WO2017177149A2 - Methods and compositions for car t cell therapy - Google Patents

Methods and compositions for car t cell therapy Download PDF

Info

Publication number
WO2017177149A2
WO2017177149A2 PCT/US2017/026618 US2017026618W WO2017177149A2 WO 2017177149 A2 WO2017177149 A2 WO 2017177149A2 US 2017026618 W US2017026618 W US 2017026618W WO 2017177149 A2 WO2017177149 A2 WO 2017177149A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
conjugate
cancer
car
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
Application number
PCT/US2017/026618
Other languages
English (en)
French (fr)
Other versions
WO2017177149A3 (en
Inventor
Philip Stewart Low
Haiyan CHU
Yong Gu Lee
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.)
Purdue Research Foundation
Endocyte Inc
Original Assignee
Purdue Research Foundation
Endocyte Inc
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
Priority to CN201780033995.3A priority Critical patent/CN109195611A/zh
Priority to BR112018070580-2A priority patent/BR112018070580B1/pt
Priority to RU2018139101A priority patent/RU2792653C2/ru
Priority to US16/092,054 priority patent/US12144850B2/en
Priority to JP2018553142A priority patent/JP7282521B2/ja
Priority to CA3019835A priority patent/CA3019835A1/en
Priority to EP17779919.4A priority patent/EP3439675A4/en
Application filed by Purdue Research Foundation, Endocyte Inc filed Critical Purdue Research Foundation
Publication of WO2017177149A2 publication Critical patent/WO2017177149A2/en
Publication of WO2017177149A3 publication Critical patent/WO2017177149A3/en
Anticipated expiration legal-status Critical
Priority to JP2023081216A priority patent/JP7631410B2/ja
Priority to US18/914,891 priority patent/US20250171803A1/en
Priority to JP2025017467A priority patent/JP2025084765A/ja
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70517—CD8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5156—Animal cells expressing foreign proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the structure of the chimeric antigen receptor [CAR]
    • A61K2239/11—Antigen recognition domain
    • A61K2239/15—Non-antibody based
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the structure of the chimeric antigen receptor [CAR]
    • A61K2239/23—On/off switch
    • A61K2239/24—Dimerizable CARs; CARs with adapter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/49—Breast
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present disclosure relates to methods of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells and administering to the patient a small molecule linked to a targeting moiety by a linker.
  • the disclosure also relates to compositions for use in such methods.
  • Immunotherapy based on adoptive transfer of lymphocytes (e.g., T cells) into a patient is a valuable therapy in the treatment of cancer and other diseases.
  • Many important advancements have been made in the development of immunotherapies based on adoptive transfer of lymphocytes.
  • T cells expressing chimeric antigen receptors (CAR T cells).
  • the chimeric antigen receptor (CAR) is a genetically engineered receptor that is designed to target a specific antigen, for example, a tumor antigen. This targeting can result in cytotoxicity against the tumor, for example, such that CAR T cells expressing CARs can target and kill tumors via the specific tumor antigens.
  • First generation CARs are composed of a recognition region, e.g., a single chain fragment variable (scFv) region derived from an antibody for recognition and binding to the antigen expressed by the tumor, and an activation signaling domain, e.g., the CD3 ⁇ chain of T cells can serve as a T cell activation signal in CARs.
  • a recognition region e.g., a single chain fragment variable (scFv) region derived from an antibody for recognition and binding to the antigen expressed by the tumor
  • an activation signaling domain e.g., the CD3 ⁇ chain of T cells can serve as a T cell activation signal in CARs.
  • a co- stimulation domain e.g. CD137, CD28 or CD134
  • second generation CARs to achieve prolonged activation of T cells in vivo.
  • Addition of a co-stimulation domain enhances the in vivo proliferation and survival of T cells containing CARs, and initial clinical data have shown that such constructs are promising therapeutic agents in the treatment of diseases, such as cancer.
  • CAR T cell therapies Although improvements have been made in CAR T cell therapies, several problems remain. First, Off-target' toxicity may occur due to normal cells that express the antigen targeted by the CAR T cells (e.g., a tumor-associated antigen). Second, unregulated CAR T cell activation may be found where the rapid and uncontrolled elimination of diseased cells (e.g., cancer cells) by CAR T cells induces a constellation of metabolic disturbances, called tumor lysis syndrome, in the case where a tumor is being treated, or cytokine release syndrome (CRS), which can be fatal to patients. Tumor lysis syndrome and CRS can result due to administered CAR T cells that cannot be easily regulated, and are activated uncontrollably. Accordingly, although CAR T cells show great promise as a tool in the treatment of diseases, such as cancer, additional CAR T cell therapies are needed that provide reduced off-target toxicity, and more precise control of CAR T cell activation.
  • diseases e.g., cancer
  • CRS cytokine release syndrome
  • a small molecule ligand linked to a targeting moiety by a linker is used as a bridge between the cancer and the CAR T cells directing the CAR T cells to the cancer for amelioration of the cancer.
  • the "small molecule ligand” can be, for example, a folate, DUPA, an NK-1R ligand, a CAIX ligand, a ligand of gamma glutamyl transpeptidase, or a CCK2R ligand, each of which is a small molecule ligand that binds specifically to cancer cells (i.e., the receptor for these ligands is overexpressed on cancers compared to normal tissues).
  • the "small molecule ligand" is linked to a "targeting moiety” that binds to the CAR expressed by CAR T cells.
  • the targeting moiety that binds to the CAR expressed by CAR T cells.
  • targeting moiety can be selected, for example, from 2,4-dinitrophenol (DNP), 2,4,6- trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS- fluorescein, pentafluorophenyl ester (PFP), tetrafluorophenyl ester (TFP), a knottin, a centyrin, and a DARPin.
  • DNP 2,4-dinitrophenol
  • TNP 2,4,6- trinitrophenol
  • biotin biotin
  • digoxigenin fluorescein, fluorescein isothiocyanate (FITC)
  • NHS- fluorescein NHS- fluorescein
  • PFP pentafluorophenyl ester
  • TFP tetrafluorophenyl ester
  • knottin a centyrin
  • centyrin a centyrin
  • DARPin DARP
  • the "targeting moiety” binds to the recognition region of the genetically engineered CAR expressed by CAR T cells. Accordingly, the recognition region of the CAR (e.g., a single chain fragment variable region (scFv) of an antibody) is directed to the "targeted moiety.”
  • the small molecule ligand linked to a targeting moiety by a linker acts as a 'bridge' between the cancer and the CAR T cells directing the CAR T cells to the cancer for amelioration of the cancer.
  • the inventors have discovered that varying the dose of the small molecule ligand linked to a targeting moiety by a linker (i.e., the bridge), can result in the ability to control CRS in vivo.
  • the inventors have discovered that varying the linker in the small molecule ligand linked to a targeting moiety (the bridge) can control CRS in vivo upon CAR T cell activation.
  • combinations of these methods can be used for precise control of CAR T cell activation and cytokine release in vivo.
  • affinity of the small molecule ligand for its receptor on the cancer can be altered to control CAR T cell activation, or to achieve specificity for the cancer avoiding toxicity towards normal tissues.
  • a method of treatment of a cancer comprises i) administering to a patient a first dose of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a CAR T cell composition wherein the CAR T cell comprises a CAR directed to the targeting moiety, ii) administering to the patient a second dose of the compound, or the pharmaceutically acceptable salt thereof, wherein the second dose is different than the first dose, and treating the patient to ameliorate the cancer.
  • a method of treatment of a cancer comprises i) administering to the patient a first conjugate, or a pharmaceutically acceptable salt thereof, ii) administering to the patient a CAR T cell composition wherein the CAR T cell comprises a CAR directed to the targeting moiety, iii) administering to the patient a second conjugate, or a pharmaceutically acceptable salt thereof, wherein the first and the second conjugate each comprise a small molecule ligand linked to a targeting moiety by a linker and wherein the first conjugate and the second conjugate are different, and iv) treating the patient to ameliorate the cancer.
  • a method of treatment of a cancer comprises i) administering to a patient a first dose of a first conjugate, or a
  • a CAR T cell comprising a nucleic acid comprising SEQ ID NO: l is provided. In another aspect, a CAR T cell comprising a polypeptide comprising SEQ ID NO:2 is provided. In another
  • an isolated nucleic acid comprising SEQ ID NO: l and encoding a
  • a chimeric antigen receptor is provided.
  • a chimeric antigen receptor polypeptide comprising SEQ ID NO:2 is provided.
  • a vector comprising SEQ ID NO: 1 is provided.
  • a vector is provided comprising SEQ ID NO: l wherein the vector is a lentiviral vector.
