) 2016-03-16 2017-09-21 Juno Therapeutics, Inc. Methods for determining dosing of a therapeutic agent and related treatments
WO2017165571A1 (en) 2016-03-22 2017-09-28 Seattle Children's Hospital (dba Seattle Children's Research Institute) Early intervention methods to prevent or ameliorate toxicity
US9777061B2 (en) 2014-07-21 2017-10-03 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
WO2017173091A1 (en) 2016-03-30 2017-10-05 Musc Foundation For Research Development Methods for treatment and diagnosis of cancer by targeting glycoprotein a repetitions predominant (garp) and for providing effective immunotherapy alone or in combination
WO2017193107A2 (en) 2016-05-06 2017-11-09 Juno Therapeutics, Inc. Genetically engineered cells and methods of making the same
JP2017533706A (ja) * 2014-10-31 2017-11-16 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア 改変ｔ細胞に関する方法および組成物
WO2017205846A1 (en) 2016-05-27 2017-11-30 Aadigen, Llc Peptides and nanoparticles for intracellular delivery of genome-editing molecules
WO2017214207A2 (en) 2016-06-06 2017-12-14 Juno Therapeutics, Inc. Methods for the treatment of b cell malignancies using adoptive cell therapy
WO2018005556A1 (en) 2016-06-27 2018-01-04 Juno Therapeutics, Inc. Mhc-e restricted epitopes, binding molecules and related methods and uses
WO2018005559A1 (en) 2016-06-27 2018-01-04 Juno Therapeutics, Inc. Method of identifying peptide epitopes, molecules that bind such epitopes and related uses
WO2018023093A1 (en) 2016-07-29 2018-02-01 Juno Therapeutics, Inc. Immunomodulatory polypeptides and related compositions and methods
WO2018023100A2 (en) 2016-07-29 2018-02-01 Juno Therapeutics, Inc. Anti-idiotypic antibodies and related methods
WO2018023094A1 (en) 2016-07-29 2018-02-01 Juno Therapeutics, Inc. Methods for assessing the presence or absence of replication competent virus
WO2018027036A1 (en) * 2016-08-03 2018-02-08 Dipersio John F Gene editing of car-t cells for the treatment of t cell malignancies with chimeric antigen receptors
WO2018049420A1 (en) 2016-09-12 2018-03-15 Juno Therapeutics, Inc. Perfusion bioreactor bag assemblies
WO2018063985A1 (en) 2016-09-28 2018-04-05 Atossa Genetics Inc. Methods of adoptive cell therapy
WO2018067618A1 (en) 2016-10-03 2018-04-12 Juno Therapeutics, Inc. Hpv-specific binding molecules
CN107922488A (zh) * 2015-04-02 2018-04-17 纪念斯隆-凯特琳癌症中心 Tnfrsf14/hvem蛋白及其使用方法
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018085731A2 (en) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and a btk inhibitor
WO2018093591A1 (en) 2016-11-03 2018-05-24 Juno Therapeutics, Inc. Combination therapy of a cell based therapy and a microglia inhibitor
EP3325504A1 (en) * 2015-07-21 2018-05-30 Novartis AG Methods for improving the efficacy and expansion of immune cells
WO2018102786A1 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods for modulation of car-t cells
WO2018102785A2 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors
WO2018102787A1 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods for determining car-t cells dosing
WO2018102612A1 (en) 2016-12-02 2018-06-07 Juno Therapeutics, Inc. Engineered b cells and related compositions and methods
AU2014214850B2 (en) * 2013-02-06 2018-06-14 Celgene Corporation Modified T lymphocytes having improved specificity
WO2018106732A1 (en) 2016-12-05 2018-06-14 Juno Therapeutics, Inc. Production of engineered cells for adoptive cell therapy
EP3336107A1 (en) 2016-12-15 2018-06-20 Miltenyi Biotec GmbH Immune cells expressing an antigen binding receptor and a chimeric costimulatory receptor
WO2018132518A1 (en) 2017-01-10 2018-07-19 Juno Therapeutics, Inc. Epigenetic analysis of cell therapy and related methods
WO2018134691A2 (en) 2017-01-20 2018-07-26 Juno Therapeutics Gmbh Cell surface conjugates and related cell compositions and methods
JP2018522567A (ja) * 2015-08-07 2018-08-16 シアトル チルドレンズ ホスピタル， ディービーエー シアトル チルドレンズ リサーチ インスティテュート 固形腫瘍を標的とする二重特異性ｃａｒ ｔ細胞
WO2018157171A2 (en) 2017-02-27 2018-08-30 Juno Therapeutics, Inc. Compositions, articles of manufacture and methods related to dosing in cell therapy
WO2018165228A1 (en) 2017-03-08 2018-09-13 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use
WO2018170188A2 (en) 2017-03-14 2018-09-20 Juno Therapeutics, Inc. Methods for cryogenic storage
WO2018167486A1 (en) 2017-03-15 2018-09-20 Oxford Biomedica (Uk) Limited Method
WO2018187791A1 (en) 2017-04-07 2018-10-11 Juno Therapeutics, Inc Engineered cells expressing prostate-specific membrane antigen (psma) or a modified form thereof and related methods
WO2018191723A1 (en) 2017-04-14 2018-10-18 Juno Therapeutics, Inc. Methods for assessing cell surface glycosylation
WO2018195175A1 (en) 2017-04-18 2018-10-25 FUJIFILM Cellular Dynamics, Inc. Antigen-specific immune effector cells
WO2018200583A1 (en) * 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
WO2018197949A1 (en) 2017-04-27 2018-11-01 Juno Therapeutics Gmbh Oligomeric particle reagents and methods of use thereof
US10117896B2 (en) 2012-10-05 2018-11-06 The Trustees Of The University Of Pennsylvania Use of a trans-signaling approach in chimeric antigen receptors
WO2018204427A1 (en) 2017-05-01 2018-11-08 Juno Therapeutics, Inc. Combination of a cell therapy and an immunomodulatory compound
WO2018223101A1 (en) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
WO2018223098A1 (en) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles of manufacture and methods related to toxicity associated with cell therapy
US20180348227A1 (en) * 2016-08-04 2018-12-06 Memorial Sloan-Kettering Cancer Center Cancer antigen targets and uses thereof
WO2018234370A1 (en) 2017-06-20 2018-12-27 Institut Curie Immune cells defective for suv39h1
WO2019006427A1 (en) 2017-06-29 2019-01-03 Juno Therapeutics, Inc. WALL MODEL FOR ASSESSING TOXICITIES ASSOCIATED WITH IMMUNOTHERAPIES
WO2019027850A1 (en) 2017-07-29 2019-02-07 Juno Therapeutics, Inc. CELL EXPANSION REAGENTS EXPRESSING RECOMBINANT RECEPTORS
WO2019032929A1 (en) 2017-08-09 2019-02-14 Juno Therapeutics, Inc. METHODS AND COMPOSITIONS FOR PREPARING GENETICALLY MODIFIED CELLS
WO2019032927A1 (en) 2017-08-09 2019-02-14 Juno Therapeutics, Inc. METHODS FOR PRODUCING GENETICALLY MODIFIED CELL COMPOSITIONS AND COMPOSITIONS THEREOF
WO2019046832A1 (en) 2017-09-01 2019-03-07 Juno Therapeutics, Inc. GENE EXPRESSION AND EVALUATION OF RISK OF DEVELOPMENT OF TOXICITY FOLLOWING CELL THERAPY
WO2019051335A1 (en) 2017-09-07 2019-03-14 Juno Therapeutics, Inc. METHODS OF IDENTIFYING CELLULAR CHARACTERISTICS RELATED TO RESPONSES ASSOCIATED WITH CELL THERAPY
WO2019057102A1 (en) 2017-09-20 2019-03-28 Tsinghua University HPK1 TARGETING ARNG AND HPK1 GENE EDITING METHOD
EP3307876A4 (en) * 2015-06-10 2019-04-03 Nantkwest, Inc. MODIFIED NK-92 CELLS FOR THE TREATMENT OF CANCER
WO2019070541A1 (en) 2017-10-03 2019-04-11 Juno Therapeutics, Inc. HPV-SPECIFIC BINDING MOLECULES
EP3328994A4 (en) * 2015-07-31 2019-04-17 Memorial Sloan-Kettering Cancer Center CD56-Faced Antigen-Binding Proteins and Uses Thereof
WO2019089982A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Method of assessing activity of recombinant antigen receptors
WO2019087151A1 (en) 2017-11-03 2019-05-09 Sorrento Therapeutics, Inc. Cd38-directed chimeric antigen receptor constructs
WO2019089858A2 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
WO2019090004A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Process for producing a t cell composition
WO2019089855A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Process for generating therapeutic compositions of engineered cells
WO2019089884A2 (en) 2017-11-01 2019-05-09 Editas Medicine, Inc. Methods, compositions and components for crispr-cas9 editing of tgfbr2 in t cells for immunotherapy
WO2019090202A1 (en) 2017-11-06 2019-05-09 Editas Medicine, Inc. Methods, compositions and components for crispr-cas9 editing of cblb in t cells for immunotherapy
WO2019090364A1 (en) 2017-11-06 2019-05-09 Juno Therapeutics, Inc. Combination of a cell therapy and a gamma secretase inhibitor
WO2019090003A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Chimeric antigen receptors specific for b-cell maturation antigen (bcma)
WO2019089848A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods associated with tumor burden for assessing response to a cell therapy
WO2019094835A1 (en) 2017-11-10 2019-05-16 Juno Therapeutics, Inc. Closed-system cryogenic vessels
WO2019109053A1 (en) 2017-12-01 2019-06-06 Juno Therapeutics, Inc. Methods for dosing and for modulation of genetically engineered cells
WO2019113557A1 (en) 2017-12-08 2019-06-13 Juno Therapeutics, Inc. Process for producing a composition of engineered t cells
WO2019113559A2 (en) 2017-12-08 2019-06-13 Juno Therapeutics, Inc. Phenotypic markers for cell therapy and related methods
WO2019113556A1 (en) 2017-12-08 2019-06-13 Juno Therapeutics, Inc. Serum-free media formulation for culturing cells and methods of use thereof
WO2019118937A1 (en) 2017-12-15 2019-06-20 Juno Therapeutics, Inc. Anti-cct5 binding molecules and methods of use thereof
WO2019141270A1 (zh) * 2018-01-19 2019-07-25 科济生物医药（上海）有限公司 SynNotch受体调控表达IL12
WO2019152747A1 (en) 2018-01-31 2019-08-08 Juno Therapeutics, Inc. Methods and reagents for assessing the presence or absence of replication competent virus
WO2019152743A1 (en) 2018-01-31 2019-08-08 Celgene Corporation Combination therapy using adoptive cell therapy and checkpoint inhibitor
WO2019148656A1 (zh) * 2018-02-05 2019-08-08 深圳市默赛尔生物医学科技发展有限公司 多信号嵌合抗原受体及其表达基因、其修饰的nk细胞及抗肿瘤的药物
US10383929B2 (en) 2014-12-12 2019-08-20 Bluebird Bio, Inc. BCMA chimeric antigen receptors
WO2019161133A1 (en) 2018-02-15 2019-08-22 Memorial Sloan Kettering Cancer Center Foxp3 targeting agent compositions and methods of use for adoptive cell therapy
WO2019170845A1 (en) 2018-03-09 2019-09-12 Ospedale San Raffaele S.R.L. Il-1 antagonist and toxicity induced by cell therapy
WO2019170147A1 (zh) 2018-03-09 2019-09-12 科济生物医药（上海）有限公司 用于治疗肿瘤的方法和组合物
US10428305B2 (en) 2014-05-15 2019-10-01 National University Of Singapore Modified natural killer cells that express IL15 and uses thereof
WO2019195486A1 (en) 2018-04-05 2019-10-10 Juno Therapeutics, Inc. T cell receptors and engineered cells expressing same
WO2019195492A1 (en) 2018-04-05 2019-10-10 Juno Therapeutics, Inc. Methods of producing cells expressing a recombinant receptor and related compositions
WO2019195491A1 (en) 2018-04-05 2019-10-10 Juno Therapeutics, Inc. T cells expressing a recombinant receptor, related polynucleotides and methods
US10464988B2 (en) 2015-10-23 2019-11-05 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
WO2019213184A1 (en) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor
US10538739B2 (en) 2013-01-28 2020-01-21 St. Jude Children's Research Hospital, Inc. Chimeric receptor with NKG2D specificity for use in cell therapy against cancer and infectious disease
WO2020020210A1 (zh) 2018-07-24 2020-01-30 科济生物医药（上海）有限公司 免疫效应细胞治疗肿瘤的方法
WO2020033927A2 (en) 2018-08-09 2020-02-13 Juno Therapeutics, Inc. Processes for generating engineered cells and compositions thereof
WO2020033916A1 (en) 2018-08-09 2020-02-13 Juno Therapeutics, Inc. Methods for assessing integrated nucleic acids
WO2020056047A1 (en) 2018-09-11 2020-03-19 Juno Therapeutics, Inc. Methods for mass spectrometry analysis of engineered cell compositions
WO2020061256A1 (en) 2018-09-19 2020-03-26 FUJIFILM Cellular Dynamics, Inc. Protein l for activation and expansion of chimeric antigen receptor-modified immune cells
WO2020089343A1 (en) 2018-10-31 2020-05-07 Juno Therapeutics Gmbh Methods for selection and stimulation of cells and apparatus for same
WO2020092854A2 (en) 2018-11-01 2020-05-07 Juno Therapeutics, Inc. Chimeric antigen receptors specific for g protein-coupled receptor class c group 5 member d (gprc5d)
WO2020092848A2 (en) 2018-11-01 2020-05-07 Juno Therapeutics, Inc. Methods for treatment using chimeric antigen receptors specific for b-cell maturation antigen
WO2020097132A1 (en) 2018-11-06 2020-05-14 Juno Therapeutics, Inc. Process for producing genetically engineered t cells
WO2020097403A1 (en) 2018-11-08 2020-05-14 Juno Therapeutics, Inc. Methods and combinations for treatment and t cell modulation
WO2020102770A1 (en) 2018-11-16 2020-05-22 Juno Therapeutics, Inc. Methods of dosing engineered t cells for the treatment of b cell malignancies
WO2020106621A1 (en) 2018-11-19 2020-05-28 Board Of Regents, The University Of Texas System A modular, polycistronic vector for car and tcr transduction
WO2020112493A1 (en) 2018-11-29 2020-06-04 Board Of Regents, The University Of Texas System Methods for ex vivo expansion of natural killer cells and use thereof
WO2020113029A2 (en) 2018-11-28 2020-06-04 Board Of Regents, The University Of Texas System Multiplex genome editing of immune cells to enhance functionality and resistance to suppressive environment
WO2020113188A2 (en) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Methods for dosing and treatment of b cell malignancies in adoptive cell therapy
WO2020113194A2 (en) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Methods for treatment using adoptive cell therapy
WO2020160050A1 (en) 2019-01-29 2020-08-06 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1)
US10738278B2 (en) 2014-07-15 2020-08-11 Juno Therapeutics, Inc. Engineered cells for adoptive cell therapy
EP3694872A1 (en) 2017-10-12 2020-08-19 Board Of Regents, The University Of Texas System T cell receptors for immunotherapy
WO2020169974A1 (en) 2019-02-19 2020-08-27 King's College London Hypoxia-responsive chimeric antigen receptors
US10774343B2 (en) 2014-04-25 2020-09-15 Bluebird Bio, Inc. MND promoter chimeric antigen receptors
US10786533B2 (en) 2015-07-15 2020-09-29 Juno Therapeutics, Inc. Engineered cells for adoptive cell therapy
WO2020223535A1 (en) 2019-05-01 2020-11-05 Juno Therapeutics, Inc. Cells expressing a recombinant receptor from a modified tgfbr2 locus, related polynucleotides and methods
WO2020223571A1 (en) 2019-05-01 2020-11-05 Juno Therapeutics, Inc. Cells expressing a chimeric receptor from a modified cd247 locus, related polynucleotides and methods
WO2020247832A1 (en) 2019-06-07 2020-12-10 Juno Therapeutics, Inc. Automated t cell culture
WO2020252218A1 (en) 2019-06-12 2020-12-17 Juno Therapeutics, Inc. Combination therapy of a cell-mediated cytotoxic therapy and an inhibitor of a prosurvival bcl2 family protein
WO2021013950A1 (en) 2019-07-23 2021-01-28 Mnemo Therapeutics Immune cells defective for suv39h1
WO2021035194A1 (en) 2019-08-22 2021-02-25 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and an enhancer of zeste homolog 2 (ezh2) inhibitor and related methods
WO2021038036A1 (en) * 2019-08-28 2021-03-04 King's College London B CELL TARGETED PARALLEL CAR (pCAR) THERAPEUTIC AGENTS
WO2021041994A2 (en) 2019-08-30 2021-03-04 Juno Therapeutics, Inc. Machine learning methods for classifying cells