  • a method of treatment of a cancer comprising i) administering to a patient a first dose of a compound, or a
  • the compound comprises a small molecule ligand linked to a targeting moiety by a linker;
  • a method of treatment of a cancer comprising i) administering to the patient a first conjugate, or a pharmaceutically acceptable salt thereof;
  • first and the second conjugate each comprise a small molecule ligand linked to a targeting moiety by a linker and wherein the first conjugate and the second conjugate are different;
  • a method of treatment of a cancer comprising i) administering to a patient a first dose of a first conjugate, or a pharmaceutically acceptable salt thereof;
  • first conjugate and the second conjugate each comprise a small molecule ligand linked to a targeting moiety, wherein the first conjugate and the second conjugate are different, and wherein the first dose and the second dose are different;
  • the targeting moiety is selected from 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS -fluorescein, pentafluorophenyl ester (PFP), tetrafluorophenyl ester (TFP), a knottin, a centyrin, and a DARPin.
  • DNP 2,4-dinitrophenol
  • TNP 2,4,6-trinitrophenol
  • biotin digoxigenin
  • fluorescein fluorescein isothiocyanate
  • FITC fluorescein isothiocyanate
  • NHS -fluorescein NHS -fluorescein
  • PFP pentafluorophenyl ester
  • TFP tetrafluorophenyl ester
  • knottin a centyrin
  • DARPin DARPin
  • linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, and/or pluronic F-127.
  • PEG polyethylene glycol
  • polyproline polyproline
  • hydrophilic amino acid a sugar
  • unnatural peptidoglycan a polyvinylpyrrolidone
  • pluronic F-127 pluronic F-127.
  • L represents the linker
  • T represents the targeting moiety
  • L comprises a structure having the formula
  • n is an integer from 0 to 200. 23. The method of clause 22 wherein n is an integer from 0 to 150.
  • n is an integer from 0 to 110.
  • the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin' s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, cancer of the bladder, Burkitt
  • pharmaceutically acceptable salt thereof is not an antibody, and does not comprise a fragment of an antibody.
  • a CAR T cell comprising a nucleic acid comprising SEQ ID NO: 1
  • a CAR T cell comprising a polypeptide comprising SEQ ID NO: l. 54.
  • a CAR T cell comprising a polypeptide comprising SEQ ID NO: l. 54.
  • An isolated nucleic acid comprising SEQ ID NO: l and encoding a chimeric antigen receptor.
  • a chimeric antigen receptor polypeptide comprising SEQ ID NO: 1
  • a vector comprising SEQ ID NO: 1.
  • CAR T cell isolated nucleic acid encoding a chimeric antigen receptor (CAR), or chimeric antigen receptor polypeptide of any one of clauses 1 to 56 wherein the CAR comprises human amino acid sequences.
  • CAR chimeric antigen receptor
  • CAR T cell isolated nucleic acid encoding a chimeric antigen receptor (CAR), or chimeric antigen receptor polypeptide of any one of clauses 1 to 56 wherein the CAR consists of human amino acid sequences.
  • CAR chimeric antigen receptor
  • a kit comprising at least two different types of bridges wherein the bridges comprise a small molecule ligand linked to a targeting moiety wherein the ligand in the at least two different types of bridges is different and wherein the ligand is selected from a folate, DUPA, a CAIX ligand, an NK-IR ligand, a ligand of gamma glutamyl transpeptidase, and a CCK2R ligand.
  • L represents the linker
  • T represents the targeting moiety
  • L comprises a structure having the formula
  • n is an integer from 0 to 200.
  • n is an integer from 0 to 110.
  • FIGURES 1A-B show CAR T cell proliferation using FITC-small molecule conjugates in different cell types with a (CAR T cell):target cell (cancer cell) ratio of 5: 1.
  • Figure 1A shows CAR T cell proliferation in KB (FR+) cells.
  • Figure IB shows CAR T cell proliferation in HEK293 (NK1R+) cells.
  • FIGURES 2A-F show inflammatory cytokine IFN- ⁇ production by CAR T cells with FITC-small molecule conjugates in different cell types.
  • Figure 2A shows inflammatory cytokine IFN- ⁇ production in KB (FR+) cells.
  • Figure 2B shows inflammatory cytokine IFN- ⁇ production in LNCaP (PSMA+) cells.
  • Figure 2C shows inflammatory cytokine IFN- ⁇ production in HEK293 (NK1R+) cells.
  • Figure 2D shows inflammatory cytokine IFN- ⁇ production in KB (FR+) cells with different concentrations of FITC-Folate.
  • Figure 2E shows inflammatory cytokine IFN- ⁇ production in KB (FR+) cells with different conjugates.
  • Figure 2F shows inflammatory cytokine IFN- ⁇ production in KB (FR+) cells with different conjugates.
  • FIGURES 3A-F show in vitro toxicity of tumor cells treated with FITC-small molecule conjugates in different cell types.
  • Figure 3A shows in vitro toxicity in KB (FR+) cells.
  • Figure 3B shows in vitro toxicity in LNCaP (PSMA+) cells.
  • Figure 3C shows in vitro toxicity in HEK293 (NK1R+) cells.
  • Figure 3D shows in vitro toxicity in KB (FR+) cells as a function of different E:T (Effector cells:Target cells) ratios.
  • Figure 3E shows in vitro toxicity in KB (FR+) cells as a function of FITC-Folate concentration.
  • Figure 3F shows in vitro toxicity in KB (FR+) cells with different conjugates.
  • FIGURES 4A-B show activation of CAR T cells is correlated with the expression level of the tumor antigen on cancer cells.
  • Figure 4A shows tumor antigen FRa level. The highest peak is for KB (FR+) cells.
  • Figure 4B shows CAR T cell activation using
  • FIGURES 5A-C show HEK293 (NK1R+) tumor xenografts and a CAR T cell therapy comprising treating CAR T cells with either a FITC-PEGl 1-NKl conjugate or no conjugate.
  • Figure 5A shows tumor volume measured over 24 days.
  • Figure 5B shows the body weight measured over 22 days of therapy.
  • Figure 5C shows the percentage of CAR T cells in CD3+ human T cells post CAR T cell injection along with FITC-PEGl 1-NKl .
  • FIGURES 6A-B show harvested organs from exemplary mice of the models used in Figures 5A-C.
  • Figure 6A shows harvested organs from the non-treatment group.
  • Figure 6B shows harvested organs after two weeks of CAR T cell therapy.
  • FIGURES 7A-C show MDA-MB-231 (FR+) xenografts under a CAR T cell therapy comprising treating the cells with CAR T cells with either a FITC-PEG12-Folate conjugate, a FITC-Folate conjugate, or no conjugate.
  • Figure 7A shows tumor volume measured over 23 days.
  • Figure 7B shows the body weight measured over 21 days of therapy.
  • Figure 7C shows the percentage of CAR T cells in CD3+ human T cells post CAR T cell injection.
  • FIGURES 8A-B show harvested organs from exemplary mice from the models shown in Figures 7A-C.
  • Figure 8A shows harvested organs from the non-treatment group.
  • Figure 8B shows harvested organs after three weeks of CAR T cell therapy comprising CAR T cells and the FITC-PEGl 2-Folate conjugate at 500 nmoles/kg body weight.
  • FIGURE 9 shows blood indices of the HEK293 (NK1R+) xenograft model from Figures 5-6 and the MDA-MB-231 (FR+) xenograft model from Figures 7-8.
  • FIGURE 10 shows differences in cytotoxicity towards KB (FR+) tumor cells treated with CAR T cells depending on the FITC-small molecule conjugate used.
  • FIGURE 11 shows body weight percentage change in a KB tumor xenograft model using CAR T cells with different concentrations of a FITC-PEG-12-Folate conjugate.
  • FIGURES 12A-C show harvested organs from exemplary mice of the KB xenograft model shown in Figure 11.
  • Figure 12A shows harvested organs from the non- treatment group.
  • Figure 12B shows harvested organs from the CAR T cell therapy group treated with 250 nmol/kg FITC-PEG-12-Folate.
  • Figure 12C shows harvested organs from the CAR T cell therapy group treated with CAR T cells and 500 nmol/kg FITC-PEG-12-Folate.
  • FIGURE 13 shows blood indices of the mice from the KB xenograft model from Figures 11-12.
  • FIGURES 14A-B show the constructs used for CAR T transduction.
  • Figure 14A shows the CAR4-1BBZ construct.
  • Figure 14B shows the lentiviral vector.
  • FIGURES 15A-B show flow cytometry analysis of transduced T cells.
  • Figure 15A shows the non-transduced cells.
  • Figure 15B shows the transduced cells.
  • FIGURES 16A-B show fluorescent microscopy of transduced CAR T cells.
  • Figure 16A shows GFP imaging indicating transduction.
  • Figure 16B shows FITC folate localizing to the positively transduced cells.
  • FIGURE 17 shows activation of CAR T cells as measured by relative expression of CD69 as a function of the conjugate used.
  • FIGURE 18 shows tumor heterogeneity of KB, LNCaP, and CAR T cells as a function of the conjugate used.
  • FIGURES 19A-C shows anti-tumor efficacy when the same anti-FITC CAR T cell (10' cells) was introduced to mice bearing two different tumors arising from two different cell lines (i.e. MDA-MB-231(FR+) and HEK (NK1R+)) on separate flanks, after which either PBS only ( Figure 19A), FITC-PEG11-NK1R (500nmole/kg) ( Figure 19B), or FITC-PEG11- NK1R (500nmole/kg) plus FITC-PEG12-Folate (500nmole/kg) ( Figure 19C) was injected every other day.
  • PBS only Figure 19A
  • FITC-PEG11-NK1R 500nmole/kg
  • Figure 19B FITC-PEG11- NK1R
  • FITC-PEG12-Folate 500nmole/kg
  • Figure 19A ( ⁇ ) FR+ (MDA-MB-231): CAR T cell + PBS, ( ⁇ ) NK1R+(HEK): CAR T cell + PBS;
  • Figure 19B ( ⁇ ) FR+ (MDA-MB-231): CAR T cell + PBS, ( ⁇ )
  • NK1R+(HEK) CAR T cell + FITC-PEG11-NK1R (500 nmole/kg);
  • Figure 19C ( ⁇ ) FR+ (MDA-MB-231): CAR T cell + FITC-PEG12-FA (500 nmole/kg),
  • ( ⁇ ) NK1R+(HEK) CAR T cell + PBS.
  • percentages generally refers to a range of numerical values (e.g., +/- 5 % to 10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result).
  • treat refers to both therapeutic treatment and prophylactic or preventative treatment.
  • the terms “ameliorate,” “ameliorating,” “amelioration,” or “ameliorated” in reference to cancer can mean reducing the symptoms of the cancer, reducing the size of a tumor, completely or partially removing the tumor (e.g., a complete or partial response), causing stable disease, preventing progression of the cancer (e.g., progression free survival), or any other effect on the cancer that would be considered by a physician to be a therapeutic or preventative treatment of the cancer.
  • administer means all means of introducing the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or
  • pharmaceutically acceptable salt thereof, or CAR T cell composition described herein to the patient including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), and transdermal.
  • off-target toxicity means organ damage or a reduction in the patient's weight that is unacceptable to the physician treating the patient, or any other effect that is unacceptable to the physician treating the patient, such as B cell aplasia.
  • transduction and “transfection” are used equivalently and the terms mean introducing a nucleic acid into a cell by any artificial method, including viral and non- viral methods.
  • a small molecule ligand linked to a targeting moiety by a linker is used as a bridge between a cancer and CAR T cells (i.e, cytotoxic T cells expressing a chimeric antigen receptor).
  • the bridge directs the CAR T cells to the cancer for amelioration of the cancer.
  • the "small molecule ligand" can be a folate, a CAIX ligand, DUPA, an NK-1R ligand, a ligand of gamma glutamyl
  • transpeptidase or a CCK2R ligand, each of which is a small molecule ligand that binds specifically to a cancer cell type (i.e., the receptor for each of these ligands is overexpressed on cancers compared to normal tissues).
  • the "targeting moiety” linked to the small molecule ligand binds to the recognition region of the genetically engineered CAR expressed by CAR T cells. Accordingly, the recognition region of the CAR (e.g., a single chain fragment variable region (scFv) of an antibody) is directed to the "targeted moiety.”
  • the small molecule ligand linked to a targeting moiety by a linker acts as a bridge between the cancer and the CAR T cells directing the CAR T cells to the cancer for amelioration of the cancer.
  • the bridge between the cancer and the CAR T cells can be any of the conjugates shown in
  • the bridge is a small organic molecule so clearance from the bloodstream can be rapidly achieved (e.g., about 20 minutes or less).
  • the CAR T cell response can be targeted to only those cancer cells expressing a receptor for the small molecule ligand portion of the 'bridge,' thereby reducing off-target toxicity to normal tissues.
  • CAR T cell activation can be controlled due to the rapid clearance of the bridge from the bloodstream and to the ability to vary the dose and structure of the bridge to regulate CAR T cell activation.
  • this system can be 'universal' because one type of CAR T cell construct can be used to target a wide variety of cancers.
  • the targeting moiety recognized by the CAR T cell may remain constant so that one type of CAR T cell construct can be used, while the small molecule ligand that binds to the cancer is altered to allow targeting of a wide variety of cancers.
  • the inventors have discovered that varying the dose of the small molecule ligand linked to a targeting moiety by a linker (i.e., the bridge), can result in the ability to control CRS in vivo upon CAR T cell activation.
  • the inventors have discovered that varying the linker in the small molecule ligand linked to a targeting moiety (the bridge) can control CRS in vivo upon CAR T cell activation.
  • combinations of these methods can be used for precise control of CAR T cell activation and cytokine release in vivo.
  • the small molecule ligand linked to a targeting moiety by a linker is referred to as a "compound,” a “first conjugate,” or a “second conjugate.”
  • the term “compound” is used in embodiments where the dose of the small molecule ligand linked to a targeting moiety by a linker is varied to control cytokine release in vivo.
  • the terms "first conjugate” and “second conjugate” are used in embodiments where two different conjugates are administered to a patient.
  • the linker in the small molecule ligand linked to a targeting moiety can be varied to control cytokine release in vivo, or the conjugates can be modified to contain different small molecule ligands or different targeting moieties.
  • a method of treatment of a cancer comprising i) administering to a patient a first dose of a compound, or a
  • the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition wherein the CAR T cell comprises a CAR directed to the targeting moiety;
  • a method of treatment of a cancer comprising i) administering to the patient a first conjugate, or a pharmaceutically acceptable salt thereof;
  • first and the second conjugate each comprise a small molecule ligand linked to a targeting moiety by a linker and wherein the first conjugate and the second conjugate are different;
  • a method of treatment of a cancer comprising i) administering to a patient a first dose of a first conjugate, or a pharmaceutically acceptable salt thereof;
  • first conjugate and the second conjugate each comprise a small molecule ligand linked to a targeting moiety, wherein the first conjugate and the second conjugate are different, and wherein the first dose and the second dose are different;
  • ligand is selected from a folate, DUPA, a CAIX ligand, an NK-IR ligand, a ligand of gamma glutamyl transpeptidase, and a CCK2R ligand.
  • the targeting moiety is selected from 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS -fluorescein, pentafluorophenyl ester (PFP), tetrafluorophenyl ester (TFP), a knottin, a centyrin, and a DARPin.
  • DNP 2,4-dinitrophenol
  • TNP 2,4,6-trinitrophenol
  • biotin digoxigenin
  • fluorescein fluorescein isothiocyanate
  • FITC fluorescein isothiocyanate
  • NHS -fluorescein NHS -fluorescein
  • PFP pentafluorophenyl ester
  • TFP tetrafluorophenyl ester
  • knottin a centyrin
  • DARPin DARPin
  • the targeting moiety is TNP.
  • the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, and/or pluronic F-127.
  • L represents the linker
  • T represents the targeting moiety
  • L comprises a structure having the formula
  • n is an integer from 0 to 200.
  • n is an integer from 0 to 110.
  • the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin' s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, cancer of the bladder, Burkitt
  • CD134 OX40
  • CD278 CD278
  • pharmaceutically acceptable salt thereof is not an antibody, and does not comprise a fragment of an antibody.
  • a CAR T cell comprising a nucleic acid comprising SEQ ID NO: l.
  • a CAR T cell comprising a polypeptide comprising SEQ ID NO: 1
  • An isolated nucleic acid comprising SEQ ID NO: l and encoding a chimeric antigen receptor.
  • a chimeric antigen receptor polypeptide comprising SEQ ID NO: 1
  • a vector comprising SEQ ID NO: 1.
  • CAR T cell isolated nucleic acid encoding a chimeric antigen receptor (CAR), or chimeric antigen receptor polypeptide of any one of clauses 1 to 56 wherein the CAR comprises human amino acid sequences.
  • CAR T cell isolated nucleic acid encoding a chimeric antigen receptor (CAR), or chimeric antigen receptor polypeptide of any one of clauses 1 to 56 wherein the CAR consists of human amino acid sequences.
  • a kit comprising at least two different types of bridges wherein the bridges comprise a small molecule ligand linked to a targeting moiety wherein the ligand in the at least two different types of bridges is different and wherein the ligand is selected from a folate, DUPA, a CAIX ligand, an NK-IR ligand, a ligand of gamma glutamyl transpeptidase, and a CCK2R ligand.
  • L represents the linker
  • T represents the targeting moiety
  • L comprises a structure having the formula
  • n is an integer from 0 to 200.
  • n is an integer from 0 to 110.
  • a "patient” can be a human or, in the case of veterinary applications, the patient can be a laboratory, an agricultural, a domestic, or a wild animal.