WO2021043804A1 (en) 2019-09-02 2021-03-11 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
US10967005B2 (en) 2013-03-15 2021-04-06 Celgene Corporation Modified T lymphocytes comprising a BAFF antibody-inducible caspase and methods of apoptosis
WO2021078910A1 (en) 2019-10-22 2021-04-29 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
WO2021084050A1 (en) 2019-10-30 2021-05-06 Juno Therapeutics Gmbh Cell selection and/or stimulation devices and methods of use
WO2021092498A1 (en) 2019-11-07 2021-05-14 Juno Therapeutics, Inc. Combination of a t cell therapy and (s)-3-[4-(4-morpholin-4 ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]- piperidine-2,6-dione
WO2021092097A1 (en) 2019-11-05 2021-05-14 Juno Therapeutics, Inc. Methods of determining attributes of therapeutic t cell compositions
WO2021113780A1 (en) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Anti-idiotypic antibodies to gprc5d-targeted binding domains and related compositions and methods
WO2021113770A1 (en) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Methods related to toxicity and response associated with cell therapy for treating b cell malignancies
WO2021113776A1 (en) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Anti-idiotypic antibodies to bcma-targeted binding domains and related compositions and methods
WO2021151008A1 (en) 2020-01-24 2021-07-29 Juno Therapuetics, Inc. Methods for dosing and treatment of follicular lymphoma and marginal zone lymphoma in adoptive cell therapy
WO2021154887A1 (en) 2020-01-28 2021-08-05 Juno Therapeutics, Inc. Methods for t cell transduction
WO2021163389A1 (en) 2020-02-12 2021-08-19 Juno Therapeutics, Inc. Bcma-directed chimeric antigen receptor t cell compositions and methods and uses thereof
WO2021163391A1 (en) 2020-02-12 2021-08-19 Juno Therapeutics, Inc. Cd19-directed chimeric antigen receptor t cell compositions and methods and uses thereof
WO2021167908A1 (en) 2020-02-17 2021-08-26 Board Of Regents, The University Of Texas System Methods for expansion of tumor infiltrating lymphocytes and use thereof
WO2021164959A1 (en) * 2020-02-17 2021-08-26 Miltenyi Biotec B.V. & Co. KG Method for providing personalized cells with chimeric antigen receptors (car) against tumor microenvironment cells
US11130820B2 (en) 2012-12-20 2021-09-28 Celgene Corporation Chimeric antigen receptors
US11141436B2 (en) 2019-03-05 2021-10-12 Nkarta, Inc. Immune cells engineered to express CD19-directed chimeric antigen receptors and uses thereof in immunotherapy
WO2021207689A2 (en) 2020-04-10 2021-10-14 Juno Therapeutics, Inc. Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen
WO2021222330A2 (en) 2020-04-28 2021-11-04 Juno Therapeutics, Inc. Combination of bcma-directed t cell therapy and an immunomodulatory compound
US11173179B2 (en) 2015-06-25 2021-11-16 Icell Gene Therapeutics Llc Chimeric antigen receptor (CAR) targeting multiple antigens, compositions and methods of use thereof
WO2021231661A2 (en) 2020-05-13 2021-11-18 Juno Therapeutics, Inc. Process for producing donor-batched cells expressing a recombinant receptor
WO2021228999A1 (en) 2020-05-12 2021-11-18 Institut Curie Neoantigenic epitopes associated with sf3b1 mutations
WO2021231657A1 (en) 2020-05-13 2021-11-18 Juno Therapeutics, Inc. Methods of identifying features associated with clinical response and uses thereof
WO2021237068A2 (en) 2020-05-21 2021-11-25 Board Of Regents, The University Of Texas System T cell receptors with vgll1 specificity and uses thereof
WO2021260186A1 (en) 2020-06-26 2021-12-30 Juno Therapeutics Gmbh Engineered t cells conditionally expressing a recombinant receptor, related polynucleotides and methods
WO2022016119A1 (en) 2020-07-17 2022-01-20 Simurx, Inc. Chimeric myd88 receptors for redirecting immunosuppressive signaling and related compositions and methods
US11229669B2 (en) 2018-02-11 2022-01-25 Memorial Sloan-Kettering Cancer Center Cells comprising non-HLA restricted T cell receptors
WO2022023576A1 (en) 2020-07-30 2022-02-03 Institut Curie Immune cells defective for socs1
WO2022029660A1 (en) 2020-08-05 2022-02-10 Juno Therapeutics, Inc. Anti-idiotypic antibodies to ror1-targeted binding domains and related compositions and methods
US11305017B2 (en) 2015-04-25 2022-04-19 The General Hospital Corporation Anti-fugetactic agent and anti-cancer agent combination therapy and compositions for the treatment of cancer
WO2022098787A1 (en) 2020-11-04 2022-05-12 Juno Therapeutics, Inc. Cells expressing a chimeric receptor from a modified invariant cd3 immunoglobulin superfamily chain locus and related polynucleotides and methods
WO2022104109A1 (en) 2020-11-13 2022-05-19 Catamaran Bio, Inc. Genetically modified natural killer cells and methods of use thereof
WO2022115611A1 (en) 2020-11-25 2022-06-02 Catamaran Bio, Inc. Cellular therapeutics engineered with signal modulators and methods of use thereof
EP4012415A2 (en) 2015-12-04 2022-06-15 Juno Therapeutics, Inc. Methods and compositions related to toxicity associated with cell therapy
EP4011381A1 (en) 2016-06-03 2022-06-15 Memorial Sloan-Kettering Cancer Center Adoptive cell therapies as early treatment options
US11365236B2 (en) 2017-03-27 2022-06-21 Nkarta, Inc. Truncated NKG2D chimeric receptors and uses thereof in natural killer cell immunotherapy
WO2022133030A1 (en) 2020-12-16 2022-06-23 Juno Therapeutics, Inc. Combination therapy of a cell therapy and a bcl2 inhibitor
WO2022150731A1 (en) 2021-01-11 2022-07-14 Sana Biotechnology, Inc. Use of cd8-targeted viral vectors
US11401332B2 (en) 2016-08-23 2022-08-02 The Regents Of The University Of California Proteolytically cleavable chimeric polypeptides and methods of use thereof
US11400116B2 (en) 2016-05-06 2022-08-02 The Regents Of The University Of California Systems and methods for targeting cancer cells
US11408005B2 (en) 2016-12-12 2022-08-09 Seattle Children's Hospital Chimeric transcription factor variants with augmented sensitivity to drug ligand induction of transgene expression in mammalian cells
WO2022187406A1 (en) 2021-03-03 2022-09-09 Juno Therapeutics, Inc. Combination of a t cell therapy and a dgk inhibitor
WO2022189620A1 (en) 2021-03-11 2022-09-15 Institut Curie Transmembrane neoantigenic peptides
WO2022189639A1 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides and uses thereof
WO2022189626A2 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides
RU2780020C2 (ru) * 2017-04-26 2022-09-19 Еурека Терапьютикс, Инк. Клетки, экспрессирующие химерные активирующие рецепторы и химерные стимулирующие рецепторы, и их применение
WO2022204071A1 (en) 2021-03-22 2022-09-29 Juno Therapeutics, Inc. Method to assess potency of viral vector particles
WO2022204070A1 (en) 2021-03-22 2022-09-29 Juno Therapeutics, Inc. Methods of determining potency of a therapeutic cell composition
WO2022212400A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022212384A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Combination of a car t cell therapy and an immunomodulatory compound for treatment of lymphoma
WO2022221726A2 (en) 2021-04-16 2022-10-20 Juno Therapeutics, Inc. Combination therapies with bcma-directed t cell therapy
WO2022221737A1 (en) 2021-04-16 2022-10-20 Juno Therapeutics, Inc. T cell therapy in patients who have had prior stem cell transplant
US11479755B2 (en) 2015-12-07 2022-10-25 2Seventy Bio, Inc. T cell compositions
WO2022234009A2 (en) 2021-05-06 2022-11-10 Juno Therapeutics Gmbh Methods for stimulating and transducing t cells
WO2022238386A1 (en) 2021-05-10 2022-11-17 Institut Curie Methods for the treatment of cancer, inflammatory diseases and autoimmune diseases
WO2022248602A1 (en) 2021-05-25 2022-12-01 Institut Curie Myeloid cells overexpressing bcl2
US11517589B2 (en) 2015-02-19 2022-12-06 Myeloid Therapeutics, Inc. Chimeric antigen receptor dendritic cell (CAR-DC) for treatment of cancer
US11547694B2 (en) 2017-03-23 2023-01-10 The General Hospital Corporation CXCR4/CXCR7 blockade and treatment of human papilloma virus-associated disease
WO2023014922A1 (en) 2021-08-04 2023-02-09 The Regents Of The University Of Colorado, A Body Corporate Lat activating chimeric antigen receptor t cells and methods of use thereof
WO2023015217A1 (en) 2021-08-04 2023-02-09 Sana Biotechnology, Inc. Use of cd4-targeted viral vectors
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
US11628218B2 (en) 2020-11-04 2023-04-18 Myeloid Therapeutics, Inc. Engineered chimeric fusion protein compositions and methods of use thereof
WO2023081715A1 (en) 2021-11-03 2023-05-11 Viracta Therapeutics, Inc. Combination of car t-cell therapy with btk inhibitors and methods of use thereof
WO2023081900A1 (en) 2021-11-08 2023-05-11 Juno Therapeutics, Inc. Engineered t cells expressing a recombinant t cell receptor (tcr) and related systems and methods
WO2023081735A1 (en) 2021-11-03 2023-05-11 Celgene Corporation Chimeric antigen receptors specific for b-cell maturation antigen for use in treating myeloma
US11655452B2 (en) 2015-06-25 2023-05-23 Icell Gene Therapeutics Inc. Chimeric antigen receptors (CARs), compositions and methods of use thereof
WO2023105000A1 (en) 2021-12-09 2023-06-15 Zygosity Limited Vector
WO2023115039A2 (en) 2021-12-17 2023-06-22 Sana Biotechnology, Inc. Modified paramyxoviridae fusion glycoproteins
WO2023115041A1 (en) 2021-12-17 2023-06-22 Sana Biotechnology, Inc. Modified paramyxoviridae attachment glycoproteins
WO2023109901A1 (en) 2021-12-17 2023-06-22 Shanghai Henlius Biotech, Inc. Anti-ox40 antibodies and methods of use
WO2023109900A1 (en) 2021-12-17 2023-06-22 Shanghai Henlius Biotech, Inc. Anti-ox40 antibodies, multispecific antibodies and methods of use
EP4200340A1 (en) 2020-08-21 2023-06-28 12343096 Canada Inc. Modular assembly receptors and uses thereof
WO2023126458A1 (en) 2021-12-28 2023-07-06 Mnemo Therapeutics Immune cells with inactivated suv39h1 and modified tcr
WO2023139269A1 (en) 2022-01-21 2023-07-27 Mnemo Therapeutics Modulation of suv39h1 expression by rnas
WO2023147515A1 (en) 2022-01-28 2023-08-03 Juno Therapeutics, Inc. Methods of manufacturing cellular compositions
WO2023150518A1 (en) 2022-02-01 2023-08-10 Sana Biotechnology, Inc. Cd3-targeted lentiviral vectors and uses thereof
US11738048B2 (en) 2016-08-30 2023-08-29 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use for treating viral and other infections
WO2023164440A1 (en) 2022-02-22 2023-08-31 Juno Therapeutics, Inc. Proteinase 3 (pr3) chimeric autoantibody receptor t cells and related methods and uses
US11759480B2 (en) 2017-02-28 2023-09-19 Endocyte, Inc. Compositions and methods for CAR T cell therapy
WO2023178348A1 (en) 2022-03-18 2023-09-21 The Regents Of The University Of Colorado, A Body Corporate Genetically engineered t-cell co-receptors and methods of use thereof
WO2023179740A1 (en) 2022-03-25 2023-09-28 Shanghai Henlius Biotech , Inc. Anti-msln antibodies and methods of use
WO2023180552A1 (en) 2022-03-24 2023-09-28 Institut Curie Immunotherapy targeting tumor transposable element derived neoantigenic peptides in glioblastoma
WO2023187024A1 (en) 2022-03-31 2023-10-05 Institut Curie Modified rela protein for inducing interferon expression and engineered immune cells with improved interferon expression
WO2023193015A1 (en) 2022-04-01 2023-10-05 Sana Biotechnology, Inc. Cytokine receptor agonist and viral vector combination therapies
US11779602B2 (en) 2018-01-22 2023-10-10 Endocyte, Inc. Methods of use for CAR T cells
WO2023196933A1 (en) 2022-04-06 2023-10-12 The Regents Of The University Of Colorado, A Body Corporate Chimeric antigen receptor t cells and methods of use thereof
WO2023196921A1 (en) 2022-04-06 2023-10-12 The Regents Of The University Of Colorado, A Body Corporate Granzyme expressing t cells and methods of use
WO2023211972A1 (en) 2022-04-28 2023-11-02 Medical University Of South Carolina Chimeric antigen receptor modified regulatory t cells for treating cancer
WO2023213969A1 (en) 2022-05-05 2023-11-09 Juno Therapeutics Gmbh Viral-binding protein and related reagents, articles, and methods of use
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy
WO2023220641A2 (en) 2022-05-11 2023-11-16 Juno Therapeutics, Inc. Methods and uses related to t cell therapy and production of same
US11820819B2 (en) 2016-06-24 2023-11-21 Icell Gene Therapeutics Inc. Chimeric antigen receptors (CARs), compositions and methods thereof
EP4279085A1 (en) 2022-05-20 2023-11-22 Mnemo Therapeutics Compositions and methods for treating a refractory or relapsed cancer or a chronic infectious disease
WO2023222617A1 (en) 2022-05-16 2023-11-23 Miltenyi Biotec B.V. & Co. KG Endogenous signaling molecule activating chimeric antigen receptors and methods of generation thereof
WO2023230581A1 (en) 2022-05-25 2023-11-30 Celgene Corporation Methods of manufacturing t cell therapies
WO2023230548A1 (en) 2022-05-25 2023-11-30 Celgene Corporation Method for predicting response to a t cell therapy
US11845803B2 (en) 2017-02-17 2023-12-19 Fred Hutchinson Cancer Center Combination therapies for treatment of BCMA-related cancers and autoimmune disorders
US11851659B2 (en) 2017-03-22 2023-12-26 Novartis Ag Compositions and methods for immunooncology
WO2023250400A1 (en) 2022-06-22 2023-12-28 Juno Therapeutics, Inc. Treatment methods for second line therapy of cd19-targeted car t cells
WO2024006960A1 (en) 2022-06-29 2024-01-04 Juno Therapeutics, Inc. Lipid nanoparticles for delivery of nucleic acids
EP4302768A2 (en) 2017-06-22 2024-01-10 Board Of Regents, The University Of Texas System Methods for producing regulatory immune cells and uses thereof
US11890348B2 (en) 2015-09-18 2024-02-06 The General Hospital Corporation Localized delivery of anti-fugetactic agent for treatment of cancer
WO2024031091A2 (en) 2022-08-05 2024-02-08 Juno Therapeutics, Inc. Chimeric antigen receptors specific for gprc5d and bcma
US11896616B2 (en) 2017-03-27 2024-02-13 National University Of Singapore Stimulatory cell lines for ex vivo expansion and activation of natural killer cells
US11896614B2 (en) 2015-04-17 2024-02-13 Novartis Ag Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
EP4326293A1 (en) 2021-04-22 2024-02-28 Baylor College of Medicine Methods of engineering immune cells having reduced fratricidal activity
WO2024044779A2 (en) 2022-08-26 2024-02-29 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for delta-like ligand 3 (dll3)
US11919937B2 (en) 2018-01-09 2024-03-05 Board Of Regents, The University Of Texas System T cell receptors for immunotherapy
WO2024054944A1 (en) 2022-09-08 2024-03-14 Juno Therapeutics, Inc. Combination of a t cell therapy and continuous or intermittent dgk inhibitor dosing
US11939389B2 (en) 2018-06-13 2024-03-26 Novartis Ag BCMA chimeric antigen receptors and uses thereof
WO2024062138A1 (en) 2022-09-23 2024-03-28 Mnemo Therapeutics Immune cells comprising a modified suv39h1 gene