  • the patient can be a laboratory animal such as a rodent (e.g.
  • the step of "treating the patient to ameliorate the cancer” can comprise or consist of the administering steps in the method.
  • the small molecule ligand linked to a targeting moiety by a linker comprises fluorescein isothiocyanate (FITC) linked to the small molecule ligand.
  • FITC fluorescein isothiocyanate
  • the cancer overexpresses a receptor for the small molecule ligand.
  • cytotoxic T cells are transformed to express a CAR that comprises anti-FITC scFv.
  • the CAR targets FITC decorating the cancer with
  • FITC molecules as a result of binding of the small molecule ligand to the cancer.
  • toxicity to normal, non-target cells can be avoided.
  • the anti-FITC CAR-expressing T cells bind FITC, the CAR T cells are activated and the cancer is ameliorated (e.g., by killing the cancer cells).
  • the "small molecule ligand” can be a folate, DUPA (a ligand bound by PSMA-positive human prostate cancer cells and other cancer cell types), an NK-1R ligand (receptors for NK-1R the ligand found, for example, on cancers of the colon and pancreas), a CAIX ligand (receptors for the CAIX ligand found, for example, on renal, ovarian, vulvar, and breast cancers), a ligand of gamma glutamyl transpeptidase (the transpeptidase overexpressed, for example, in ovarian cancer, colon cancer, liver cancer, astrocytic gliomas, melanomas, and leukemias), or a CCK2R ligand (receptors for the CCK2R ligand found on cancers of the thyroid, lung, pancreas, ovary, brain, stomach, gastrointestinal stroma, and colon, among others), each of which is
  • the small molecule ligand is a folate.
  • the folate can be folic acid, a folic acid analog, or another folate receptor-binding molecule.
  • analogs of folate that can be used include folinic acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins, dihydrofolates, tetrahydrofolates, and their deaza and dideaza analogs.
  • the terms “deaza” and “dideaza” analogs refers to the art recognized analogs having a carbon atom substituted for one or two nitrogen atoms in the naturally occurring folic acid structure.
  • the deaza analogs include the 1-deaza, 3- deaza, 5-deaza, 8-deaza, and 10-deaza analogs.
  • the dideaza analogs include, for example, 1,5 dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs.
  • the foregoing folic acid analogs are conventionally termed "folates," reflecting their capacity to bind to folate receptors.
  • folate receptor-binding analogs include aminopterin, amethopterin (methotrexate), N10- methylfolate, 2-deamino-hydroxyfolate, deaza analogs such as 1-deazamethopterin or 3- deazamethopterin, and 3',5'-dichloro-4-amino-4-deoxy-N10-methylpteroylglutamic acid (dichloromethotrexate) .
  • the small molecule ligand may have a mass of less than about 10,000 Daltons, less than about 9000 Daltons, less than about 8,000 Daltons, less than about 7000 Daltons, less than about 6000 Daltons, less than about 5000 Daltons, less than about 4500 Daltons, less than about 4000 Daltons, less than about 3500 Daltons, less than about 3000 Daltons, less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, or less than about 500 Daltons.
  • the small molecule ligand may have a mass of about 1 to about 10,000 Daltons, about 1 to about 9000 Daltons, about 1 to about 8,000 Daltons, about 1 to about 7000 Daltons, about 1 to about 6000 Daltons, about 1 to about 5000 Daltons, about 1 to about 4500 Daltons, about 1 to about 4000 Daltons, about 1 to about 3500 Daltons, about 1 to about 3000 Daltons, about 1 to about 2500 Daltons, about 1 to about 2000 Daltons, about 1 to about 1500 Daltons, about 1 to about 1000 Daltons, or about 1 to about 500 Daltons.
  • the "targeting moiety" that binds to the CAR expressed by CAR T cells can be selected, for example, from 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS -fluorescein, pentafluorophenyl ester (PFP), tetrafluorophenyl ester (TFP), a knottin, a centyrin, and a DARPin.
  • DNP 2,4-dinitrophenol
  • TNP 2,4,6-trinitrophenol
  • biotin digoxigenin
  • fluorescein fluorescein isothiocyanate
  • NHS -fluorescein NHS -fluorescein
  • PFP pentafluorophenyl ester
  • TFP tetrafluorophenyl ester
  • knottin a centyrin
  • DARPin DARPin
  • the targeting moiety can have the following illustrative structure:
  • X oxygen, nitrogen, or sulfur, and where X is attached to linker L;
  • Y is OR a , NR A 2 , or NRY; and
  • Y' is O, NR A , or NR A 2 + ;
  • each R is independently selected in each instance from H, fluoro, sulfonic acid, sulfonate, and salts thereof, and the like; and
  • R a is hydrogen or alkyl.
  • the linker in the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, described herein can be a direct linkage (e.g., a reaction between the isothiocyanate group of FITC and a free amine group of a small molecule ligand) or the linkage can be through an intermediary linker.
  • a direct linkage e.g., a reaction between the isothiocyanate group of FITC and a free amine group of a small molecule ligand
  • an intermediary linker can be any biocompatible linker known in the art, such as a divalent linker.
  • the divalent linker can comprise about 1 to about 30 carbon atoms.
  • the divalent linker can comprise about 2 to about 20 carbon atoms.
  • lower molecular weight divalent linkers i.e., those having an approximate molecular weight of about 30 to about 300 are employed.
  • linkers lengths that are suitable include, but are not limited to, linkers having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, or more atoms.
  • the small molecule ligand linked to a targeting moiety can be of the formula
  • L represents the linker
  • T represents the targeting moiety
  • L comprises a structure having the formula
  • n is an integer from 0 to 200.
  • n can be an integer from 0 to 150, 0 to 110, 0 to 100, 0 to 90, 0 to 80, 0 to 70, 0 to 60, 0 to 50, 0 to 40, 0 to 30, 0 to 20, 0 to 15, 0 to 14, 0 to 13, 0 to 12, 0 to 11, 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, 0 to 1, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 15 to 31, 15 to 32, 15 to 33, 15 to 34, 15 to 35, 15 to 36, 15 to 37, 15 to 38, 15 to 39, 15 to 40, 15 to 50, 15 to 60, 15 to 70, 15 to 80, 15 to 90, 15 to 100, 15 to 110, 15 to 120, 15 to
  • the linker may be a divalent linker that may include one or more spacers.
  • Illustrative spacers are shown in the following table. The following non- limiting, illustrative spacers are described where * indicates the point of attachment to the small molecule ligand or the targeting moiety.
  • the small molecule ligand linked to a targeting moiety is linked to a targeting moiety
  • the compound, or the pharmaceutically acceptable salt thereof, the first conjugate, or the pharmaceutically acceptable salt thereof, or the second conjugate, or the pharmaceutically acceptable salt thereof is not an antibody, and does not comprise a fragment of an antibody.
  • the compound, or the pharmaceutically acceptable salt thereof, the first conjugate, or the pharmaceutically acceptable salt thereof, or the second conjugate, or the pharmaceutically acceptable salt thereof is not an antibody, and does not comprise a fragment of an antibody.
  • targeting moiety is not a peptide epitope.
  • conjugates e.g., a first conjugate and a second conjugate
  • the linker in the first conjugate, or the pharmaceutically acceptable salt thereof, and the linker in the second conjugate, or the pharmaceutically acceptable salt thereof can be the same or different.
  • the ligand in the first conjugate, or the pharmaceutically acceptable salt thereof, and the ligand in the second conjugate, or the pharmaceutically acceptable salt thereof can be the same or different.
  • the targeting moiety in the first conjugate, or the pharmaceutically acceptable salt thereof, and the targeting moiety in the second conjugate, or the pharmaceutically acceptable salt thereof can be the same or different. Any combinations of these embodiments are also contemplated along with any combinations of the doses described below.
  • a kit comprising at least two different types of bridges, wherein the bridges comprise a small molecule ligand linked to a targeting moiety wherein the ligand in the at least two different types of bridges is different and wherein the ligand is selected from a folate, DUPA, a CAIX ligand, an NK-1R ligand, a ligand of gamma glutamyl transpeptidase, and a CCK2R ligand.
  • the ligand in at least one of the bridges can be an NK-1R ligand, a ligand of gamma glutamyl transpeptidase, a folate, a CAIX ligand, a CCK2R ligand, or DUPA.
  • the bridge in the kit can have the formula
  • L represents the linker
  • T represents the targeting moiety
  • L comprises a structure having the formula
  • n is an integer from 0 to 200.
  • n can be an integer from 0 to 150, an integer from 0 to 110, an integer from 0 to 20, an integer from 15 to 20, an integer from 15 to 110, or any other value or range of integers described herein for n.
  • a “pharmaceutically acceptable salt” of a small molecule ligand linked to a targeting moiety by a linker is contemplated.
  • the term “pharmaceutically acceptable salt” refers to those salts whose counter ions may be used in pharmaceuticals.
  • Such salts include 1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,
  • ethanesulfonic acid p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or 2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.
  • Pharmaceutically acceptable salts are well-known to those skilled in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the embodiments described herein.
  • suitable acid addition salts are formed from acids which form non-toxic salts.
  • Illustrative examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, to
  • suitable base salts are formed from bases which form non-toxic salts.
  • bases which form non-toxic salts.
  • Illustrative examples include the arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compound, or a pharmaceutically salt thereof, the first conjugate, or a pharmaceutically acceptable salt thereof, or the second conjugate, or a pharmaceutically acceptable salt thereof, described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. Accordingly, various embodiments may include pure stereoisomers as well as mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. In one aspect, the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or
  • compositions may be capable of existing as geometric isomers. Accordingly, various embodiments may include pure geometric isomers or mixtures of geometric isomers.
  • cytotoxic T lymphocytes engineered to express a chimeric antigen receptor (CAR) that recognizes and binds to the targeting moiety (e.g., FITC, DNP, or TNP) of the bridge.
  • CAR chimeric antigen receptor
  • the CARs described herein comprise three domains including 1) a recognition region (e.g., a single chain fragment variable (scFv) region of an antibody) which recognizes and binds to the targeting moiety with specificity, 2) a co-stimulation domain which enhances the proliferation and survival of the T lymphocytes, and 3) an activation signaling domain which generates a cytotoxic T lymphocyte activation signal.
  • a recognition region e.g., a single chain fragment variable (scFv) region of an antibody
  • scFv single chain fragment variable
  • scFv regions of antibodies that bind a folate, DUPA, a CAIX ligand, an NK-1R ligand, a ligand of gamma glutamyl transpeptidase, or a CCK2R ligand can be used.
  • the scFv regions can be prepared from (i) an antibody known in the art that binds a targeting moiety, (ii) an antibody newly prepared using a selected targeting moiety, such as a hapten, and (iii) sequence variants derived from the scFv regions of such antibodies, e.g., scFv regions having at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to the amino acid sequence of the scFv region from which they are derived.
  • the binding portion of the CAR can be, for example, a single chain fragment variable region (scFv) of an antibody, an Fab, Fv, Fc, or (Fab')2 fragment, and the like.
  • scFv single chain fragment variable region
  • the co-stimulation domain serves to enhance the proliferation and survival of the cytotoxic T lymphocytes upon binding of the CAR to a targeting moiety.
  • Suitable co- stimulation domains include: 1) CD28, 2) CD137 (4-1BB), a member of the tumor necrosis factor (TNF) receptor family, 3) CD134 (OX40), a member of the TNFR-superfamily of receptors, and 4) CD278 (ICOS), a CD28-superfamily co-stimulatory molecule expressed on activated T cells, or combinations thereof.
  • Suitable co-stimulation domains also include, but are not limited to, CD27, CD30, CD150, DAP10, and NKG2D, or combinations thereof. A skilled artisan will understand that sequence variants of these co-stimulation domains can be used without adversely impacting the invention, where the variants have the same or similar activity as the domain on which they are modeled.
  • such variants have at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to the amino acid sequence of the domain from which they are derived.
  • the activation signaling domain serves to activate cytotoxic T lymphocytes upon binding of the CAR to a targeting moiety.
  • Suitable activation signaling domains include the T cell CD3 ⁇ chain and Fc receptor ⁇ . The skilled artisan will understand that sequence variants of these noted activation signaling domains can be used where the variants have the same or similar activity as the domain on which they are modeled.
  • the variants have at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to the amino acid sequence of the domain from which they are derived.
  • constructs encoding the CARs are prepared using genetic engineering techniques. Such techniques are described in detail in Sambrook et al., "Molecular Cloning: A Laboratory Manual", 3rd Edition, Cold Spring Harbor Laboratory Press, (2001), incorporated herein by reference.
  • a plasmid or viral expression vector e.g., a lentiviral vector, a retrovirus vector, sleeping beauty, and piggyback (transposon/transposase systems that include a non- viral mediated CAR gene delivery system)
  • a fusion protein comprising a recognition region, one or more co-stimulation domains, and an activation signaling domain, in frame and linked in a 5' to 3' direction.
  • the CARs may include additional elements, such as a signal peptide to ensure proper export of the fusion protein to the cell surface, a transmembrane domain to ensure the fusion protein is maintained as an integral membrane protein, and a hinge domain that imparts flexibility to the recognition region and allows strong binding to the targeting moiety.
  • FIGS 14A and B Diagrams of an exemplary CAR are shown in Figures 14A and B where the fusion protein sequence is incorporated into a lentivirus expression vector and where "SP" is a signal peptide, the CAR is an anti-FITC CAR, a CD8a hinge and a transmembrane (TM) region is present, the co- stimulation domain is 4-lBB, and the activation signaling domain is CD3 ⁇ .
  • the nucleic acid sequence of the CAR insert is provided as SEQ ID NO: l and the amino acid sequence of the insert is provided as SEQ ID NO:2.
  • the CAR has a recognition region and the recognition region is a single chain fragment variable (scFv) region of an anti-FITC antibody, a co- stimulation domain and the co- stimulation domain is CD137 (4-lBB), and an activation signaling domain and the activation signaling domain is a T cell CD3 ⁇ chain.
  • scFv single chain fragment variable
  • cytotoxic T lymphocytes can be genetically engineered to express CAR constructs by transfecting a population of the cytotoxic T lymphocytes with an expression vector encoding the CAR construct.
  • Suitable methods for preparing a transduced population of T lymphocytes expressing a selected CAR construct are well-known to the skilled artisan, and are described in Sambrook et al., "Molecular Cloning: A Laboratory Manual", 3rd Edition, Cold Spring Harbor Laboratory Press, (2001), incorporated herein by reference.
  • CAR T cells comprising a nucleic acid of SEQ ID NO: l or 3 are provided. In another embodiment, CAR T cells comprising a polypeptide of SEQ ID NO:2 are provided. In another illustrative aspect, an isolated nucleic acid comprising SEQ ID NO: l or 3 and encoding a chimeric antigen receptor is provided. In yet another embodiment, a chimeric antigen receptor polypeptide comprising SEQ ID NO:2 is provided. In another embodiment, a vector is provided comprising SEQ ID NO: l or 3. In another aspect, a lentiviral vector is provided comprising SEQ ID NO: 1 or 3. In another embodiment, SEQ ID NO:2 can comprise or consist of human or humanized amino acid sequences.
  • variant nucleic acid sequences or amino acid sequences having at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to SEQ ID NO: 1, SEQ ID NO:2, or SEQ ID NO:3 are contemplated.
  • the nucleic acid sequence can be a variant nucleic acid sequence having at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to SEQ ID NO: l or 3 as long as the variant sequence encodes a polypeptide of SEQ ID NO:2.
  • the nucleic acid or amino acid sequence can be a variant nucleic acid or amino acid sequence having at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to SEQ ID NO: l or SEQ ID NO:2 or SEQ ID NO:3 along a stretch of 200 nucleic acids or 200 amino acids of SEQ ID NO: 1 or SEQ ID NO:2 or SEQ ID NO:3.
  • Determination of percent identity or similarity between sequences can be done, for example, by using the GAP program (Genetics Computer Group, software; now available via Accelrys on http://www.accelrys.com), and alignments can be done using, for example, the ClustalW algorithm (VNTI software, InforMax Inc.).
  • a sequence database can be searched using the nucleic acid or amino acid sequence of interest. Algorithms for database searching are typically based on the BLAST software (Altschul et al., 1990).
  • the percent identity can be determined along the full-length of the nucleic acid or amino acid sequence.
  • nucleic acids complementary to the nucleic acid represented by SEQ ID NO: 1 or 3, and those that hybridize to the nucleic acid represented by SEQ ID NO: l or 3 or those that hybridize to its complement under highly stringent conditions are also within the scope of the invention.
  • “highly stringent conditions” means hybridization at 65 °C in 5X SSPE and 50% formamide, and washing at 65 °C in 0.5X SSPE. Conditions for high stringency, low stringency and moderately stringent hybridization are described in Sambrook et al., “Molecular Cloning: A Laboratory Manual", 3rd Edition, Cold Spring Harbor Laboratory Press, (2001), incorporated herein by reference. In some illustrative aspects, hybridization occurs along the full-length of the nucleic acid.
  • the cytotoxic T lymphocytes used to prepare the CAR T cells can be autologous cells, although heterologous cells can also be used, such as when the patient being treated has received high-dose chemotherapy or radiation treatment to destroy the patient's immune system. In one embodiment, allogenic cells can be used.
  • the cytotoxic lymphocytes T can be obtained from a patient by means well-known in the art.