US11944644B2 (en) 2017-12-05 2024-04-02 The Medical Research Infrastructure And Health Services Fund Of The Tel Aviv Medical Center T-cells comprising anti-CD38 and anti-CD138 chimeric antigen receptors and uses thereof
WO2024081820A1 (en) 2022-10-13 2024-04-18 Sana Biotechnology, Inc. Viral particles targeting hematopoietic stem cells
US11975026B2 (en) 2019-11-26 2024-05-07 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
WO2024097905A1 (en) 2022-11-02 2024-05-10 Celgene Corporation Methods of treatment with t cell therapy and immunomodulatory agent maintenance therapy
WO2024100604A1 (en) 2022-11-09 2024-05-16 Juno Therapeutics Gmbh Methods for manufacturing engineered immune cells
WO2024102948A1 (en) 2022-11-11 2024-05-16 Celgene Corporation Fc receptor-homolog 5 (fcrh5) specific binding molecules and bispecific t-cell engaging antibodies including same and related methods
US11993661B2 (en) 2018-06-18 2024-05-28 Eureka Therapeutics, Inc. Constructs targeting prostate-specific membrane antigen (PSMA) and uses thereof
US12006369B2 (en) 2014-07-24 2024-06-11 2Seventy Bio, Inc. BCMA chimeric antigen receptors
WO2024124132A1 (en) 2022-12-09 2024-06-13 Juno Therapeutics, Inc. Machine learning methods for predicting cell phenotype using holographic imaging
WO2024129778A2 (en) 2022-12-13 2024-06-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for baff-r and cd19 and methods and uses thereof
US12024559B2 (en) 2020-10-23 2024-07-02 Asher Biotherapeutics, Inc. Fusions with CD8 antigen binding molecules for modulating immune cell function
US12030938B2 (en) 2021-03-17 2024-07-09 Myeloid Therapeutics, Inc. Engineered chimeric fusion protein compositions and methods of use thereof
US12037583B2 (en) 2015-12-04 2024-07-16 Novartis Ag Compositions and methods for immunooncology
WO2024161021A1 (en) 2023-02-03 2024-08-08 Juno Therapeutics Gmbh Methods for non-viral manufacturing of engineered immune cells
WO2024182516A1 (en) 2023-02-28 2024-09-06 Juno Therapeutics, Inc. Cell therapy for treating systemic autoimmune diseases
US12109234B2 (en) 2016-11-04 2024-10-08 2Seventy Bio, Inc. Anti-BCMA CAR T cell compositions
WO2024220574A1 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Universal protein g fusogens and adapter systems thereof and related lipid particles and uses
WO2024220588A1 (en) 2023-04-18 2024-10-24 Juno Therapeutics, Inc. Cytotoxicity assay for assessing potency of therapeutic cell compositions
WO2024220560A1 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Engineered protein g fusogens and related lipid particles and methods thereof
WO2024220598A2 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Lentiviral vectors with two or more genomes
WO2024226858A1 (en) 2023-04-26 2024-10-31 Juno Therapeutics, Inc. Methods for viral vector manufacturing
US12139522B2 (en) 2017-12-05 2024-11-12 The Medical Research Infrastructure And Heal Serviced Fund Of The Tel Aviv Medecal Center T-cells comprising two different chimeric antigen receptors and uses thereof
US12144850B2 (en) 2016-04-08 2024-11-19 Purdue Research Foundation Methods and compositions for car T cell therapy
US12150981B2 (en) 2012-12-20 2024-11-26 Purdue Research Foundation Chimeric antigen receptor-expressing T cells as anti-cancer therapeutics
WO2024243365A2 (en) 2023-05-23 2024-11-28 Juno Therapeutics, Inc. Activation markers of t cells and method for assessing t cell activation
US12202897B2 (en) 2014-04-10 2025-01-21 Seattle Children's Hospital Drug regulated transgene expression
US12208137B2 (en) 2014-04-23 2025-01-28 Juno Therapeutics, Inc. Methods for isolating, culturing, and genetically engineering immune cell populations for adoptive therapy
US12214037B2 (en) 2014-07-21 2025-02-04 Novartis Ag Treatment of cancer using humanized anti-BCMA chimeric antigen receptor
US12240870B2 (en) 2018-02-23 2025-03-04 Purdue Research Foundation Sequencing method for CAR T cell therapy
EP4520334A1 (en) 2023-09-07 2025-03-12 Mnemo Therapeutics Methods and compositions for improving immune response
WO2025052001A1 (en) 2023-09-07 2025-03-13 Mnemo Therapeutics Methods and compositions for improving immune response
WO2025054202A1 (en) 2023-09-05 2025-03-13 Sana Biotechnology, Inc. Method of screening a sample comprising a transgene with a unique barcode
US12252545B2 (en) 2019-12-11 2025-03-18 Myeloid Therapeutics, Inc. Therapeutic cell compositions and methods of manufacturing and use thereof
WO2025059362A1 (en) 2023-09-13 2025-03-20 Juno Therapeutics, Inc. Combination therapies with a cell therapy expressing a gprc5d-targeting car and related methods and uses
US12257304B2 (en) 2023-03-03 2025-03-25 Arsenal Biosciences, Inc. Systems targeting PSMA and CA9
US12258381B2 (en) 2018-02-09 2025-03-25 National University Of Singapore Activating chimeric receptors and uses thereof in natural killer cell immunotherapy
WO2025076472A1 (en) 2023-10-06 2025-04-10 Juno Therapeutics, Inc. Combination therapies with a cell therapy expressing a gprc5d-targeting car and related methods and uses
US12275787B2 (en) 2017-06-21 2025-04-15 Icell Gene Therapeutics Llc Chimeric antigen receptors (CARs), compositions and methods thereof
US12291722B2 (en) 2014-04-25 2025-05-06 2Seventy Bio, Inc. Methods for manufacturing adoptive cell therapies
WO2025096975A1 (en) 2023-11-02 2025-05-08 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods of enhancing immune cell therapies by runx2 modulation
WO2025097055A2 (en) 2023-11-02 2025-05-08 The Broad Institute, Inc. Compositions and methods of use of t cells in immunotherapy
US12319925B2 (en) 2021-05-11 2025-06-03 Myeloid Therapeutics, Inc. Methods and compositions for genomic integration
US12344657B2 (en) 2015-04-08 2025-07-01 Novartis Ag CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
EP4582146A2 (en) 2017-07-25 2025-07-09 Board of Regents, The University of Texas System Enhanced chimeric antigen receptors and use thereof
WO2025147545A1 (en) 2024-01-03 2025-07-10 Juno Therapeutics, Inc. Lipid nanoparticles for delivery of nucleic acids and related methods and uses
WO2025151838A1 (en) 2024-01-12 2025-07-17 Sana Biotechnology, Inc. Safety switches to control in vitro and in vivo proliferation of cell therapy products
US12377147B2 (en) 2018-04-19 2025-08-05 Baylor College Of Medicine Reprogramming CD4 t cells into cytotoxic CD8 cells by forced expression of CD8ab and class 1 restricted t cell receptors
WO2025163107A1 (en) 2024-02-01 2025-08-07 Institut Gustave Roussy Immune cells defective for znf217 and uses thereof
WO2025184421A1 (en) 2024-02-28 2025-09-04 Juno Therapeutics, Inc. Chimeric antigen receptors and antibodies specific for delta-like ligand 3 (dll3) and related methods
US12409224B2 (en) 2023-12-14 2025-09-09 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods for the treatment of VEN/AZA resistant acute myeloid leukemia
WO2025212519A1 (en) 2024-04-01 2025-10-09 Moonlight Bio, Inc. Dll3 binding proteins and uses thereof
US12441787B2 (en) 2018-04-02 2025-10-14 National University Of Singapore Neutralization of human cytokines with membrane-bound anti-cytokine non-signaling binders expressed in immune cells
WO2025235851A1 (en) 2024-05-10 2025-11-13 Juno Therapeutics, Inc. Genetically engineered t cells expressing a cd19 chimeric antigen receptor (car) and uses thereof for allogeneic cell therapy
US12486514B2 (en) 2018-08-29 2025-12-02 National University Of Singapore Method to specifically stimulate survival and expansion of genetically-modified immune cells
WO2025250011A1 (en) 2024-05-29 2025-12-04 Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Treatment for cancer

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2014010185A (es) 2012-02-22 2014-11-14 Univ Pennsylvania Uso de dominio de señalizacion cd2 en receptores de antigeno quimericos de segunda generacion.
RU2729401C2 (ru) 2012-10-02 2020-08-06 Мемориал Слоан-Кеттеринг Кэнсер Сентер Композиции и способы для иммунотерапии
DK2981607T3 (da) * 2013-04-03 2020-11-16 Memorial Sloan Kettering Cancer Center Effektiv generering af tumormålrettede t-celler afledt af pluripotente stamceller
ES2792849T3 (es) * 2014-02-10 2020-11-12 Univ Emory Expresión de polipéptido químico con receptores de linfocitos variables en células inmunes y usos para tratar el cáncer
US10626372B1 (en) 2015-01-26 2020-04-21 Fate Therapeutics, Inc. Methods and compositions for inducing hematopoietic cell differentiation
EP3261651B1 (en) 2015-02-27 2022-05-04 iCell Gene Therapeutics LLC Chimeric antigen receptors (cars) targeting hematologic malignancies, compositions and methods of use thereof
KR20180029201A (ko) 2015-05-18 2018-03-20 티씨알2 테라퓨틱스 인크. 융합 단백질을 이용하는 tcr 리프로그래밍을 위한 조성물 및 방법
CN105087495B (zh) * 2015-08-21 2016-04-27 深圳市茵冠生物科技有限公司 双嵌合抗原受体修饰的t淋巴细胞及其制备方法
CN105924529B (zh) * 2015-10-13 2019-08-06 中国人民解放军总医院 嵌合抗原受体及其基因和重组表达载体、car138-nkt细胞及其制备方法和应用
KR20250141836A (ko) 2015-11-04 2025-09-29 페이트 세러퓨틱스, 인코포레이티드 만능 세포의 유전자 조작
CN108473961B (zh) 2015-11-04 2022-11-29 菲特治疗公司 用于诱导造血细胞分化的方法和组合物
WO2017112877A1 (en) * 2015-12-22 2017-06-29 Icell Gene Therapeutics, Llc Chimeric antigen receptors and enhancement of anti-tumor activity
CA3023820A1 (en) * 2016-05-25 2017-11-30 The Council Of The Queensland Institute Of Medical Research Methods of immunotherapy
SG11201810871WA (en) * 2016-07-25 2019-01-30 Us Health Methods of producing modified natural killer cells and methods of use
WO2018026953A1 (en) 2016-08-02 2018-02-08 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
IL302917A (en) 2016-10-07 2023-07-01 Tcr2 Therapeutics Inc Compositions and methods for t-cell receptors reprogramming using fusion proteins
JP7291396B2 (ja) 2016-11-22 2023-06-15 ティーシーアール２ セラピューティクス インク． 融合タンパク質を用いたｔｃｒの再プログラミングのための組成物及び方法
CN106749677B (zh) * 2017-01-04 2020-06-12 上海交通大学医学院附属瑞金医院 一种靶向mll白血病的双特异性嵌合抗原受体基因及其应用
MX2019011958A (es) 2017-04-05 2019-12-11 Korea Res Inst Bioscience & Biotechnology Proteína de fusión activadora de células nk, célula nk, y composición farmacéutica que las incluye.
CN107326014B (zh) * 2017-07-31 2019-09-24 时力生物科技（北京）有限公司 一种双特异性嵌合抗原受体修饰的t淋巴细胞及其制备方法和应用
EP3710020A4 (en) * 2017-11-14 2021-06-23 Memorial Sloan-Kettering Cancer Center IL-36 SECRECTING IMMUNOREACTIVE CELLS AND RELATED USES
CN109988242A (zh) * 2018-01-02 2019-07-09 武汉波睿达生物科技有限公司 联合嵌合抗原受体、表达载体、慢病毒及t细胞
US12491153B2 (en) 2018-01-03 2025-12-09 Qu Biologics Inc. Innate targeting of adoptive cellular therapies
JP7414226B2 (ja) * 2018-03-30 2024-01-16 エウレカ セラピューティクス インコーポレイテッド Ｃｄ２２を標的とする構築物及びその使用
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JP7558151B2 (ja) * 2018-09-05 2024-09-30 アダプティミューン・リミテッド Ｔ細胞改変
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WO2020172177A1 (en) * 2019-02-18 2020-08-27 Memorial Sloan-Kettering Cancer Center Combinations of multiple chimeric antigen receptors for immunotherapy
EP3941493A4 (en) * 2019-03-22 2022-12-28 The Regents of the University of California SWITCHABLE CHIMERA ANTIGEN RECEPTOR MANIPULATED HUMAN NATURAL KILLER CELLS
US20220184129A1 (en) * 2019-04-12 2022-06-16 The Trustees Of The University Of Pennsylvania Compositions and Methods Comprising a High Affinity Chimeric Antigen Receptor (CAR) with Cross-Reactivity to Clinically-Relevant EGFR Mutated Proteins
SG11202111130SA (en) 2019-04-30 2021-11-29 Senti Biosciences Inc Chimeric receptors and methods of use thereof
IL299886A (en) 2020-07-17 2023-03-01 Instil Bio Uk Ltd Receptors that provide targeted costimulation for host cell therapy
AU2021392032A1 (en) 2020-12-03 2023-06-22 Century Therapeutics, Inc. Genetically engineered cells and uses thereof
US11661459B2 (en) 2020-12-03 2023-05-30 Century Therapeutics, Inc. Artificial cell death polypeptide for chimeric antigen receptor and uses thereof
EP4263600A1 (en) 2020-12-18 2023-10-25 Century Therapeutics, Inc. Chimeric antigen receptor systems with adaptable receptor specificity
EP4355340A4 (en) 2021-06-16 2025-05-21 Instil Bio, Inc. RECEPTORS FOR TARGETED COSTIMULATION FOR ADOPTIVE CELL THERAPY
WO2023288278A1 (en) 2021-07-16 2023-01-19 Instil Bio (Uk) Limited Chimeric molecules providing targeted costimulation for adoptive cell therapy
CN117836405A (zh) * 2021-08-13 2024-04-05 先声创新公司 三维培养多能干细胞产生造血干细胞
CN115058387B (zh) * 2022-06-11 2023-12-01 重庆医科大学 一种人胚胎干细胞与前列腺癌细胞共培养制备抗前列腺癌药物的方法
CN117736335A (zh) * 2022-09-20 2024-03-22 深圳先进技术研究院 靶向间皮素和nkg2d配体的双靶向car-t细胞及其应用
TW202430215A (zh) 2022-12-14 2024-08-01 美商旗艦先鋒創新有限責任（Ｖｉｉ）公司 用於將治療劑遞送至骨之組成物和方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5399346A (en) 1989-06-14 1995-03-21 The United States Of America As Represented By The Department Of Health And Human Services Gene therapy
WO2008121420A1 (en) * 2007-03-30 2008-10-09 Memorial Sloan-Kettering Cancer Center Constitutive expression of costimulatory ligands on adoptively transferred t lymphocytes
WO2012109624A2 (en) * 2011-02-11 2012-08-16 Zyngenia, Inc. Monovalent and multivalent multispecific complexes and uses thereof

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5712149A (en) 1995-02-03 1998-01-27 Cell Genesys, Inc. Chimeric receptor molecules for delivery of co-stimulatory signals
GB9605515D0 (en) 1996-03-15 1996-05-15 Medical Res Council Improvements in or relating to cell stimulation
US7446190B2 (en) * 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
US7629440B2 (en) * 2002-08-20 2009-12-08 Genitrix, Llc Lectin compositions and methods for modulating an immune response to an antigen
US20050129671A1 (en) 2003-03-11 2005-06-16 City Of Hope Mammalian antigen-presenting T cells and bi-specific T cells
US20050113564A1 (en) * 2003-11-05 2005-05-26 St. Jude Children's Research Hospital Chimeric receptors with 4-1BB stimulatory signaling domain
US8315214B2 (en) 2007-05-18 2012-11-20 Research In Motion Limited Method and system for discontinuous reception de-synchronization detection
GB201108236D0 (en) * 2011-05-17 2011-06-29 Ucl Business Plc Method
PE20141520A1 (es) * 2011-07-29 2014-11-17 Univ Pennsylvania Receptores coestimuladores de cambio
RU2729401C2 (ru) * 2012-10-02 2020-08-06 Мемориал Слоан-Кеттеринг Кэнсер Сентер Композиции и способы для иммунотерапии
WO2014055657A1 (en) * 2012-10-05 2014-04-10 The Trustees Of The University Of Pennsylvania Use of a trans-signaling approach in chimeric antigen receptors
DK2917359T3 (da) 2012-11-09 2019-09-23 Dsm Ip Assets Bv Fremgangsmåde til enzymatisk hydrolyse af lignocellulosematerialer ved anvendelse af oxygen
WO2014124143A1 (en) 2013-02-06 2014-08-14 Anthrogenesis Corporation Modified t lymphocytes having improved specificity
EP2970426B1 (en) 2013-03-15 2019-08-28 Michael C. Milone Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5399346A (en) 1989-06-14 1995-03-21 The United States Of America As Represented By The Department Of Health And Human Services Gene therapy
WO2008121420A1 (en) * 2007-03-30 2008-10-09 Memorial Sloan-Kettering Cancer Center Constitutive expression of costimulatory ligands on adoptively transferred t lymphocytes
WO2012109624A2 (en) * 2011-02-11 2012-08-16 Zyngenia, Inc. Monovalent and multivalent multispecific complexes and uses thereof