  • cytotoxic T cells can be obtained by collecting peripheral blood from the patient, subjecting the blood to Ficoll density gradient centrifugation, and then using a negative T cell isolation kit (such as EasySepTM T Cell Isolation Kit) to isolate a population of cytotoxic T cells from the peripheral blood.
  • the population of cytotoxic T lymphocytes need not be pure and may contain other cells such as other T cells, monocytes, macrophages, natural killer cells, and B cells.
  • the population being collected can comprise at least about 90% of the selected cell type, at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the selected cell type.
  • the cells are cultured under conditions that promote the activation of the cells.
  • the culture conditions may be such that the cells can be administered to a patient without concern for reactivity against components of the culture medium.
  • the culture conditions may not include bovine serum products, such as bovine serum albumin.
  • the activation can be achieved by introducing known activators into the culture medium, such as anti-CD3 antibodies in the case of cytotoxic T cells. Other suitable activators include anti-CD28 antibodies.
  • the population of lymphocytes can be cultured under conditions promoting activation for about 1 to about 4 days.
  • the appropriate level of activation can be determined by cell size, proliferation rate, or activation markers determined by flow cytometry.
  • the cells after the population of cytotoxic T lymphocytes has been cultured under conditions promoting activation, the cells can be transfected with an expression vector encoding a CAR. Suitable vectors and transfection methods are described above.
  • the cells after transfection, can be immediately administered to the patient or the cells can be cultured for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more days, or between about 5 and about 12 days, between about 6 and about 13 days, between about 7 and about 14 days, or between about 8 and about 15 days, for example, to allow time for the cells to recover from the transfection.
  • Suitable culture conditions can be similar to the conditions under which the cells were cultured for activation either with or without the agent that was used to promote activation.
  • the methods of treatment described herein can further comprise 1) obtaining a population of autologous or heterologous cytotoxic T lymphocytes, 2) culturing the T lymphocytes under conditions that promote the activation of the cells, and 3) transfecting the lymphocytes with an expression vector encoding a CAR to form CAR T cells.
  • a composition comprising the CAR T cells can be prepared and administered to the patient.
  • culture media that lacks any animal products, such as bovine serum, can be used.
  • tissue culture conditions typically used by the skilled artisan to avoid contamination with bacteria, fungi and mycoplasma can be used.
  • the cells prior to being administered to a patient, the cells are pelleted, washed, and resuspended in a pharmaceutically acceptable carrier or diluent.
  • compositions comprising CAR-expressing cytotoxic T lymphocytes include compositions comprising the cells in sterile 290 mOsm saline, in infusible cryomedia (containing Plasma-Lyte A, dextrose, sodium chloride injection, human serum albumin and DMSO), in 0.9% NaCl with 2% human serum albumin, or in any other sterile 290 mOsm infusible materials.
  • the CAR T cells can be administered in the culture media as the composition, or concentrated and resuspended in the culture medium before
  • the CAR T cell compositon can be administered to the patient via any suitable means, such as parenteral administration, e.g., intradermally, subcutaneously, intramuscularly, intraperitoneally, intravenously, or intrathecally.
  • parenteral administration e.g., intradermally, subcutaneously, intramuscularly, intraperitoneally, intravenously, or intrathecally.
  • the total number of CAR T cells and the concentration of the cells in the composition administered to the patient will vary depending on a number of factors including the type of cytotoxic T lymphocytes being used, the binding specificity of the CAR, the identity of the targeting moiety and the small molecule ligand, the identity of the cancer, the location of the cancer in the patient, the means used to administer the compositions to the patient, and the health, age and weight of the patient being treated.
  • suitable compositions comprising transduced CAR T cells include those having a volume of between about 5 ml and about 200 ml, containing from about 1 X 10 5 to about 1 X 10 15 transduced CAR T cells.
  • compositions comprise a volume of between about 10 ml and about 125 ml, containing from about 1 X 10 7 to about 1 X 1010 CAR T cells.
  • An exemplary composition comprises about 1 X 10 9 CAR T cells in a volume of about 100 ml.
  • a single dose or multiple doses of the CAR T cells can be administered to the patient.
  • the cancer to be treated is a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, or a myeloma.
  • the cancer may be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, prostate cancer, chronic leukemia, acute leukemia, a lymphocytic lymphoma, pleural mesothelioma, cancer of the bladder, Burkitt's lymphoma, cancer of the
  • the cancer is a folate receptor expressing cancer.
  • the cancer is an endometrial cancer, a non-small cell lung cancer, an ovarian cancer, or a triple-negative breast cancer.
  • the cancer being imaged is a tumor.
  • the cancer is malignant.
  • the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or CAR T cell composition described herein can be administered to the patient using any suitable method known in the art. As described herein, the term
  • administering includes all means of introducing the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or CAR T cell composition to the patient, including, but not limited to, oral (po), intravenous (iv),
  • pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
  • compositions as described herein may be administered directly into the blood stream, into muscle, or into an internal organ.
  • routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial,
  • means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • parenteral formulations are typically aqueous solutions which may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water or sterile saline. In other embodiments, any of the liquid
  • formulations described herein may be adapted for parenteral administration as described herein.
  • the preparation under sterile conditions, by lyophilization to produce a sterile lyophilized powder for a parenteral formulation, may readily be accomplished using standard
  • solubility of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • the rate of tumor lysis can be regulated by adjusting the concentration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof. Accordingly, by varying the concentration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or
  • the cytotoxicity of the CAR T cell composition can be regulated.
  • the cytotoxicity of the CAR T cell composition can be balanced against the risk of tumor lysis syndrome, or cytokine release syndrome (CRS), as described herein by adjusting the concentration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof.
  • CRS cytokine release syndrome
  • the concentration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof can be a function of the amount or dose of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof that is administered to the patient.
  • pharmaceutically acceptable salt thereof, to be administered to the patient can vary significantly depending on the cancer being treated, the route of administration of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, and the tissue distribution.
  • the amount to be administered to a patient can be based on body surface area, mass, and physician assessment.
  • amounts to be administered can range, for example, from about 0.05 mg to about 30 mg, 0.05 mg to about 25.0 mg, about 0.05 mg to about 20.0 mg, about 0.05 mg to about 15.0 mg, about 0.05 mg to about 10.0 mg, about 0.05 mg to about 9.0 mg, about 0.05 mg to about 8.0 mg, about 0.05 mg to about 7.0 mg, about 0.05 mg to about 6.0 mg, about 0.05 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.05 mg to about 1.0 mg, about 0.05 mg to about 0.5 mg, about 0.05 mg to about 0.4 mg, about 0.05 mg to about 0.3 mg, about 0.05 mg to about 0.2 mg, about 0.05 mg to about 0.1 mg, about .01 mg to about 2 mg, about 0.3 mg to about 10 mg, about 0.1 mg to about 20 mg, or about 0.8 to about 3 mg.
  • the dose may vary within
  • the dose of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof can range, for example, from about 50 nmol/kg to about 3000 nmol/kg of patient body weight, about 50 nmol/kg to about 2000 nmol/kg, about 50 nmol/kg to about 1000 nmol/kg, about 50 nmol/kg to about 900 nmol/kg, about 50 nmol/kg to about 800 nmol/kg, about 50 nmol/kg to about 700 nmol/kg, about 50 nmol/kg to about 600 nmol/kg, about 50 nmol/kg to about 500 nmol/kg, about 50 nmol/kg to about 400 nmol/kg, about 50 nmol/kg to about 300 nmol/kg, about 50 nmol/kg to about 200 nmol/kg, about 50 nmol/kg to about 100 nmol/kg, about 100 nmol/kg to about 100 nmol
  • the dose may be about 100 nmol/kg, about 150 nmol/kg, about 200 nmol/kg, about 250 nmol/kg, about 300 nmol/kg, about 350 nmol/kg, about 400 nmol/kg, about 450 nmol/kg, about 500 nmol/kg, about 600 nmol/kg, about 700 nmol/kg, about 800 nmol/kg, about 900 nmol/kg, about 1000 nmol/kg, about 2000 nmol/kg, or about 3000 nmol/kg of patient body weight.
  • "kg" is kilograms of patient body weight.
  • a single dose or multiple doses of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof may be administered to the patient.
  • between about 20 ug/kg of patient body weight and about 3 mg/kg of patient body weight of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof is administered to the patient.
  • amounts can be between about 0.2 mg/kg of patient body weight and about 0.4 mg/kg of patient body weight, or can be about 50 ug/kg of patient body weight.
  • a single dose or multiple doses of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, may be administered to the patient.
  • the small molecule ligand linked to the targeting moiety can be administered to the patient before the CAR T cell composition. In another embodiment, the small molecule ligand linked to the targeting moiety can be administered to the patient at the same time as the CAR T cell composition, but in different formulations. In yet another embodiment, the small molecule ligand linked to the targeting moiety can be administered to the patient after the CAR T cell composition.
  • the timing between the administration of CAR T cells and the small molecule linked to the targeting moiety may vary widely depending on factors that include the type of CAR T cells being used, the binding specificity of the CAR, the identity of the targeting moiety and the ligand, the identity of the cancer, the location in the patient of the cancer, the means used to administer to the patient the CAR T cells and the small molecule ligand linked to the targeting moiety, and the health, age, and weight of the patient.
  • the small molecule ligand linked to the targeting moiety can be administered before or after the CAR T cells, such as within about 3, 6, 9, 12, 15, 18, 21, or 24 hours, or within about 0.5, 1, 1.5, 2, 2.5, 3, 4 5, 6, 7, 8, 9, 10 or more days.
  • the rate of tumor lysis can be regulated by adjusting the rate of administration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof. Accordingly, by varying the rate of administration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof, the cytotoxicity of the CAR T cell composition can be regulated. In some embodiments, the cytotoxicity of the CAR T cell composition can be balanced against the risk of tumor lysis syndrome, or cytokine release syndrome (CRS), as described herein by adjusting the rate of administration of the first conjugate, or
  • the rate of administration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof can be a function of any applicable dosing schedule known in the art.
  • the rate of administration can be a function of a dosing schedule that is based on continuous dosing, once per day dosing (a.k.a qd) , twice per day dosing (a.k.a. bid), three times per day dosing (a.k.a. tid), twice per week (a.k.a.
  • first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or both the first and second conjugate, or pharmaceutically acceptable salt thereof can be applied in connection with the concentration to regulate the cytotoxicity of the CAR T cell
  • the cytotoxicity of the CAR T cell composition can be balanced against the risk of tumor lysis syndrome, or cytokine release syndrome (CRS), as described herein by adjusting the dosing schedule in connection with the concentration of the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or
  • the cancer is imaged prior to administration to the patient of the compound, or pharmaceutically acceptable salt thereof, the first conjugate, or pharmaceutically acceptable salt thereof, the second conjugate, or pharmaceutically acceptable salt thereof, or prior to administration of the CAR T cell composition to the patient.
  • imaging occurs by PET imaging.
  • imaging occurs by MRI imaging or SPECT/CT imaging. It is appreciated by one skilled in the art that the imaging method can be any suitable imaging method known in the art.
  • Off-target' toxicity in the patient may not occur even though CAR T cell toxicity to the cancer occurs.
  • Off-target' tissue toxicity may not occur in the patient even though CAR T cell toxicity to the cancer occurs.
  • the cancer may comprise a tumor, and tumor size may be reduced in the patient, even though Off-target' toxicity does not occur.
  • the resulting CAR construct (1551bp) was inserted into EcoRI/NotI cleaved lentiviral expression vector pCDH-EFl-MCS-(PGK-GFP) ( Figure 14B, System Biosciences). The sequence of the CAR construct in lentiviral vector was confirmed by DNA sequencing.
  • An exemplary CAR nucleic acid coding sequence may comprise:
  • An exemplary CAR amino acid sequence may comprise:
  • An exemplary insert may comprise:
  • lentiviral virus containing an anti-fluorescein single chain fragment variable (scFv) CAR a 293TN packaging cell line was co-transfected with the lentiviral vector encoding anti-fluorescein scFv CAR and a 2nd generation of a mixture of packaging plasmids (Cellecta). After 24 and 48 hours of transfection, supematants containing the lentivirus with the CAR gene were harvested and virus particles were concentrated by the standard polyethylene glycol virus concentration method (Clontech) for future transduction with human T cells.
  • scFv anti-fluorescein single chain fragment variable
  • T cells were isolated from human peripheral blood mononuclear cells (PBMC) by Ficoll density gradient centrifugation (GE Healthcare Lifesciences). After washing away remaining Ficoll solution, T cells were isolated by using an EasySepTM Human T Cell Isolation Kit (STEM CELL technologies). Purified T cells were cultured in TexMACSTM medium (Miltenyi Biotech Inc) with 1% penicillin and streptomycin sulfate in the presence of human IL-2 (100 IU/mL, Miltenyi Biotech Inc). T cells were cultured at density of lxlO 6 cells/mL in multi-well plates. T cells were split and re-feed every 2-3 days.
  • Isolated T cells were activated with Dynabeads coupled with anti-CD3/CD28 antibodies (Life Technologies) for 12-24 hours in the presence of human IL-2 (100 IU/mL), then transduced with lentivirus encoding an anti-fluorescein CAR gene. Cells were harvested after 72 hours and the expression of CAR on transduced T cells was identified by measuring GFP fluorescent cells using flow cytometry. As shown in Figure 15 A, non-transduced T cells do not show GFP expression. As shown in Figure 15B, transduced T-cells express GFP. EXAMPLE 5
  • FITC-folate main peak typically eluted at 27-50 min.
  • the quality of the FITC-folate fraction was monitored by analytical reverse-phase HPLC with a UV detector. Fractions with greater than 98.0% purity (LCMS) were lyophilized to obtain the final FITC-folate product.
  • the pure fractions were pooled and freeze-dried, providing the FITC-PEG12-Folate.
  • Ethylenediamine, polymer-bound (200-400 mesh)-resin (50 mg) was loaded into a peptide synthesis vessel and swollen with DCM (3 mL) followed by DMF (3 mL).
  • DCM 3 mL
  • DMF 3 mL
  • Fmoc-PEG 2 o-COOH solution 131 mg, 1.0 equiv
  • i- Pr 2 NEt 6.0 equiv
  • PyBOP 4.0 equiv
  • Argon was bubbled for 6 h, the coupling solution was drained, and the resin was washed with DMF (3 x 10 mL) and z-PrOH (3 x 10 mL). Kaiser tests were performed to assess reaction progress.
  • Fmoc deprotection was carried out using 20% piperidine in DMF (3 x 10 mL), before each amino acid coupling. The above sequence was repeated to complete the reaction with Fmoc-Glu-OtBu (72 mg, 2.0 equiv) and Tfa.Pteroic-acid (41 mg, 1.2 equiv) coupling steps.
  • the resin was washed with 2% hydrazine in DMF 3 x 10 mL (5 min) to cleave the trifluoro-acetyl protecting group on pteroic acid and washed with i- PrOH (3 x 10 mL) followed by DMF (3 x lOmL). The resin was dried under argon for 30 min.
  • the folate-peptide was cleaved from the resin using the Cleavage Solution. 10 mL of the cleavage mixture was introduced and argon was bubbled for 1.5 h. The cleavage mixture was drained into a clean flask. The resin was washed 3 times with more cleavage mixture. The combined mixture was concentrated under reduced pressure to a smaller volume ( ⁇ 5 mL) and precipitated in ethyl ether.
  • the precipitate was collected by centrifugation, washed with ethyl ether (3 times) and dried under high vacuum.
  • the dried Folate-PEG 2 o-EDA (1.0 equiv) was treated with FITC (50 mg, 1.5 equiv) in DMSO and DIPEA at room temperature. Progress of the reaction monitored by LCMS. After 8 h the starting material was consumed to give the product.
  • Ethylenediamine, polymer-bound (200-400 mesh)-resin (50 mg) was loaded in a peptide synthesis vessel and swollen with DCM (3 mL) followed by DMF (3 mL).
  • DCM 3 mL
  • DMF 3 mL
  • Fmoc-PEG 3 6-COOH solution 161 mg, 1.0 equiv
  • i- Pr 2 NEt 6.0 equiv
  • PyBOP 4.0 equiv
  • Argon was bubbled for 6 h, the coupling solution was drained, and the resin was washed with DMF (3 x 10 mL) and z ' -PrOH (3 x 10 mL). Kaiser tests were performed to assess reaction progress.
  • Fmoc deprotection was carried out using 20% piperidine in DMF (3 x 10 mL), before each amino acid coupling. The above sequence was repeated to complete reaction with 2X Fmoc-PEG 36 -COOH (161 mg, 1.0 equiv), Fmoc-Glu- OtBu (72 mg, 2.0 equiv ) and Tfa.Pteroic-acid ( 41.0 mg, 1.2 equiv) coupling steps.
  • DUPA-FITC was synthesized by solid phase methodology as follows. Universal Nova TagTM resin (50 mg, 0.53 mM) was swollen with DCM (3 mL) followed by DMF 3 mL). A solution of 20% piperidine in DMF (3 x 3 mL) was added to the resin, and argon was bubbled for 5 min. The resin was washed with DMF (3 x 3 mL) and isopropyl alcohol (z ' -PrOH, 3 x 3 mL).
  • 1,2-Diaminoethane trityl-resin (0.025 g) was loaded into a peptide synthesis vessel and washed with z ' -PrOH (3 x 10 mL), followed by DMF (3 x lOmL). To the vessel was then introduced a solution of Fmoc-NH-(PEG)i 2 -COOH (42.8 mg) in DMF, z ' -Pr 2 NEt (2.5 equiv), and PyBOP (2.5 equiv). The resulting solution was bubbled with Ar for 1 h, the coupling solution was drained, and the resin washed with DMF (3 x 10 mL) and z ' -PrOH (3 x 10 mL).