Non-Patent Citations (96)

* Cited by examiner, † Cited by third party
Title
"REMINGTON'S PHARMACEUTICAL SCIENCE", 1985
"Sequence Analysis Software Package of the Genetics Computer Group", UNIVERSITY OF WISCONSIN BIOTECHNOLOGY CENTER
"The Cambridge Dictionary of Science and Technology", 1988
"The Glossary of Genetics", 1991, SPRINGER VERLAG
ANDERSON, SCIENCE, vol. 226, 1984, pages 401 - 409
AUSUBEL ET AL.: "Current Protocols in Molecular Biology", 2001, WILEY INTERSCIENCE
AUSUBEL, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, 1987
BENTON; DAVIS, SCIENCE, vol. 196, 1977, pages 180
BERGER; KIMMEL: "Guide to Molecular Cloning Techniques", 1987, ACADEMIC PRESS
BLOOMER ET AL., JOURNAL OF VIROLOGY, vol. 71, 1997, pages 6641 - 6649
BREGNI ET AL., BLOOD, vol. 80, 1992, pages 1418 - 1422
BRENTJENS, R.J. ET AL.: "Eradication of systemic B-ce!l tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15", NATURE MEDICINE, vol. 9, 2003, pages 279 - 286, XP002389127, DOI: doi:10.1038/nm827
BRENTJENS, R.J. ET AL.: "Safety and persistence of adoptively transferred autologous CD19- ta rgeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias", BLOOD, vol. 118, 2011, pages 4817 - 4828, XP055169039, DOI: doi:10.1182/blood-2011-04-348540
BRIGHAM ET AL., AM. J. MED. SCI., vol. 298, 1989, pages 278
CA RPE N ITO, C . ET AL.: "Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 106, 2009, pages 3360 - 3365
CAYOUETTE ET AL., HUMAN GENE THERAPY, vol. 8, 1997, pages 423 - 430
COLIGAN, CURRENT PROTOCOLS IN IMMUNOLOGY, 1991
CORNETTA ET AL., NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY, vol. 36, 1987, pages 311 - 322
DANOS ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 6460 - 6464
DUPONT, J. ET AL., CANCERRES, vol. 65, 2005, pages 5417 - 5427
EGLITIS ET AL., BIOTECHNIQUES, vol. 6, 1988, pages 608 - 614
FEIGNER ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 84, 1987, pages 7413
FRESHNEY: "Animal Cell Culture", 1987
FRIEDMAN, SCIENCE, vol. 244, 1989, pages 1275 - 1281
GAIT: "Oligonucleotide Synthesis", 1984
GRUNSTEIN; HOGNESS, PROC. NATL. ACAD.SCI., USA, vol. 72, 1975, pages 3961
HALE; MARHAM, THE HARPER COLLINS DICTIONARY OF BIOLOGY, 1991
HO, W.Y.; BLATTMAN, J.N.; DOSSETT, M.L.; YEE, C.; GREENBERG, P.O.: "Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction", CANCER CELL, vol. 3, 2003, pages 431 - 437, XP002409705, DOI: doi:10.1016/S1535-6108(03)00113-2
HUGHES ET AL., J. CLIN. INVEST., vol. 89, 1992, pages 1817
JOHNSON, CHEST, vol. 107, 1995, pages 77S - 83S
JOHNSON, L.A. ET AL.: "Gene therapy with human and mouse T, cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen", BLOOD, vol. 114, 2009, pages 535 - 546
JORRITSMA, A.; SCHOTTE, R.; COCCORIS, M.; DE WITTE, M.A.; SCHUMACHER, T.N.: "Prospects and limitations of T cell receptor gene therapy", CURRENT GENE THERAPY, vol. 11, 2011, pages 276 - 287
KALOS, M. ET AL.: "T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia", SCI TRANSL MED, vol. 3, 2011, pages 95ra73, XP002667262, DOI: doi:10.1126/scitranslmed.3002842
KIDO ET AL., CURRENT EYE RESEARCH, vol. 15, 1996, pages 833 - 844
KIMMEL, A. R., METHODS ENZYMOL., vol. 152, 1987, pages 507
KOCHENDERFER, J.N. ET AL.: "B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor- transduced T cells", BLOOD, vol. 119, 2012, pages 2709 - 2720, XP055145503, DOI: doi:10.1182/blood-2011-10-384388
KOWOLIK, C ET AL.: "CD28 Costimulation Provided Through A CD19-Specific Chimeric Antigen Receptor Enhances In Vivo Persistence And Antitumor Efficacy Of Adoptively Transferred T Cells.", CANCER RESEARCH., vol. 66, 15 November 2006 (2006-11-15), pages 10995 - 11004, XP055044266 *
KRAUSE, A. ET AL.: "Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes", J EXP MED, vol. 188, 1998, pages 619 - 626, XP001240431, DOI: doi:10.1084/jem.188.4.619
LAM, J.S. ET AL.: "Prostate stem cell antigen is overexpressed in prostate cancer metastases", CLINICAL CANCER RESEARCH : AN OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, vol. 11, 2005, pages 2591 - 2596, XP002494615, DOI: doi:10.1158/1078-0432.CCR-04-1842
LE GAL LA SALLE ET AL., SCIENCE, vol. 259, 1993, pages 988 - 990
LIAO, W.; LIN, J .X; LEONARD, W.J: "I L-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation", CURRENT OPINION IN IMMUNOLOGY, vol. 23, 2011, pages 598 - 604, XP028309071, DOI: doi:10.1016/j.coi.2011.08.003
LIU, J.C. ET AL.: "Seventeen-gene signature from enriched Her2/Neu mammary tumor- initiating cells predicts clinical outcome for human HER2+:ERalpha- breast cancer", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 109, 2012, pages 58325837
MAGEE, J.A.; PISKOUNOVA, E.; MORRISON, S.J.: "Cancer stem cells: impact, heterogeneity, and uncertainty", CANCER CELL, vol. 21, 2012, pages 283 - 296, XP055023489, DOI: doi:10.1016/j.ccr.2012.03.003
MAHER, J.; BRENTJENS, R.J.; GUNSET, G.; RIVIERE, I.; SADELAIN, M.: "Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor", NAT BIO TECHNOL, vol. 20, 2002, pages 70 - 75, XP002588277
MATSUI, K ET AL.: "Low Affinity Interaction Of Peptide-MHC Complexes With T Cell Receptors.", SCIENCE., vol. 254, 20 December 1991 (1991-12-20), pages 1788 - 1791, XP001094133 *
MEYER, M.J. ET AL.: "CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer", CANCER RESEARCH, vol. 70, 2010, pages 4624 - 4633
MILLER ET AL., BIOTECHNOLOGY, vol. 7, 1989, pages 980 - 990
MILLER ET AL., MOL. CELL. BIOL., vol. 5, 1985, pages 431 - 437
MILLER ET AL., MOL. CELL. BIOL., vol. 6, 1986, pages 2895 - 2902
MILLER, HUMAN GENE THERAPY, 1990, pages 15 - 14
MILLER; CALES, GENE TRANSFER VECTORS FOR MAMMALIAN CELLS, 1987
MIYOSHI ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 94, 1997, pages 10319
MOEN, BLOOD CELLS, vol. 17, 1991, pages 407 - 416
MORGAN, R.A. ET AL., SCIENCE, vol. 314, 2006, pages 126 - 129
MORGAN, R.A. ET AL.: "Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2", MOLECULAR THERAPY: THE JOURNAL OF THE AMERICAN SOCIETY OF GENE THERAPY, vol. 18, 2010, pages 843 - 851, XP055023624, DOI: doi:10.1038/mt.2010.24
MULLIS, PCR: THE POLYMERASE CHAIN REACTION, 1994
NALDINI ET AL., SCIENCE, vol. 272, 1996, pages 263 - 267
NAM, K. 0 .; SHIN, S . M .; LEE, H.W.: "Cross-linking of 4-IBB up-regulates IL-13 expression in CDS(+) T lymphocytes", CYTOKINE, vol. 33, 2006, pages 87 - 94
NGUYEN, L.V.; VANNER, R.; DIRKS, P.; EAVES, C.J.: "Cancer stem cells: an evolving concept. Nature reviews", CANCER, vol. 12, 2012, pages 133 - 143
OLSON, W.C.; HESTON, W.D.; RAJASEKARAN, A.K.: "Clinical trials of cancer therapies targeting prostate-specific membrane antigen", REVIEWS ON RECENT CLINICAL TRIALS, vol. 2, no. 30, 2007, pages 182 - 190, XP007922264, DOI: doi:10.2174/157488707781662724
ONO ET AL., NEUROSCIENCE LETTERS, vol. 17, 1990, pages 259
ORLANDI, R.; GUSSOW, D.H.; JONES, P.T.; WINTER, G.: "Cloning immunoglobulin variable domains for expression by the polymerase chain reaction", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 86, 1989, pages 3833 - 3837, XP000026475, DOI: doi:10.1073/pnas.86.10.3833
PANELLI, M.C. ET AL., J IMMUNO, vol. 164, 2000, pages 4382 - 4392
PANELLI, M.C. ET AL., J IMMUNOL, vol. 164, 2000, pages 495 - 504
PAPANICOLAOU, G.A. ET AL., BLOOD, vol. 102, 2003, pages 2498 - 2505
ROBBINS, P.F. ET AL.: "Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1", JOURNAL OF CLINICAL ONCOLOGY: OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY, vol. 29, 2011, pages 917 - 924, XP002705979, DOI: doi:10.1200/JCO.2010.32.2537
ROSENBERG ET AL., N. ENGL. J. MED, vol. 323, 1990, pages 370
ROSENBERG, S.A.; RESTIFO, N.P.; YANG, J.C.; MORGAN, R.A.; DUDLEY, M.E.: "Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature reviews", CANCER, vol. 8, 2008, pages 299 - 308
SADELAIN, M. ET AL., NAT REV CANCER, vol. 3, 2003, pages 35 - 45
SADELAIN, M.; BRENTJENS, R.; RIVIERE, I.: "The promise and potential pitfalls of chimeric antigen receptors", CURR OPIN IMMUNOL, vol. 21, 2009, pages 215 - 223, XP026058399, DOI: doi:10.1016/j.coi.2009.02.009
SADELAIN, M.; RIVIERE, I.; BRENTJENS, R.: "Targeting tumours with genetically enhanced T lymphocytes", NAT REV CANCER, vol. 3, 2003, pages 35 - 45, XP009026020, DOI: doi:10.1038/nrc971
SAEKI, N.; GU, J.; YOSHIDA, T.; WU, X.: "Prostate stem cell antigen: a Jekyll and Hyde molecule?", CLINICAL CANCER RESEARCH :AN OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, vol. 16, 2010, pages 3533 - 3538
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", COLD SPRING HARBOR LABORATORY PRESS
SAMBROOK: "Molecular Cloning: A Laboratory Manual", 1989
SAMBROOK; FRITSCH; MANIATIS: "Molecular Cloning: A Laboratory Manual", 1989, CSH PRESS
SCHWARTZ, R . H . T: "cell a n e rgy", ANNUAL REVIEW OF IMMUNOLOGY, vol. 21, 2003, pages 305 - 334
SHARP, THE LANCET, vol. 337, 1991, pages 1277 - 1278
SHIHLE, M .; DAVIDSON, B.: "Pathogenesis of ovarian cancer: clues from selected overexpressed genes", FUTURE ONCOL, vol. 5, 2009, pages 1641 - 1657
SHIN, S M: "1.4- IBB triggers IL-13 production from T cells to limit the polarized, Thl-mediated inflammation", JOURNAL OF LEUKOCYTE BIOLOGY, vol. 81, 2007, pages 1455 - 1465
SILVER, D.A.; PELLICER, I.; FAIR, W.R.; HESTON, W.D.; CORDON-CARDO, C.: "Prostate-specific membrane antigen expression in normal and malignant human tissues", CLINICAL CANCER RESEARCH : AN OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH, vol. 3, 1997, pages 81 - 85, XP000941663
SINGLETON ET AL.: "Dictionary of Microbiology and Molecular Biology", 1994
STAUBINGER ET AL., METHODS IN ENZYMOLOGY, vol. 101, 1983, pages 512
STEPHAN, M .T. ET AL.: "T cell-encoded CD80 and 4-1 BBL induce auto-and transcostimulation, resulting in potent tumor rejection", NATURE MEDICINE, vol. 13, 2007, pages 1440 - 1449, XP002571429, DOI: doi:10.1038/nm1676
STRAUSS, R. ET AL.: "Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity", PLOS ONE, vol. 6, 2011, pages el 6186
TAMMANA, S.: "1. 4-1 BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies", HUM GENE THER, vol. 2, no. 1, 2000, pages 75 - 86
TOLSTOSHEV ET AL., CURRENT OPINION IN BIOTECHNOLOGY, vol. 1, 1990, pages 55 - 61
WAHL, G. M.; S. L. BERGER, METHODS ENZYMOL., vol. 152, 1987, pages 399
WANG, J. ET AL.: "Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains", HUMAN GENE THERAPY, vol. 18, 2007, pages 712 - 725, XP002605938, DOI: doi:10.1089/HUM.2007.028
WATTS, T.H.: "TNF/TNFR family members in costimulation of T cell responses", ANNUAL REVIEW OF IMMUNOLOGY, vol. 23, 2005, pages 23 - 68, XP008051583, DOI: doi:10.1146/annurev.immunol.23.021704.115839
WEIR: "Handbook of Experimental Immunology", 1996, article "Methods in Enzymology"
WILKIE, S. ET AL.: "Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling", JOURNAL OF CLINICAL IMMUNOLOGY, 2012
WOLFF ET AL., SCIENCE, vol. 247, 1990, pages 1465
WU ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 263, 1988, pages 14621
WU ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 264, 1989, pages 16985
XU ET AL., EXP. HEMAT., vol. 22, 1994, pages 223 - 230
ZHONG, X.S.; MATSUSHITA, M.; PLOTKIN, J.; RIVIERE, I.; SADELAIN, M.: "Chimeric antigen receptors combining 4-1 BB and CD28 signaling domains augment PI3kinase/AKT/Bc1-X L activation and C D8+ T cell-mediated tumor eradication", MOLECULAR THERAPY: THE JOURNAL OF THE AMERICAN SOCIETY OF GENE THERAPY, vol. 18, 2010, pages 413 - 420, XP055023623, DOI: doi:10.1038/mt.2009.210

Cited By (517)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10117896B2 (en) 2012-10-05 2018-11-06 The Trustees Of The University Of Pennsylvania Use of a trans-signaling approach in chimeric antigen receptors
US11484552B2 (en) 2012-10-05 2022-11-01 The Trustees Of The University Of Pennsylvania Use of trans-signaling approach in chimeric antigen receptors
US12325756B2 (en) 2012-10-05 2025-06-10 The Trustees Of The University Of Pennsylvania Use of trans-signaling approach in chimeric antigen receptors
US11130820B2 (en) 2012-12-20 2021-09-28 Celgene Corporation Chimeric antigen receptors
US12150981B2 (en) 2012-12-20 2024-11-26 Purdue Research Foundation Chimeric antigen receptor-expressing T cells as anti-cancer therapeutics
US10836999B2 (en) 2013-01-28 2020-11-17 St. Jude Children's Research Hospital, Inc. Chimeric receptor with NKG2D specificity for use in cell therapy against cancer and infectious disease
US10829737B2 (en) 2013-01-28 2020-11-10 St. Jude Children's Research Hospital, Inc. Chimeric receptor with NKG2D specificity for use in cell therapy against cancer and infectious disease
US10801012B2 (en) 2013-01-28 2020-10-13 St. Jude Children's Research Hospital, Inc. Chimeric receptor with NKG2D specificity for use in cell therapy against cancer and infectious disease
US10538739B2 (en) 2013-01-28 2020-01-21 St. Jude Children's Research Hospital, Inc. Chimeric receptor with NKG2D specificity for use in cell therapy against cancer and infectious disease
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AU2014214850B2 (en) * 2013-02-06 2018-06-14 Celgene Corporation Modified T lymphocytes having improved specificity
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US12258397B2 (en) 2014-04-10 2025-03-25 Seattle Children's Hospital Production of engineered T-cells by sleeping beauty transposon coupled with methotrexate selection
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US12208137B2 (en) 2014-04-23 2025-01-28 Juno Therapeutics, Inc. Methods for isolating, culturing, and genetically engineering immune cell populations for adoptive therapy
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US10774343B2 (en) 2014-04-25 2020-09-15 Bluebird Bio, Inc. MND promoter chimeric antigen receptors
US12291722B2 (en) 2014-04-25 2025-05-06 2Seventy Bio, Inc. Methods for manufacturing adoptive cell therapies
US12264335B2 (en) 2014-05-15 2025-04-01 National University Of Singapore Natural killer cells expressing membrane-bound interleukin 15 (mbIL15) and uses thereof
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US10774311B2 (en) 2014-05-15 2020-09-15 National University Of Singapore Natural killer cells modified to express membrane-bound interleukin 15 and uses thereof
US10428305B2 (en) 2014-05-15 2019-10-01 National University Of Singapore Modified natural killer cells that express IL15 and uses thereof
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AU2015269197B2 (en) * 2014-06-06 2018-10-04 2Seventy Bio, Inc. Improved T cell compositions
JP2020072756A (ja) * 2014-06-06 2020-05-14 ブルーバード バイオ， インコーポレイテッド 改善されたｔ細胞組成物
WO2015188119A1 (en) * 2014-06-06 2015-12-10 Bluebird Bio, Inc. Improved t cell compositions
WO2015188141A2 (en) 2014-06-06 2015-12-10 Memorial Sloan-Kettering Cancer Ceneter Mesothelin-targeted chimeric antigen receptors and uses thereof
US11560547B2 (en) 2014-06-06 2023-01-24 2Seventy Bio, Inc. Methods of making T cell compositions
EP4166148A1 (en) 2014-06-06 2023-04-19 Memorial Sloan-Kettering Cancer Center Mesothelin-targeted chimeric antigen receptors and uses thereof
CN106793780B (zh) * 2014-06-06 2020-05-26 蓝鸟生物公司 改善的t细胞组合物
US10479975B2 (en) 2014-06-06 2019-11-19 Bluebird Bio, Inc. Methods of making T cell compositions
EP3685842A1 (en) 2014-06-06 2020-07-29 Memorial Sloan-Kettering Cancer Center Mesothelin-targeted chimeric antigen receptors and uses thereof
US10738278B2 (en) 2014-07-15 2020-08-11 Juno Therapeutics, Inc. Engineered cells for adoptive cell therapy
US12338287B2 (en) 2014-07-21 2025-06-24 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US12214037B2 (en) 2014-07-21 2025-02-04 Novartis Ag Treatment of cancer using humanized anti-BCMA chimeric antigen receptor
US10851166B2 (en) 2014-07-21 2020-12-01 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US9777061B2 (en) 2014-07-21 2017-10-03 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US12006369B2 (en) 2014-07-24 2024-06-11 2Seventy Bio, Inc. BCMA chimeric antigen receptors
US11814419B2 (en) 2014-08-08 2023-11-14 The Board Of Trustees Of The Leland Stanford Junior University High affinity PD-1 agents and methods of use
US9546206B2 (en) 2014-08-08 2017-01-17 The Board Of Trustees Of The Leland Stanford Junior University High affinity PD-1 agents and methods of use
US9562087B2 (en) 2014-08-08 2017-02-07 The Board Of Trustees Of The Leland Stanford Junior University High affinity PD-1 agents and methods of use
US10533055B2 (en) 2014-08-28 2020-01-14 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for CD19
EP3805267A1 (en) 2014-08-28 2021-04-14 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for cd19
WO2016033570A1 (en) 2014-08-28 2016-03-03 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for cd19
US11827714B2 (en) 2014-08-28 2023-11-28 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for CD19
CN106574272A (zh) * 2014-08-29 2017-04-19 哥莫阿波单克隆有限责任公司 靶向多样的多种抗原的通用嵌合抗原受体表达性免疫细胞及其制造方法及其在癌症、感染和自身免疫病的治疗中的应用
CN106574272B (zh) * 2014-08-29 2022-04-29 哥莫阿波有限责任公司 靶向多样的多种抗原的通用嵌合抗原受体表达性免疫细胞及其制造方法及其在癌症、感染和自身免疫病的治疗中的应用
US10507219B2 (en) 2014-10-20 2019-12-17 Juno Therapeutics, Inc. Methods and compositions for dosing in adoptive cell therapy
EP3932950A1 (en) 2014-10-20 2022-01-05 Juno Therapeutics, Inc. Methods and compositions for dosing in adoptive cell therapy
US11633426B2 (en) 2014-10-20 2023-04-25 Juno Therapeutics, Inc. Methods and compositions for dosing in adoptive cell therapy
WO2016064929A1 (en) 2014-10-20 2016-04-28 Juno Therapeutics, Inc. Methods and compositions for dosing in adoptive cell therapy
JP2017533706A (ja) * 2014-10-31 2017-11-16 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア 改変ｔ細胞に関する方法および組成物
JP7372728B2 (ja) 2014-10-31 2023-11-01 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア 改変ｔ細胞に関する方法および組成物
JP2023024691A (ja) * 2014-11-05 2023-02-16 ジュノー セラピューティクス インコーポレイテッド 形質導入および細胞プロセシングのための方法
US10428351B2 (en) 2014-11-05 2019-10-01 Juno Therapeutics, Inc. Methods for transduction and cell processing
EP4407036A2 (en) 2014-11-05 2024-07-31 Juno Therapeutics, Inc. Methods for transduction and cell processing
WO2016073602A2 (en) 2014-11-05 2016-05-12 Juno Therapeutics, Inc. Methods for transduction and cell processing
US11802295B2 (en) 2014-11-05 2023-10-31 Juno Therapeutics, Inc. Methods for transduction and cell processing
EP3757206A1 (en) 2014-11-05 2020-12-30 Juno Therapeutics, Inc. Methods for transduction and cell processing
WO2016090190A1 (en) 2014-12-03 2016-06-09 Juno Therapeutics, Inc. Methods and compositions for adoptive cell therapy
EP3766895A1 (en) 2014-12-03 2021-01-20 Juno Therapeutics, Inc. Methods and compositions for adoptive cell therapy
US11266739B2 (en) 2014-12-03 2022-03-08 Juno Therapeutics, Inc. Methods and compositions for adoptive cell therapy
US10639358B2 (en) 2014-12-12 2020-05-05 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US10383929B2 (en) 2014-12-12 2019-08-20 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US10639359B2 (en) 2014-12-12 2020-05-05 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US12029784B2 (en) 2014-12-12 2024-07-09 2Seventy Bio, Inc. BCMA chimeric antigen receptors
US10646558B2 (en) 2014-12-12 2020-05-12 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US10624960B2 (en) 2014-12-12 2020-04-21 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US11382965B2 (en) 2014-12-12 2022-07-12 2Seventy Bio, Inc. BCMA chimeric antigen receptors
US11633463B2 (en) 2014-12-12 2023-04-25 2Seventy Bio, Inc. BCMA chimeric antigen receptors
US11351236B2 (en) 2014-12-12 2022-06-07 2Seventy Bio, Inc. BCMA chimeric antigen receptors
US11020466B2 (en) 2014-12-12 2021-06-01 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US10981970B2 (en) 2014-12-24 2021-04-20 Autolus Limited Chimeric antigen receptor (CAR) comprising a CD22-binding domain
EP3237442B1 (en) 2014-12-24 2019-07-10 UCL Business PLC Cell
CN107002045A (zh) * 2014-12-24 2017-08-01 Ucl商务股份有限公司 细胞
US11034750B2 (en) 2014-12-24 2021-06-15 Autolus Limited Chimeric antigen receptor (CAR) comprising a CD19-binding domain
US11091532B2 (en) 2014-12-24 2021-08-17 Autolus Limited T cell which co-expresses a CD19 chimeric antigen receptor and a CD22 chimeric antigen receptor
US12398194B2 (en) 2014-12-24 2025-08-26 Autolus Limited Cell lexpressing two chimeric antigen receptors (CARs) at the cell surface
RU2768019C2 (ru) * 2014-12-24 2022-03-23 Отолус Лимитед Клетка
CN107002045B (zh) * 2014-12-24 2025-10-21 奥托路斯有限公司 细胞
WO2016115177A1 (en) 2015-01-12 2016-07-21 Juno Therapeutics, Inc. Modified hepatitis post-transcriptional regulatory elements
US10363269B2 (en) 2015-01-12 2019-07-30 Juno Therapeutics, Inc. Modified hepatitis post-transcriptional regulatory elements
WO2016115559A1 (en) 2015-01-16 2016-07-21 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for ror1
US10889652B2 (en) 2015-01-16 2021-01-12 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for ROR1
EP3760644A1 (en) 2015-01-16 2021-01-06 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for ror1
US11919970B2 (en) 2015-01-16 2024-03-05 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for ROR1
US11918605B1 (en) 2015-02-19 2024-03-05 Myeloid Therapeutics, Inc. Chimeric antigen receptor dendritic cell (CAR-DC) for treatment of cancer
US11517589B2 (en) 2015-02-19 2022-12-06 Myeloid Therapeutics, Inc. Chimeric antigen receptor dendritic cell (CAR-DC) for treatment of cancer
US11918604B2 (en) 2015-02-19 2024-03-05 Myeloid Therapeutics, Inc. Chimeric antigen receptor dendritic cell (CAR-DC) for treatment of cancer
US10590182B2 (en) 2015-02-24 2020-03-17 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
WO2016138034A1 (en) * 2015-02-24 2016-09-01 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
US10822387B2 (en) 2015-02-24 2020-11-03 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
US9670281B2 (en) 2015-02-24 2017-06-06 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
US10836808B2 (en) 2015-02-24 2020-11-17 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
US9834608B2 (en) 2015-02-24 2017-12-05 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
CN107922488A (zh) * 2015-04-02 2018-04-17 纪念斯隆-凯特琳癌症中心 Tnfrsf14/hvem蛋白及其使用方法
US12344657B2 (en) 2015-04-08 2025-07-01 Novartis Ag CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
WO2016168493A1 (en) * 2015-04-15 2016-10-20 Prospect CharterCare RWMC, LLC d/b/a Roger Williams Medical Center Hepatic arterial infusion of car-t cells
US10471098B2 (en) 2015-04-15 2019-11-12 Prospect Chartercare Rwmc, Llc Hepatic arterial infusion of CAR-T cells
WO2016166568A1 (en) 2015-04-16 2016-10-20 Juno Therapeutics Gmbh Methods, kits and apparatus for expanding a population of cells
US11896614B2 (en) 2015-04-17 2024-02-13 Novartis Ag Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
US10786549B2 (en) 2015-04-23 2020-09-29 Baylor College Of Medicine CD5 chimeric antigen receptor for adoptive T cell therapy
WO2016172606A1 (en) * 2015-04-23 2016-10-27 Baylor College Of Medicine Cd5 chimeric antigen receptor for adoptive t cell therapy
US11305017B2 (en) 2015-04-25 2022-04-19 The General Hospital Corporation Anti-fugetactic agent and anti-cancer agent combination therapy and compositions for the treatment of cancer
WO2016196388A1 (en) 2015-05-29 2016-12-08 Juno Therapeutics, Inc. Composition and methods for regulating inhibitory interactions in genetically engineered cells
IL255884B2 (en) * 2015-06-10 2024-05-01 Immunitybio Inc Modified NK-92 cells for cancer treatment
EP4272757A3 (en) * 2015-06-10 2023-12-27 ImmunityBio, Inc. Modified nk-92 cells for treating cancer
US10738279B2 (en) 2015-06-10 2020-08-11 Nantkwest, Inc. Modified NK-92 cells for treating cancer
US11788059B2 (en) 2015-06-10 2023-10-17 Immunity Bio, Inc. Modified NK-92 cells for treating cancer
IL255884B1 (en) * 2015-06-10 2024-01-01 Immunitybio Inc Modified NK-92 cells for cancer treatment
EP4424326A3 (en) * 2015-06-10 2024-11-13 ImmunityBio, Inc. Modified nk-92 cells for treating cancer
EP3307876A4 (en) * 2015-06-10 2019-04-03 Nantkwest, Inc. MODIFIED NK-92 CELLS FOR THE TREATMENT OF CANCER
US11173179B2 (en) 2015-06-25 2021-11-16 Icell Gene Therapeutics Llc Chimeric antigen receptor (CAR) targeting multiple antigens, compositions and methods of use thereof
US11655452B2 (en) 2015-06-25 2023-05-23 Icell Gene Therapeutics Inc. Chimeric antigen receptors (CARs), compositions and methods of use thereof
US10786533B2 (en) 2015-07-15 2020-09-29 Juno Therapeutics, Inc. Engineered cells for adoptive cell therapy
TWI859112B (zh) * 2015-07-21 2024-10-21 瑞士商諾華公司 改良免疫細胞之功效及擴展之方法
US12240884B2 (en) 2015-07-21 2025-03-04 Novartis Ag Methods for improving the efficacy and expansion of immune cells
US10829735B2 (en) 2015-07-21 2020-11-10 The Trustees Of The University Of Pennsylvania Methods for improving the efficacy and expansion of immune cells
EP3325504A1 (en) * 2015-07-21 2018-05-30 Novartis AG Methods for improving the efficacy and expansion of immune cells
EP3328994A4 (en) * 2015-07-31 2019-04-17 Memorial Sloan-Kettering Cancer Center CD56-Faced Antigen-Binding Proteins and Uses Thereof
EP3939992A1 (en) * 2015-07-31 2022-01-19 King's College London Therapeutic agents
US10730941B2 (en) 2015-07-31 2020-08-04 Memorial Sloan-Kettering Cancer Center Antigen-binding proteins targeting CD56 and uses thereof
RU2747733C1 (ru) * 2015-07-31 2021-05-13 Кинг'С Колледж Лондон Терапевтические средства
CN107735407A (zh) * 2015-07-31 2018-02-23 伦敦国王学院 治疗剂
US12018077B2 (en) 2015-07-31 2024-06-25 Memorial Sloan-Kettering Cancer Center Methods of treatments using antigen-binding proteins targeting CD56
US11802143B2 (en) 2015-07-31 2023-10-31 King's College London Therapeutic agents
US10703794B2 (en) 2015-07-31 2020-07-07 King's College London Therapeutic agents
US10865231B2 (en) 2015-07-31 2020-12-15 King's College London Therapeutic agents
JP2021168675A (ja) * 2015-07-31 2021-10-28 キングス カレッジ ロンドンKings College London 治療薬
JP2018521663A (ja) * 2015-07-31 2018-08-09 キングス カレッジ ロンドンＫｉｎｇｓ Ｃｏｌｌｅｇｅ Ｌｏｎｄｏｎ 治療薬
US10899818B2 (en) 2015-07-31 2021-01-26 King's College London Therapeutic agents
CN107735407B (zh) * 2015-07-31 2022-08-16 伦敦国王学院 治疗剂
JP7053037B2 (ja) 2015-07-31 2022-04-12 キングス カレッジ ロンドン 治療薬
WO2017021701A1 (en) * 2015-07-31 2017-02-09 King's College London Therapeutic agents
JP2022119759A (ja) * 2015-08-07 2022-08-17 シアトル チルドレンズ ホスピタル （ディービーエイ シアトル チルドレンズ リサーチ インスティテュート） 固形腫瘍を標的とする二重特異性ｃａｒ ｔ細胞
US11458167B2 (en) 2015-08-07 2022-10-04 Seattle Children's Hospital Bispecific CAR T-cells for solid tumor targeting
JP2018522567A (ja) * 2015-08-07 2018-08-16 シアトル チルドレンズ ホスピタル， ディービーエー シアトル チルドレンズ リサーチ インスティテュート 固形腫瘍を標的とする二重特異性ｃａｒ ｔ細胞
US11123369B2 (en) 2015-08-07 2021-09-21 Seattle Children's Hospital Bispecific CAR T-cells for solid tumor targeting
JP7162530B2 (ja) 2015-08-07 2022-10-28 シアトル チルドレンズ ホスピタル （ディービーエイ シアトル チルドレンズ リサーチ インスティテュート） 固形腫瘍を標的とする二重特異性ｃａｒ ｔ細胞
JP7566817B2 (ja) 2015-08-07 2024-10-15 シアトル チルドレンズ ホスピタル ディー／ビー／エイ シアトル チルドレンズ リサーチ インスティテュート 固形腫瘍を標的とする二重特異性ｃａｒ ｔ細胞
WO2017040945A1 (en) 2015-09-04 2017-03-09 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use
US11242375B2 (en) 2015-09-04 2022-02-08 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use
US12139524B2 (en) 2015-09-04 2024-11-12 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use
US11890348B2 (en) 2015-09-18 2024-02-06 The General Hospital Corporation Localized delivery of anti-fugetactic agent for treatment of cancer
WO2017053906A1 (en) 2015-09-24 2017-03-30 Abvitro Llc Hiv antibody compositions and methods of use
EP3662930A1 (en) 2015-09-24 2020-06-10 AbVitro LLC Hiv antibody compositions and methods of use
WO2017068421A1 (en) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
US11248238B2 (en) 2015-10-22 2022-02-15 Juno Therapeutics Gmbh Methods, kits, agents and apparatuses for transduction
WO2017068419A2 (en) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Methods, kits, agents and apparatuses for transduction
US11466253B2 (en) 2015-10-22 2022-10-11 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
US11913024B2 (en) 2015-10-22 2024-02-27 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
WO2017068425A1 (en) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
US12129477B2 (en) 2015-10-22 2024-10-29 Juno Therapeutics Gmbh Methods, kits, agents and apparatuses for transduction
US10464988B2 (en) 2015-10-23 2019-11-05 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US10822389B2 (en) 2015-10-23 2020-11-03 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US11421013B2 (en) 2015-10-23 2022-08-23 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US11976105B2 (en) 2015-10-23 2024-05-07 Eureka Therapeutics, Inc. Antibody/T-cell receptor chimeric constructs and uses thereof
US11020429B2 (en) 2015-11-05 2021-06-01 Juno Therapeutics, Inc. Vectors and genetically engineered immune cells expressing metabolic pathway modulators and uses in adoptive cell therapy
WO2017079705A1 (en) 2015-11-05 2017-05-11 Juno Therapeutics, Inc. Chimeric receptors containing traf-inducing domains and related compositions and methods
WO2017079703A1 (en) 2015-11-05 2017-05-11 Juno Therapeutics, Inc. Vectors and genetically engineered immune cells expressing metabolic pathway modulators and uses in adoptive cell therapy
US12139526B2 (en) 2015-12-03 2024-11-12 Juno Therapeutics, Inc. Modified chimeric receptors and related compositions and methods
WO2017096329A1 (en) 2015-12-03 2017-06-08 Juno Therapeutics, Inc. Modified chimeric receptors and related compositions and methods
WO2017096327A2 (en) 2015-12-03 2017-06-08 Juno Therapeutics, Inc. Compositions and methods for reducing immune responses against cell therapies
EP4212547A1 (en) 2015-12-03 2023-07-19 Juno Therapeutics, Inc. Modified chimeric receptors and related compositions and methods
EP4212166A1 (en) 2015-12-03 2023-07-19 Juno Therapeutics, Inc. Compositions and methods for reducing immune responses against cell therapies
US11815514B2 (en) 2015-12-04 2023-11-14 Juno Therapeutics, Inc. Methods and compositions related to toxicity associated with cell therapy
US12037583B2 (en) 2015-12-04 2024-07-16 Novartis Ag Compositions and methods for immunooncology
EP4012415A2 (en) 2015-12-04 2022-06-15 Juno Therapeutics, Inc. Methods and compositions related to toxicity associated with cell therapy
US11479755B2 (en) 2015-12-07 2022-10-25 2Seventy Bio, Inc. T cell compositions
WO2017120501A1 (en) 2016-01-07 2017-07-13 Mayo Foundation For Medical Education And Research Methods of treating cancer with interferon
WO2017161208A1 (en) 2016-03-16 2017-09-21 Juno Therapeutics, Inc. Methods for determining dosing of a therapeutic agent and related treatments
WO2017161212A1 (en) 2016-03-16 2017-09-21 Juno Therapeutics, Inc. Methods for adaptive design of a treatment regimen and related treatments
WO2017165571A1 (en) 2016-03-22 2017-09-28 Seattle Children's Hospital (dba Seattle Children's Research Institute) Early intervention methods to prevent or ameliorate toxicity
US11760804B2 (en) 2016-03-22 2023-09-19 Seattle Children's Hospital Early intervention methods to prevent or ameliorate toxicity
US11518814B2 (en) 2016-03-22 2022-12-06 Seattle Children's Hospital Early intervention methods to prevent or ameliorate toxicity
EP4015536A1 (en) 2016-03-22 2022-06-22 Seattle Children's Hospital (DBA Seattle Children's Research Institute) Early intervention methods to prevent or ameliorate toxicity
US12098208B2 (en) 2016-03-22 2024-09-24 Seattle Children's Hospital Early intervention methods to prevent or ameliorate toxicity
EP4545143A2 (en) 2016-03-22 2025-04-30 Seattle Children's Hospital (DBA Seattle Children's Research Institute) EARLY INTERVENTION METHODS TO PREVENT OR AMELIAZE TOXICITY
WO2017173091A1 (en) 2016-03-30 2017-10-05 Musc Foundation For Research Development Methods for treatment and diagnosis of cancer by targeting glycoprotein a repetitions predominant (garp) and for providing effective immunotherapy alone or in combination
US12144850B2 (en) 2016-04-08 2024-11-19 Purdue Research Foundation Methods and compositions for car T cell therapy
WO2017193107A2 (en) 2016-05-06 2017-11-09 Juno Therapeutics, Inc. Genetically engineered cells and methods of making the same
US11400116B2 (en) 2016-05-06 2022-08-02 The Regents Of The University Of California Systems and methods for targeting cancer cells
EP3910059A1 (en) 2016-05-27 2021-11-17 Aadigen, Llc Peptides and nanoparticles for intracellular delivery of genome-editing molecules
WO2017205846A1 (en) 2016-05-27 2017-11-30 Aadigen, Llc Peptides and nanoparticles for intracellular delivery of genome-editing molecules
EP4011381A1 (en) 2016-06-03 2022-06-15 Memorial Sloan-Kettering Cancer Center Adoptive cell therapies as early treatment options
WO2017214207A2 (en) 2016-06-06 2017-12-14 Juno Therapeutics, Inc. Methods for the treatment of b cell malignancies using adoptive cell therapy
US11820819B2 (en) 2016-06-24 2023-11-21 Icell Gene Therapeutics Inc. Chimeric antigen receptors (CARs), compositions and methods thereof
WO2018005556A1 (en) 2016-06-27 2018-01-04 Juno Therapeutics, Inc. Mhc-e restricted epitopes, binding molecules and related methods and uses
WO2018005559A1 (en) 2016-06-27 2018-01-04 Juno Therapeutics, Inc. Method of identifying peptide epitopes, molecules that bind such epitopes and related uses
EP3992632A1 (en) 2016-06-27 2022-05-04 Juno Therapeutics, Inc. Mhc-e restricted epitopes, binding molecules and related methods and uses
WO2018023100A2 (en) 2016-07-29 2018-02-01 Juno Therapeutics, Inc. Anti-idiotypic antibodies and related methods
WO2018023093A1 (en) 2016-07-29 2018-02-01 Juno Therapeutics, Inc. Immunomodulatory polypeptides and related compositions and methods
WO2018023094A1 (en) 2016-07-29 2018-02-01 Juno Therapeutics, Inc. Methods for assessing the presence or absence of replication competent virus
US12304935B2 (en) 2016-07-29 2025-05-20 Juno Therapeutics, Inc. Immunomodulatory polypeptides and related compositions and methods
US11421287B2 (en) 2016-07-29 2022-08-23 Juno Therapeutics, Inc. Methods for assessing the presence or absence of replication competent virus
US12350349B2 (en) 2016-08-03 2025-07-08 Washington University Gene editing of CAR-T cells for the treatment of T cell malignancies with chimeric antigen receptors
WO2018027036A1 (en) * 2016-08-03 2018-02-08 Dipersio John F Gene editing of car-t cells for the treatment of t cell malignancies with chimeric antigen receptors
US20180348227A1 (en) * 2016-08-04 2018-12-06 Memorial Sloan-Kettering Cancer Center Cancer antigen targets and uses thereof
US12259390B2 (en) 2016-08-04 2025-03-25 Memorial Sloan-Kettering Cancer Center Cancer antigen targets and uses thereof
US11193938B2 (en) * 2016-08-04 2021-12-07 Memorial Sloan-Kettering Cancer Center Cancer antigen targets and uses thereof
US12345712B2 (en) 2016-08-04 2025-07-01 Memorial Sloan-Kettering Cancer Center Cancer antigen targets and uses thereof
US12358988B2 (en) 2016-08-23 2025-07-15 The Regents Of The University Of California Proteolytically cleavable chimeric polypeptides and methods of use thereof
US11401332B2 (en) 2016-08-23 2022-08-02 The Regents Of The University Of California Proteolytically cleavable chimeric polypeptides and methods of use thereof
US11738048B2 (en) 2016-08-30 2023-08-29 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use for treating viral and other infections
WO2018049420A1 (en) 2016-09-12 2018-03-15 Juno Therapeutics, Inc. Perfusion bioreactor bag assemblies
EP4353319A2 (en) 2016-09-28 2024-04-17 Atossa Therapeutics, Inc. Methods of adoptive cell therapy
WO2018063985A1 (en) 2016-09-28 2018-04-05 Atossa Genetics Inc. Methods of adoptive cell therapy
WO2018067618A1 (en) 2016-10-03 2018-04-12 Juno Therapeutics, Inc. Hpv-specific binding molecules
US11072660B2 (en) 2016-10-03 2021-07-27 Juno Therapeutics, Inc. HPV-specific binding molecules
US11896615B2 (en) 2016-10-13 2024-02-13 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
EP4190335A1 (en) 2016-10-13 2023-06-07 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018093591A1 (en) 2016-11-03 2018-05-24 Juno Therapeutics, Inc. Combination therapy of a cell based therapy and a microglia inhibitor
WO2018085731A2 (en) 2016-11-03 2018-05-11 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and a btk inhibitor
US12109234B2 (en) 2016-11-04 2024-10-08 2Seventy Bio, Inc. Anti-BCMA CAR T cell compositions
WO2018102612A1 (en) 2016-12-02 2018-06-07 Juno Therapeutics, Inc. Engineered b cells and related compositions and methods
US11793833B2 (en) 2016-12-02 2023-10-24 Juno Therapeutics, Inc. Engineered B cells and related compositions and methods
WO2018102787A1 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods for determining car-t cells dosing
WO2018102786A1 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods for modulation of car-t cells
US11590167B2 (en) 2016-12-03 2023-02-28 Juno Therapeutic, Inc. Methods and compositions for use of therapeutic T cells in combination with kinase inhibitors
EP4279136A2 (en) 2016-12-03 2023-11-22 Juno Therapeutics, Inc. Methods for determining car-t cells dosing
WO2018102785A2 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors
WO2018106732A1 (en) 2016-12-05 2018-06-14 Juno Therapeutics, Inc. Production of engineered cells for adoptive cell therapy
US11408005B2 (en) 2016-12-12 2022-08-09 Seattle Children's Hospital Chimeric transcription factor variants with augmented sensitivity to drug ligand induction of transgene expression in mammalian cells
EP3336107A1 (en) 2016-12-15 2018-06-20 Miltenyi Biotec GmbH Immune cells expressing an antigen binding receptor and a chimeric costimulatory receptor
WO2018108766A1 (en) 2016-12-15 2018-06-21 Miltenyi Biotec Gmbh Immune cells expressing an antigen binding receptor and a chimeric costimulatory receptor
WO2018132518A1 (en) 2017-01-10 2018-07-19 Juno Therapeutics, Inc. Epigenetic analysis of cell therapy and related methods
US11821027B2 (en) 2017-01-10 2023-11-21 Juno Therapeutics, Inc. Epigenetic analysis of cell therapy and related methods
US11517627B2 (en) 2017-01-20 2022-12-06 Juno Therapeutics Gmbh Cell surface conjugates and related cell compositions and methods
WO2018134691A2 (en) 2017-01-20 2018-07-26 Juno Therapeutics Gmbh Cell surface conjugates and related cell compositions and methods
US11845803B2 (en) 2017-02-17 2023-12-19 Fred Hutchinson Cancer Center Combination therapies for treatment of BCMA-related cancers and autoimmune disorders
WO2018157171A2 (en) 2017-02-27 2018-08-30 Juno Therapeutics, Inc. Compositions, articles of manufacture and methods related to dosing in cell therapy
US12163952B2 (en) 2017-02-27 2024-12-10 Juno Therapeutics, Inc. Determining toxicity risk in CAR T-cell therapy
EP4353818A2 (en) 2017-02-27 2024-04-17 Juno Therapeutics, Inc. Compositions, articles of manufacture and methods related to dosing in cell therapy
US11850262B2 (en) 2017-02-28 2023-12-26 Purdue Research Foundation Compositions and methods for CAR T cell therapy
US11759480B2 (en) 2017-02-28 2023-09-19 Endocyte, Inc. Compositions and methods for CAR T cell therapy
WO2018165228A1 (en) 2017-03-08 2018-09-13 Memorial Sloan Kettering Cancer Center Immune cell compositions and methods of use
WO2018170188A2 (en) 2017-03-14 2018-09-20 Juno Therapeutics, Inc. Methods for cryogenic storage
US11427645B2 (en) 2017-03-15 2022-08-30 Oxford Biomedica (Uk) Limited 5T4-targeting agents and methods
WO2018167486A1 (en) 2017-03-15 2018-09-20 Oxford Biomedica (Uk) Limited Method
US11851659B2 (en) 2017-03-22 2023-12-26 Novartis Ag Compositions and methods for immunooncology
US11547694B2 (en) 2017-03-23 2023-01-10 The General Hospital Corporation CXCR4/CXCR7 blockade and treatment of human papilloma virus-associated disease
US12351617B2 (en) 2017-03-27 2025-07-08 National University Of Singapore Immune cells comprising truncated NKG2D chimeric receptors
US11896616B2 (en) 2017-03-27 2024-02-13 National University Of Singapore Stimulatory cell lines for ex vivo expansion and activation of natural killer cells
US11365236B2 (en) 2017-03-27 2022-06-21 Nkarta, Inc. Truncated NKG2D chimeric receptors and uses thereof in natural killer cell immunotherapy
WO2018187791A1 (en) 2017-04-07 2018-10-11 Juno Therapeutics, Inc Engineered cells expressing prostate-specific membrane antigen (psma) or a modified form thereof and related methods
US11796534B2 (en) 2017-04-14 2023-10-24 Juno Therapeutics, Inc. Methods for assessing cell surface glycosylation
US12379375B2 (en) 2017-04-14 2025-08-05 Juno Therapeutics, Inc. Methods for assessing cell surface glycosylation
WO2018191723A1 (en) 2017-04-14 2018-10-18 Juno Therapeutics, Inc. Methods for assessing cell surface glycosylation
EP4083063A2 (en) 2017-04-18 2022-11-02 FUJIFILM Cellular Dynamics, Inc. Antigen-specific immune effector cells
WO2018195175A1 (en) 2017-04-18 2018-10-25 FUJIFILM Cellular Dynamics, Inc. Antigen-specific immune effector cells
US20200115448A1 (en) * 2017-04-26 2020-04-16 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US11613573B2 (en) 2017-04-26 2023-03-28 Eureka Therapeutics, Inc. Chimeric antibody/T-cell receptor constructs and uses thereof
WO2018200583A1 (en) * 2017-04-26 2018-11-01 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
US11965021B2 (en) 2017-04-26 2024-04-23 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
AU2018258046B2 (en) * 2017-04-26 2025-03-20 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
AU2018258046C1 (en) * 2017-04-26 2025-11-06 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
RU2780020C2 (ru) * 2017-04-26 2022-09-19 Еурека Терапьютикс, Инк. Клетки, экспрессирующие химерные активирующие рецепторы и химерные стимулирующие рецепторы, и их применение
US10822413B2 (en) 2017-04-26 2020-11-03 Eureka Therapeutics, Inc. Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof
WO2018197949A1 (en) 2017-04-27 2018-11-01 Juno Therapeutics Gmbh Oligomeric particle reagents and methods of use thereof
US11866465B2 (en) 2017-04-27 2024-01-09 Juno Therapeutics Gmbh Oligomeric particle reagents and methods of use thereof
EP4647493A2 (en) 2017-04-27 2025-11-12 Juno Therapeutics, Inc. Oligomeric particle reagents and methods of use thereof
WO2018204427A1 (en) 2017-05-01 2018-11-08 Juno Therapeutics, Inc. Combination of a cell therapy and an immunomodulatory compound
EP4327878A2 (en) 2017-05-01 2024-02-28 Juno Therapeutics, Inc. Combination of a cell therapy and an immunomodulatory compound
US11413310B2 (en) 2017-06-02 2022-08-16 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
WO2018223101A1 (en) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
US11740231B2 (en) 2017-06-02 2023-08-29 Juno Therapeutics, Inc. Articles of manufacture and methods related to toxicity associated with cell therapy
US11944647B2 (en) 2017-06-02 2024-04-02 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
WO2018223098A1 (en) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles of manufacture and methods related to toxicity associated with cell therapy
WO2018234370A1 (en) 2017-06-20 2018-12-27 Institut Curie Immune cells defective for suv39h1
EP3828264A1 (en) 2017-06-20 2021-06-02 Institut Curie Immune cells defective for suv39h1
US12275787B2 (en) 2017-06-21 2025-04-15 Icell Gene Therapeutics Llc Chimeric antigen receptors (CARs), compositions and methods thereof
EP4302768A2 (en) 2017-06-22 2024-01-10 Board Of Regents, The University Of Texas System Methods for producing regulatory immune cells and uses thereof
WO2019006427A1 (en) 2017-06-29 2019-01-03 Juno Therapeutics, Inc. WALL MODEL FOR ASSESSING TOXICITIES ASSOCIATED WITH IMMUNOTHERAPIES
EP4582146A2 (en) 2017-07-25 2025-07-09 Board of Regents, The University of Texas System Enhanced chimeric antigen receptors and use thereof
WO2019027850A1 (en) 2017-07-29 2019-02-07 Juno Therapeutics, Inc. CELL EXPANSION REAGENTS EXPRESSING RECOMBINANT RECEPTORS
EP4549554A2 (en) 2017-07-29 2025-05-07 Juno Therapeutics, Inc. Reagents for expanding cells expressing recombinant receptors
US12215348B2 (en) 2017-08-09 2025-02-04 Juno Therapeutics, Inc. Methods for producing genetically engineered cell compositions and related compositions
US11851678B2 (en) 2017-08-09 2023-12-26 Juno Therapeutics, Inc. Methods for producing genetically engineered cell compositions and related compositions
WO2019032927A1 (en) 2017-08-09 2019-02-14 Juno Therapeutics, Inc. METHODS FOR PRODUCING GENETICALLY MODIFIED CELL COMPOSITIONS AND COMPOSITIONS THEREOF
WO2019032929A1 (en) 2017-08-09 2019-02-14 Juno Therapeutics, Inc. METHODS AND COMPOSITIONS FOR PREPARING GENETICALLY MODIFIED CELLS
EP4516896A2 (en) 2017-08-09 2025-03-05 Juno Therapeutics, Inc. Methods and compositions for preparing genetically engineered cells
WO2019046832A1 (en) 2017-09-01 2019-03-07 Juno Therapeutics, Inc. GENE EXPRESSION AND EVALUATION OF RISK OF DEVELOPMENT OF TOXICITY FOLLOWING CELL THERAPY
WO2019051335A1 (en) 2017-09-07 2019-03-14 Juno Therapeutics, Inc. METHODS OF IDENTIFYING CELLULAR CHARACTERISTICS RELATED TO RESPONSES ASSOCIATED WITH CELL THERAPY
WO2019057102A1 (en) 2017-09-20 2019-03-28 Tsinghua University HPK1 TARGETING ARNG AND HPK1 GENE EDITING METHOD
EP4215543A2 (en) 2017-10-03 2023-07-26 Juno Therapeutics, Inc. Hpv-specific binding molecules
US11952408B2 (en) 2017-10-03 2024-04-09 Juno Therapeutics, Inc. HPV-specific binding molecules
WO2019070541A1 (en) 2017-10-03 2019-04-11 Juno Therapeutics, Inc. HPV-SPECIFIC BINDING MOLECULES
EP3694872A1 (en) 2017-10-12 2020-08-19 Board Of Regents, The University Of Texas System T cell receptors for immunotherapy
WO2019090004A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Process for producing a t cell composition
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
WO2019089848A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods associated with tumor burden for assessing response to a cell therapy
US11564946B2 (en) 2017-11-01 2023-01-31 Juno Therapeutics, Inc. Methods associated with tumor burden for assessing response to a cell therapy
US12258580B2 (en) 2017-11-01 2025-03-25 Juno Therapeutics, Inc. Process for generating therapeutic compositions of engineered cells
US12031975B2 (en) 2017-11-01 2024-07-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
US11066475B2 (en) 2017-11-01 2021-07-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
WO2019089858A2 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
WO2019089982A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Method of assessing activity of recombinant antigen receptors
US11851679B2 (en) 2017-11-01 2023-12-26 Juno Therapeutics, Inc. Method of assessing activity of recombinant antigen receptors
WO2019089855A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Process for generating therapeutic compositions of engineered cells
EP4512823A2 (en) 2017-11-01 2025-02-26 Juno Therapeutics, Inc. Process for generating therapeutic compositions of engineered cells
WO2019089884A2 (en) 2017-11-01 2019-05-09 Editas Medicine, Inc. Methods, compositions and components for crispr-cas9 editing of tgfbr2 in t cells for immunotherapy
US12168027B2 (en) 2017-11-01 2024-12-17 Juno Therapeutics, Inc. Methods associated with tumor burden for assessing response to a cell therapy
US12428486B2 (en) 2017-11-01 2025-09-30 Juno Therapeutics, Inc. Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
WO2019090003A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Chimeric antigen receptors specific for b-cell maturation antigen (bcma)
WO2019087151A1 (en) 2017-11-03 2019-05-09 Sorrento Therapeutics, Inc. Cd38-directed chimeric antigen receptor constructs
US12193994B2 (en) 2017-11-06 2025-01-14 Juno Therapeutics, Inc. Combination of a cell therapy and a gamma secretase inhibitor
WO2019090364A1 (en) 2017-11-06 2019-05-09 Juno Therapeutics, Inc. Combination of a cell therapy and a gamma secretase inhibitor
WO2019090202A1 (en) 2017-11-06 2019-05-09 Editas Medicine, Inc. Methods, compositions and components for crispr-cas9 editing of cblb in t cells for immunotherapy
WO2019094835A1 (en) 2017-11-10 2019-05-16 Juno Therapeutics, Inc. Closed-system cryogenic vessels
WO2019109053A1 (en) 2017-12-01 2019-06-06 Juno Therapeutics, Inc. Methods for dosing and for modulation of genetically engineered cells
US12139522B2 (en) 2017-12-05 2024-11-12 The Medical Research Infrastructure And Heal Serviced Fund Of The Tel Aviv Medecal Center T-cells comprising two different chimeric antigen receptors and uses thereof
US11944644B2 (en) 2017-12-05 2024-04-02 The Medical Research Infrastructure And Health Services Fund Of The Tel Aviv Medical Center T-cells comprising anti-CD38 and anti-CD138 chimeric antigen receptors and uses thereof
WO2019113556A1 (en) 2017-12-08 2019-06-13 Juno Therapeutics, Inc. Serum-free media formulation for culturing cells and methods of use thereof
WO2019113557A1 (en) 2017-12-08 2019-06-13 Juno Therapeutics, Inc. Process for producing a composition of engineered t cells
WO2019113559A2 (en) 2017-12-08 2019-06-13 Juno Therapeutics, Inc. Phenotypic markers for cell therapy and related methods
US12161670B2 (en) 2017-12-08 2024-12-10 Juno Therapeutics, Inc. Phenotypic markers for cell therapy and related methods
WO2019118937A1 (en) 2017-12-15 2019-06-20 Juno Therapeutics, Inc. Anti-cct5 binding molecules and methods of use thereof
US12006356B2 (en) 2017-12-15 2024-06-11 Juno Therapeutics, Inc. Anti-CCT5 binding molecules and chimeric antigen receptors comprising the same
US11919937B2 (en) 2018-01-09 2024-03-05 Board Of Regents, The University Of Texas System T cell receptors for immunotherapy
WO2019141270A1 (zh) * 2018-01-19 2019-07-25 科济生物医药（上海）有限公司 SynNotch受体调控表达IL12
US11779602B2 (en) 2018-01-22 2023-10-10 Endocyte, Inc. Methods of use for CAR T cells
US12269862B2 (en) 2018-01-22 2025-04-08 Endocyte, Inc. Methods of use for CAR T cells
US11535903B2 (en) 2018-01-31 2022-12-27 Juno Therapeutics, Inc. Methods and reagents for assessing the presence or absence of replication competent virus
WO2019152743A1 (en) 2018-01-31 2019-08-08 Celgene Corporation Combination therapy using adoptive cell therapy and checkpoint inhibitor
US12264371B2 (en) 2018-01-31 2025-04-01 Juno Therapeutics, Inc. Methods and reagents for assessing the presence or absence of replication competent virus
WO2019152747A1 (en) 2018-01-31 2019-08-08 Juno Therapeutics, Inc. Methods and reagents for assessing the presence or absence of replication competent virus
WO2019148656A1 (zh) * 2018-02-05 2019-08-08 深圳市默赛尔生物医学科技发展有限公司 多信号嵌合抗原受体及其表达基因、其修饰的nk细胞及抗肿瘤的药物
US12258381B2 (en) 2018-02-09 2025-03-25 National University Of Singapore Activating chimeric receptors and uses thereof in natural killer cell immunotherapy
US11229669B2 (en) 2018-02-11 2022-01-25 Memorial Sloan-Kettering Cancer Center Cells comprising non-HLA restricted T cell receptors
US12036244B2 (en) 2018-02-11 2024-07-16 Memorial Sloan-Kettering Cancer Center Cells comprising non-HLA restricted T cell receptors
WO2019161133A1 (en) 2018-02-15 2019-08-22 Memorial Sloan Kettering Cancer Center Foxp3 targeting agent compositions and methods of use for adoptive cell therapy
US12240870B2 (en) 2018-02-23 2025-03-04 Purdue Research Foundation Sequencing method for CAR T cell therapy
US12186343B2 (en) 2018-03-09 2025-01-07 Crage Medical Co., Limited Method and composition for treating tumors
WO2019170147A1 (zh) 2018-03-09 2019-09-12 科济生物医药（上海）有限公司 用于治疗肿瘤的方法和组合物
WO2019170845A1 (en) 2018-03-09 2019-09-12 Ospedale San Raffaele S.R.L. Il-1 antagonist and toxicity induced by cell therapy
US12441787B2 (en) 2018-04-02 2025-10-14 National University Of Singapore Neutralization of human cytokines with membrane-bound anti-cytokine non-signaling binders expressed in immune cells
US11471489B2 (en) 2018-04-05 2022-10-18 Juno Therapeutics, Inc. T cell receptors and engineered cells expressing same
WO2019195491A1 (en) 2018-04-05 2019-10-10 Juno Therapeutics, Inc. T cells expressing a recombinant receptor, related polynucleotides and methods
WO2019195486A1 (en) 2018-04-05 2019-10-10 Juno Therapeutics, Inc. T cell receptors and engineered cells expressing same
WO2019195492A1 (en) 2018-04-05 2019-10-10 Juno Therapeutics, Inc. Methods of producing cells expressing a recombinant receptor and related compositions
US12377147B2 (en) 2018-04-19 2025-08-05 Baylor College Of Medicine Reprogramming CD4 t cells into cytotoxic CD8 cells by forced expression of CD8ab and class 1 restricted t cell receptors
WO2019213184A1 (en) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Combination therapy of a chimeric antigen receptor (car) t cell therapy and a kinase inhibitor
US11939389B2 (en) 2018-06-13 2024-03-26 Novartis Ag BCMA chimeric antigen receptors and uses thereof
US11952428B2 (en) 2018-06-13 2024-04-09 Novartis Ag BCMA chimeric antigen receptors and uses thereof
US11993661B2 (en) 2018-06-18 2024-05-28 Eureka Therapeutics, Inc. Constructs targeting prostate-specific membrane antigen (PSMA) and uses thereof
WO2020020210A1 (zh) 2018-07-24 2020-01-30 科济生物医药（上海）有限公司 免疫效应细胞治疗肿瘤的方法
WO2020033927A2 (en) 2018-08-09 2020-02-13 Juno Therapeutics, Inc. Processes for generating engineered cells and compositions thereof
WO2020033916A1 (en) 2018-08-09 2020-02-13 Juno Therapeutics, Inc. Methods for assessing integrated nucleic acids
US12486514B2 (en) 2018-08-29 2025-12-02 National University Of Singapore Method to specifically stimulate survival and expansion of genetically-modified immune cells
WO2020056047A1 (en) 2018-09-11 2020-03-19 Juno Therapeutics, Inc. Methods for mass spectrometry analysis of engineered cell compositions
US12366580B2 (en) 2018-09-11 2025-07-22 Juno Therapeutics, Inc. Methods for mass spectrometry analysis of engineered cell compositions
WO2020061256A1 (en) 2018-09-19 2020-03-26 FUJIFILM Cellular Dynamics, Inc. Protein l for activation and expansion of chimeric antigen receptor-modified immune cells
WO2020089343A1 (en) 2018-10-31 2020-05-07 Juno Therapeutics Gmbh Methods for selection and stimulation of cells and apparatus for same
US12473345B2 (en) 2018-11-01 2025-11-18 Juno Therapeutics, Inc. Methods for treatment using chimeric antigen receptors specific for B-cell maturation antigen
WO2020092854A2 (en) 2018-11-01 2020-05-07 Juno Therapeutics, Inc. Chimeric antigen receptors specific for g protein-coupled receptor class c group 5 member d (gprc5d)
WO2020092848A2 (en) 2018-11-01 2020-05-07 Juno Therapeutics, Inc. Methods for treatment using chimeric antigen receptors specific for b-cell maturation antigen
WO2020097132A1 (en) 2018-11-06 2020-05-14 Juno Therapeutics, Inc. Process for producing genetically engineered t cells
WO2020097403A1 (en) 2018-11-08 2020-05-14 Juno Therapeutics, Inc. Methods and combinations for treatment and t cell modulation
US12263190B2 (en) 2018-11-08 2025-04-01 Juno Therapeutics, Inc. Methods and combinations for treatment and T cell modulation
WO2020102770A1 (en) 2018-11-16 2020-05-22 Juno Therapeutics, Inc. Methods of dosing engineered t cells for the treatment of b cell malignancies
WO2020106621A1 (en) 2018-11-19 2020-05-28 Board Of Regents, The University Of Texas System A modular, polycistronic vector for car and tcr transduction
WO2020113029A2 (en) 2018-11-28 2020-06-04 Board Of Regents, The University Of Texas System Multiplex genome editing of immune cells to enhance functionality and resistance to suppressive environment
EP4471129A2 (en) 2018-11-29 2024-12-04 Board of Regents, The University of Texas System Methods for ex vivo expansion of natural killer cells and use thereof
WO2020112493A1 (en) 2018-11-29 2020-06-04 Board Of Regents, The University Of Texas System Methods for ex vivo expansion of natural killer cells and use thereof
EP4393547A2 (en) 2018-11-30 2024-07-03 Juno Therapeutics, Inc. Methods for dosing and treatment of b cell malignancies in adoptive cell therapy
EP4427810A2 (en) 2018-11-30 2024-09-11 Juno Therapeutics, Inc. Methods for treatment using adoptive cell therapy
WO2020113188A2 (en) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Methods for dosing and treatment of b cell malignancies in adoptive cell therapy
WO2020113194A2 (en) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Methods for treatment using adoptive cell therapy
US12268741B2 (en) 2019-01-29 2025-04-08 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ROR1)
WO2020160050A1 (en) 2019-01-29 2020-08-06 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1)
WO2020169974A1 (en) 2019-02-19 2020-08-27 King's College London Hypoxia-responsive chimeric antigen receptors
US11141436B2 (en) 2019-03-05 2021-10-12 Nkarta, Inc. Immune cells engineered to express CD19-directed chimeric antigen receptors and uses thereof in immunotherapy
US11253547B2 (en) 2019-03-05 2022-02-22 Nkarta, Inc. CD19-directed chimeric antigen receptors and uses thereof in immunotherapy
US12398187B2 (en) 2019-03-05 2025-08-26 Nkarta, Inc. CD19-directed chimeric antigen receptors and uses thereof in immunotherapy
US11154575B2 (en) 2019-03-05 2021-10-26 Nkarta, Inc. Cancer immunotherapy using CD19-directed chimeric antigen receptors
US12435120B2 (en) 2019-05-01 2025-10-07 Juno Therapeutics, Inc. Cells expressing a chimeric receptor from a modified CD247 locus, related polynucleotides and methods
WO2020223535A1 (en) 2019-05-01 2020-11-05 Juno Therapeutics, Inc. Cells expressing a recombinant receptor from a modified tgfbr2 locus, related polynucleotides and methods
WO2020223571A1 (en) 2019-05-01 2020-11-05 Juno Therapeutics, Inc. Cells expressing a chimeric receptor from a modified cd247 locus, related polynucleotides and methods
WO2020247832A1 (en) 2019-06-07 2020-12-10 Juno Therapeutics, Inc. Automated t cell culture
WO2020252218A1 (en) 2019-06-12 2020-12-17 Juno Therapeutics, Inc. Combination therapy of a cell-mediated cytotoxic therapy and an inhibitor of a prosurvival bcl2 family protein
WO2021013950A1 (en) 2019-07-23 2021-01-28 Mnemo Therapeutics Immune cells defective for suv39h1
WO2021035194A1 (en) 2019-08-22 2021-02-25 Juno Therapeutics, Inc. Combination therapy of a t cell therapy and an enhancer of zeste homolog 2 (ezh2) inhibitor and related methods
WO2021038036A1 (en) * 2019-08-28 2021-03-04 King's College London B CELL TARGETED PARALLEL CAR (pCAR) THERAPEUTIC AGENTS
CN114641308A (zh) * 2019-08-28 2022-06-17 伦敦国王学院 B细胞靶向的平行CAR(pCAR)治疗剂
US12444491B2 (en) 2019-08-30 2025-10-14 Juno Therapeutics, Inc. Machine learning methods for classifying cells
WO2021041994A2 (en) 2019-08-30 2021-03-04 Juno Therapeutics, Inc. Machine learning methods for classifying cells
US12152077B1 (en) 2019-09-02 2024-11-26 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
WO2021043804A1 (en) 2019-09-02 2021-03-11 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
WO2021078910A1 (en) 2019-10-22 2021-04-29 Institut Curie Immunotherapy targeting tumor neoantigenic peptides
WO2021084050A1 (en) 2019-10-30 2021-05-06 Juno Therapeutics Gmbh Cell selection and/or stimulation devices and methods of use
WO2021092097A1 (en) 2019-11-05 2021-05-14 Juno Therapeutics, Inc. Methods of determining attributes of therapeutic t cell compositions
WO2021092498A1 (en) 2019-11-07 2021-05-14 Juno Therapeutics, Inc. Combination of a t cell therapy and (s)-3-[4-(4-morpholin-4 ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]- piperidine-2,6-dione
US11975026B2 (en) 2019-11-26 2024-05-07 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
US12344651B2 (en) 2019-11-26 2025-07-01 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
WO2021113770A1 (en) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Methods related to toxicity and response associated with cell therapy for treating b cell malignancies
WO2021113780A1 (en) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Anti-idiotypic antibodies to gprc5d-targeted binding domains and related compositions and methods
WO2021113776A1 (en) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Anti-idiotypic antibodies to bcma-targeted binding domains and related compositions and methods
US12252545B2 (en) 2019-12-11 2025-03-18 Myeloid Therapeutics, Inc. Therapeutic cell compositions and methods of manufacturing and use thereof
WO2021151008A1 (en) 2020-01-24 2021-07-29 Juno Therapuetics, Inc. Methods for dosing and treatment of follicular lymphoma and marginal zone lymphoma in adoptive cell therapy
WO2021154887A1 (en) 2020-01-28 2021-08-05 Juno Therapeutics, Inc. Methods for t cell transduction
WO2021163389A1 (en) 2020-02-12 2021-08-19 Juno Therapeutics, Inc. Bcma-directed chimeric antigen receptor t cell compositions and methods and uses thereof
WO2021163391A1 (en) 2020-02-12 2021-08-19 Juno Therapeutics, Inc. Cd19-directed chimeric antigen receptor t cell compositions and methods and uses thereof
WO2021167908A1 (en) 2020-02-17 2021-08-26 Board Of Regents, The University Of Texas System Methods for expansion of tumor infiltrating lymphocytes and use thereof
WO2021164959A1 (en) * 2020-02-17 2021-08-26 Miltenyi Biotec B.V. & Co. KG Method for providing personalized cells with chimeric antigen receptors (car) against tumor microenvironment cells
WO2021207689A2 (en) 2020-04-10 2021-10-14 Juno Therapeutics, Inc. Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen
WO2021222330A2 (en) 2020-04-28 2021-11-04 Juno Therapeutics, Inc. Combination of bcma-directed t cell therapy and an immunomodulatory compound
WO2021228999A1 (en) 2020-05-12 2021-11-18 Institut Curie Neoantigenic epitopes associated with sf3b1 mutations
WO2021231661A2 (en) 2020-05-13 2021-11-18 Juno Therapeutics, Inc. Process for producing donor-batched cells expressing a recombinant receptor
WO2021231657A1 (en) 2020-05-13 2021-11-18 Juno Therapeutics, Inc. Methods of identifying features associated with clinical response and uses thereof
WO2021237068A2 (en) 2020-05-21 2021-11-25 Board Of Regents, The University Of Texas System T cell receptors with vgll1 specificity and uses thereof
WO2021260186A1 (en) 2020-06-26 2021-12-30 Juno Therapeutics Gmbh Engineered t cells conditionally expressing a recombinant receptor, related polynucleotides and methods
WO2022016119A1 (en) 2020-07-17 2022-01-20 Simurx, Inc. Chimeric myd88 receptors for redirecting immunosuppressive signaling and related compositions and methods
WO2022023576A1 (en) 2020-07-30 2022-02-03 Institut Curie Immune cells defective for socs1
WO2022029660A1 (en) 2020-08-05 2022-02-10 Juno Therapeutics, Inc. Anti-idiotypic antibodies to ror1-targeted binding domains and related compositions and methods
EP4200340A1 (en) 2020-08-21 2023-06-28 12343096 Canada Inc. Modular assembly receptors and uses thereof
US12024559B2 (en) 2020-10-23 2024-07-02 Asher Biotherapeutics, Inc. Fusions with CD8 antigen binding molecules for modulating immune cell function
WO2022098787A1 (en) 2020-11-04 2022-05-12 Juno Therapeutics, Inc. Cells expressing a chimeric receptor from a modified invariant cd3 immunoglobulin superfamily chain locus and related polynucleotides and methods
US11628218B2 (en) 2020-11-04 2023-04-18 Myeloid Therapeutics, Inc. Engineered chimeric fusion protein compositions and methods of use thereof
WO2022104109A1 (en) 2020-11-13 2022-05-19 Catamaran Bio, Inc. Genetically modified natural killer cells and methods of use thereof
WO2022115611A1 (en) 2020-11-25 2022-06-02 Catamaran Bio, Inc. Cellular therapeutics engineered with signal modulators and methods of use thereof
WO2022133030A1 (en) 2020-12-16 2022-06-23 Juno Therapeutics, Inc. Combination therapy of a cell therapy and a bcl2 inhibitor
WO2022150731A1 (en) 2021-01-11 2022-07-14 Sana Biotechnology, Inc. Use of cd8-targeted viral vectors
WO2022187406A1 (en) 2021-03-03 2022-09-09 Juno Therapeutics, Inc. Combination of a t cell therapy and a dgk inhibitor
WO2022189620A1 (en) 2021-03-11 2022-09-15 Institut Curie Transmembrane neoantigenic peptides
WO2022189639A1 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides and uses thereof
WO2022189626A2 (en) 2021-03-11 2022-09-15 Mnemo Therapeutics Tumor neoantigenic peptides
US12030938B2 (en) 2021-03-17 2024-07-09 Myeloid Therapeutics, Inc. Engineered chimeric fusion protein compositions and methods of use thereof
WO2022204071A1 (en) 2021-03-22 2022-09-29 Juno Therapeutics, Inc. Method to assess potency of viral vector particles
WO2022204070A1 (en) 2021-03-22 2022-09-29 Juno Therapeutics, Inc. Methods of determining potency of a therapeutic cell composition
WO2022212384A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Combination of a car t cell therapy and an immunomodulatory compound for treatment of lymphoma
WO2022212400A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022221726A2 (en) 2021-04-16 2022-10-20 Juno Therapeutics, Inc. Combination therapies with bcma-directed t cell therapy
WO2022221737A1 (en) 2021-04-16 2022-10-20 Juno Therapeutics, Inc. T cell therapy in patients who have had prior stem cell transplant
EP4326293A1 (en) 2021-04-22 2024-02-28 Baylor College of Medicine Methods of engineering immune cells having reduced fratricidal activity
WO2022234009A2 (en) 2021-05-06 2022-11-10 Juno Therapeutics Gmbh Methods for stimulating and transducing t cells
WO2022238386A1 (en) 2021-05-10 2022-11-17 Institut Curie Methods for the treatment of cancer, inflammatory diseases and autoimmune diseases
US12319925B2 (en) 2021-05-11 2025-06-03 Myeloid Therapeutics, Inc. Methods and compositions for genomic integration
WO2022248602A1 (en) 2021-05-25 2022-12-01 Institut Curie Myeloid cells overexpressing bcl2
WO2023014922A1 (en) 2021-08-04 2023-02-09 The Regents Of The University Of Colorado, A Body Corporate Lat activating chimeric antigen receptor t cells and methods of use thereof
WO2023015217A1 (en) 2021-08-04 2023-02-09 Sana Biotechnology, Inc. Use of cd4-targeted viral vectors
WO2023081735A1 (en) 2021-11-03 2023-05-11 Celgene Corporation Chimeric antigen receptors specific for b-cell maturation antigen for use in treating myeloma
WO2023081715A1 (en) 2021-11-03 2023-05-11 Viracta Therapeutics, Inc. Combination of car t-cell therapy with btk inhibitors and methods of use thereof
WO2023081900A1 (en) 2021-11-08 2023-05-11 Juno Therapeutics, Inc. Engineered t cells expressing a recombinant t cell receptor (tcr) and related systems and methods
WO2023105000A1 (en) 2021-12-09 2023-06-15 Zygosity Limited Vector
WO2023109900A1 (en) 2021-12-17 2023-06-22 Shanghai Henlius Biotech, Inc. Anti-ox40 antibodies, multispecific antibodies and methods of use
WO2023115039A2 (en) 2021-12-17 2023-06-22 Sana Biotechnology, Inc. Modified paramyxoviridae fusion glycoproteins
WO2023109901A1 (en) 2021-12-17 2023-06-22 Shanghai Henlius Biotech, Inc. Anti-ox40 antibodies and methods of use
WO2023115041A1 (en) 2021-12-17 2023-06-22 Sana Biotechnology, Inc. Modified paramyxoviridae attachment glycoproteins
WO2023126458A1 (en) 2021-12-28 2023-07-06 Mnemo Therapeutics Immune cells with inactivated suv39h1 and modified tcr
WO2023139269A1 (en) 2022-01-21 2023-07-27 Mnemo Therapeutics Modulation of suv39h1 expression by rnas
WO2023147515A1 (en) 2022-01-28 2023-08-03 Juno Therapeutics, Inc. Methods of manufacturing cellular compositions
WO2023150518A1 (en) 2022-02-01 2023-08-10 Sana Biotechnology, Inc. Cd3-targeted lentiviral vectors and uses thereof
WO2023164440A1 (en) 2022-02-22 2023-08-31 Juno Therapeutics, Inc. Proteinase 3 (pr3) chimeric autoantibody receptor t cells and related methods and uses
WO2023178348A1 (en) 2022-03-18 2023-09-21 The Regents Of The University Of Colorado, A Body Corporate Genetically engineered t-cell co-receptors and methods of use thereof
WO2023180552A1 (en) 2022-03-24 2023-09-28 Institut Curie Immunotherapy targeting tumor transposable element derived neoantigenic peptides in glioblastoma
WO2023179740A1 (en) 2022-03-25 2023-09-28 Shanghai Henlius Biotech , Inc. Anti-msln antibodies and methods of use
WO2023187024A1 (en) 2022-03-31 2023-10-05 Institut Curie Modified rela protein for inducing interferon expression and engineered immune cells with improved interferon expression
WO2023193015A1 (en) 2022-04-01 2023-10-05 Sana Biotechnology, Inc. Cytokine receptor agonist and viral vector combination therapies
WO2023196933A1 (en) 2022-04-06 2023-10-12 The Regents Of The University Of Colorado, A Body Corporate Chimeric antigen receptor t cells and methods of use thereof
WO2023196921A1 (en) 2022-04-06 2023-10-12 The Regents Of The University Of Colorado, A Body Corporate Granzyme expressing t cells and methods of use
US12503507B2 (en) 2022-04-21 2025-12-23 Seattle Children's Hospital Defined composition gene modified T-cell products
WO2023211972A1 (en) 2022-04-28 2023-11-02 Medical University Of South Carolina Chimeric antigen receptor modified regulatory t cells for treating cancer
WO2023213969A1 (en) 2022-05-05 2023-11-09 Juno Therapeutics Gmbh Viral-binding protein and related reagents, articles, and methods of use
WO2023220641A2 (en) 2022-05-11 2023-11-16 Juno Therapeutics, Inc. Methods and uses related to t cell therapy and production of same
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy
WO2023222617A1 (en) 2022-05-16 2023-11-23 Miltenyi Biotec B.V. & Co. KG Endogenous signaling molecule activating chimeric antigen receptors and methods of generation thereof
EP4279085A1 (en) 2022-05-20 2023-11-22 Mnemo Therapeutics Compositions and methods for treating a refractory or relapsed cancer or a chronic infectious disease
WO2023222928A2 (en) 2022-05-20 2023-11-23 Mnemo Therapeutics Compositions and methods for treating a refractory or relapsed cancer or a chronic infectious disease
WO2023230581A1 (en) 2022-05-25 2023-11-30 Celgene Corporation Methods of manufacturing t cell therapies
WO2023230548A1 (en) 2022-05-25 2023-11-30 Celgene Corporation Method for predicting response to a t cell therapy
WO2023250400A1 (en) 2022-06-22 2023-12-28 Juno Therapeutics, Inc. Treatment methods for second line therapy of cd19-targeted car t cells
WO2024006960A1 (en) 2022-06-29 2024-01-04 Juno Therapeutics, Inc. Lipid nanoparticles for delivery of nucleic acids
WO2024031091A2 (en) 2022-08-05 2024-02-08 Juno Therapeutics, Inc. Chimeric antigen receptors specific for gprc5d and bcma
WO2024044779A2 (en) 2022-08-26 2024-02-29 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for delta-like ligand 3 (dll3)
WO2024054944A1 (en) 2022-09-08 2024-03-14 Juno Therapeutics, Inc. Combination of a t cell therapy and continuous or intermittent dgk inhibitor dosing
WO2024062138A1 (en) 2022-09-23 2024-03-28 Mnemo Therapeutics Immune cells comprising a modified suv39h1 gene
WO2024081820A1 (en) 2022-10-13 2024-04-18 Sana Biotechnology, Inc. Viral particles targeting hematopoietic stem cells
WO2024097905A1 (en) 2022-11-02 2024-05-10 Celgene Corporation Methods of treatment with t cell therapy and immunomodulatory agent maintenance therapy
WO2024100604A1 (en) 2022-11-09 2024-05-16 Juno Therapeutics Gmbh Methods for manufacturing engineered immune cells
WO2024102948A1 (en) 2022-11-11 2024-05-16 Celgene Corporation Fc receptor-homolog 5 (fcrh5) specific binding molecules and bispecific t-cell engaging antibodies including same and related methods
WO2024124132A1 (en) 2022-12-09 2024-06-13 Juno Therapeutics, Inc. Machine learning methods for predicting cell phenotype using holographic imaging
WO2024129778A2 (en) 2022-12-13 2024-06-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for baff-r and cd19 and methods and uses thereof
WO2024161021A1 (en) 2023-02-03 2024-08-08 Juno Therapeutics Gmbh Methods for non-viral manufacturing of engineered immune cells
WO2024182516A1 (en) 2023-02-28 2024-09-06 Juno Therapeutics, Inc. Cell therapy for treating systemic autoimmune diseases
US12257304B2 (en) 2023-03-03 2025-03-25 Arsenal Biosciences, Inc. Systems targeting PSMA and CA9
WO2024220598A2 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Lentiviral vectors with two or more genomes
WO2024220588A1 (en) 2023-04-18 2024-10-24 Juno Therapeutics, Inc. Cytotoxicity assay for assessing potency of therapeutic cell compositions
WO2024220560A1 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Engineered protein g fusogens and related lipid particles and methods thereof
WO2024220574A1 (en) 2023-04-18 2024-10-24 Sana Biotechnology, Inc. Universal protein g fusogens and adapter systems thereof and related lipid particles and uses
WO2024226858A1 (en) 2023-04-26 2024-10-31 Juno Therapeutics, Inc. Methods for viral vector manufacturing
WO2024243365A2 (en) 2023-05-23 2024-11-28 Juno Therapeutics, Inc. Activation markers of t cells and method for assessing t cell activation
WO2025054202A1 (en) 2023-09-05 2025-03-13 Sana Biotechnology, Inc. Method of screening a sample comprising a transgene with a unique barcode
EP4520334A1 (en) 2023-09-07 2025-03-12 Mnemo Therapeutics Methods and compositions for improving immune response
WO2025052001A1 (en) 2023-09-07 2025-03-13 Mnemo Therapeutics Methods and compositions for improving immune response
WO2025059362A1 (en) 2023-09-13 2025-03-20 Juno Therapeutics, Inc. Combination therapies with a cell therapy expressing a gprc5d-targeting car and related methods and uses
WO2025076472A1 (en) 2023-10-06 2025-04-10 Juno Therapeutics, Inc. Combination therapies with a cell therapy expressing a gprc5d-targeting car and related methods and uses
WO2025096975A1 (en) 2023-11-02 2025-05-08 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods of enhancing immune cell therapies by runx2 modulation
WO2025097055A2 (en) 2023-11-02 2025-05-08 The Broad Institute, Inc. Compositions and methods of use of t cells in immunotherapy
US12409224B2 (en) 2023-12-14 2025-09-09 The Regents Of The University Of Colorado, A Body Corporate Compositions and methods for the treatment of VEN/AZA resistant acute myeloid leukemia
WO2025147545A1 (en) 2024-01-03 2025-07-10 Juno Therapeutics, Inc. Lipid nanoparticles for delivery of nucleic acids and related methods and uses
WO2025151838A1 (en) 2024-01-12 2025-07-17 Sana Biotechnology, Inc. Safety switches to control in vitro and in vivo proliferation of cell therapy products
WO2025163107A1 (en) 2024-02-01 2025-08-07 Institut Gustave Roussy Immune cells defective for znf217 and uses thereof
WO2025184421A1 (en) 2024-02-28 2025-09-04 Juno Therapeutics, Inc. Chimeric antigen receptors and antibodies specific for delta-like ligand 3 (dll3) and related methods
WO2025212519A1 (en) 2024-04-01 2025-10-09 Moonlight Bio, Inc. Dll3 binding proteins and uses thereof
WO2025235851A1 (en) 2024-05-10 2025-11-13 Juno Therapeutics, Inc. Genetically engineered t cells expressing a cd19 chimeric antigen receptor (car) and uses thereof for allogeneic cell therapy
WO2025250011A1 (en) 2024-05-29 2025-12-04 Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Treatment for cancer

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