  • NK-1 compound was synthesized by a two-step procedure starting from the base ligand, which was prepared by using a procedure in the literature. (Ref: DESIGN AND DEVELOPMENT OF NEUROKININ- 1 RECEPTOR-BINDING AGENT DELIVERY CONJUGATES, Application Number: PCT/US2015/44229; incorporated herein by reference.
  • CA9 ligand (53.6mg) was dissolved in DMF (2-3mL) in a 50mL round bottom flask using a Teflon magnetic stir bar. Ambient air was removed using a vacuum and replaced with nitrogen gas, this was done in three cycles. The round bottom flask was kept under constant nitrogen gas. To the flask, 28.9mg of N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC) was added followed by 21.6mg 1- Hydroxybenzotriazole hydrate (HOBt) and 18.9 ⁇ of Boc-PEG 2 -NH 2 (Sigma Aldrich).
  • EDC N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride
  • a standard lactate dehydrogenase (LDH) release assay was performed using a PierceTM LDH cytotoxicity assay kit from ThermoFisher Scientific.
  • LDH lactate dehydrogenase
  • cancer cells were seeded at a density of 10 4 cells/100 ⁇ L ⁇ of media in each well of a 96 well plate and grown overnight.
  • FITC- ligands at various concentrations were introduced into each well and co-cultured for 6-24 hours. After co-incubation, the plate containing CAR T cells and cancer cells was centrifuged at 350 x g at room temperature for 10 min to remove cell debris or remaining cells. 50 ⁇ ⁇ of the supernatants of each sample were then transferred into a new 96 well plate. 50 ⁇ ⁇ of the prepared LDH reaction mixture was added to the transferred 50 ⁇ ⁇ of each sample and incubated at room temperature for 30 min. 50 ⁇ ⁇ of stop solution was added and the absorbance of each sample was measured at 490nm and 680nm. The percent of cytotoxicity was calculated for each sample by using the equation below:
  • FIG. 3A shows the cytotoxicity of CAR T cells in a KB (FR+) model with an E:T of 10: 1 using 100 nM of each conjugate.
  • FITC-Folate, FITC- PEG20-Folate, and FITC-PEG108-Folate activation is greater than activation with FITC-DUPA or in the absence of a conjugate.
  • Figure 3B shows the cytotoxicity of CAR T cells in an LNCaP (PSMA+) model with an E:T of 10:1 using 100 nM FITC-DUPA or FITC-PEG12-DUPA.
  • the FITC-DUPA conjugates show greater activation than using FITC-Folate or in the absence of a conjugate.
  • Figure 3C shows the cytotoxicity of CAR T cells in a HEK293 (NK1R+) model with an E:T of 10: 1 using 100 nM FITC-PEGl l-NKl.
  • FITC-PEG11-NK1 shows greater than activation using FITC-Folate or in the absence of a conjugate.
  • CAR T cell cytotoxicity to tumor cells in a KB (FR+) model is a function of the E:T ratio used during the assay with ⁇ of FITC-Folate and FITC-DUPA.
  • CAR T cell cytotoxicity to tumor cells in a KB (FR+) model is a function of the concentration of FITC-Folate used during the co-incubation (E:T ratio of 10: 1).
  • CAR T cytotoxicity in a KB (FR+) model can be controlled by adjusting concentration of the conjugate bridge, or using linkers with different lengths of PEG with a E:T of 10: 1.
  • CAR T cell proliferation and CAR T cell activation CAR T cell proliferation were mainly measured by flow cytometry.
  • cancer cells KB (FR+) or HEK (NK1R+)
  • CAR T cells were introduced into each well in either the presence or absence of the desired FITC-ligands and the cells were co- cultured for 5 days (120 hours).
  • CAR T cells were stained with anti-human CD3 APC antibody (Biolegend) by standard immuno staining procedures (20 min on ice). Cells positive for both anti-human CD3 staining and GFP were counted for CAR T cell proliferation.
  • Figure 1A shows CAR T cell proliferation in the presence of KB (FR+) cells with different conjugates.
  • Figure IB shows CAR T cell proliferation in the presence of HEK (NK1R+) cells with different conjugates.
  • the presence of linkers with different lengths of PEG affect the levels of CAR-T cell proliferation.
  • cancer cells were prepared by the same procedure described above.
  • Cancer cells and CAR T cells were co-cultured in the presence or absence of 100 nM FITC-ligands with an E:T ratio of 10: 1 for 24 hours and harvested. After washing, cells from each sample were stained with anti-human CD69 Alexa Fluor 647
  • CD69 expression is related to the co-cultured conjugate.
  • a standard ELISA assay was performed using a Human IFN- ⁇ detection ELISA kit from Biolegend. Briefly, cancer cells were seeded at density of 10 4 cells/100 ⁇ L ⁇ of media in each well of a 96 well plate and grown overnight. CAR T cells were introduced into each cancer sample with desired FITC-ligands and co-cultured for 24 hours. After co-incubation, supematants of each sample were harvested and centrifuged at 1000 x g and 4 °C for 10 min to remove cell debris. Clear supematants from each sample were then either used to detect IFN- ⁇ by ELISA or stored at -80 °C for future usage. After completing preparation of each sample, standard ELISA was performed based on the manufacturer's instructions.
  • KB (FR+) cells and MDA-MB-231 cells were incubated with 100 nM FITC- folate for 30 min on ice. After washing, FITC-folate binding to FRa tumor antigen on cells was measured by flow cytometry. As shown in Figure 4A, KB (FR+) cells have a higher level of FR expression and corresponding FITC binding than MDA-MB-231 cells.
  • mice Immnuodeficient NSG mice (Jackson Laboratory) were used to identify the efficacy of CAR T cell anti-tumor activity in vivo.
  • Each tumor- specific antigen expressing cancer cell line was subcutaneously injected into the shoulder of NSG mice to establish solid tumor xenografts.
  • CAR T cells were introduced into mice bearing tumors and desired FITC-ligands were also introduced (i.v.) every other day.
  • Control mice were administered PBS instead of FITC-ligands.
  • Tumor volume and cytokine levels in the blood IL2, IL6, IL10, IFNy, and TNFa
  • mice were administered PBS instead of FITC-ligands.
  • Tumor volume and cytokine levels in the blood IL2, IL6, IL10, IFNy, and TNFa
  • mice were measured.
  • General toxicity of the therapy was monitored by measuring weight loss.
  • mice blood was collected to test for anemia, number of white blood cells and CAR
  • FIG. 5A-C A xenograft model using HEK293 (NK1R+) cells is shown in Figures 5A-C and 6A-B.
  • Figure 5 A tumor size decreased in the mice treated with FITC-PEGl 1-NKl (500 nmol/kg) but continued to grow in the control mouse.
  • Figure 5B the body weight of mice treated with FITC-PEGl 1-NKl was unchanged relative to the control mouse.
  • FIG 5C the percentage of CAR T cells in human T cells increased after CAR T cell injection.
  • harvested organs from the treatment group (6B) appeared normal in size with no indications of cytokine release syndrome after two weeks of therapy when compared to the harvested mouse organs from a control group (6A).
  • FIG. 7A-C and 8A-B A xenograft model using MDA-MB-231 (FR+) cells is shown in Figures 7A-C and 8A-B.
  • Figure 7A tumor size decreased in the mice treated with FITC-PEG12- Folate (500 nmol/kg) or FITC-Folate ( 500 nmoles/kg) but tumors continued to grow in the control mouse.
  • Figure 7B the body weight of mice treated with FITC-PEGl 1-NKl was unchanged during treatment.
  • FIG 7C the percentage of CAR T cells in human T cells increased after CAR T cell and conjugate therapy.
  • blood indices of the HEK-NK1R model using FITC- PEGl 1-NKl (500 nmoles/kg) and the MDA-MB-231 model using FITC-PEG12-Folate (500 nmoles/kg) also indicated that a cytokine storm had not occurred during the course of the treatment.
  • KB (FR+) tumor xenografts were treated with two difference concentrations of FITC-PEG12-Folate.
  • the mice treated with the lower dose 250 nmoles/kg
  • had milder body weight loss compared to the mice treated with a higher dose 500 nmoles/kg.
  • FIGs 12A-C harvested organs from untreated mice ( Figure 12A) and mice receiving the lower dose (Figure 12B) showed milder cytokine release syndrome compared to the higher dose ( Figure 12C).
  • Figure 13 KB xenograft mice receiving lower dosing showed better blood indices indicating milder cytokine release.
  • immunodeficient NSG mice In order to study whether same anti-FITC CAR T cell can eradicate mixture of heterogeneous cancer cells with cocktail of FITC-ligands, immunodeficient NSG mice (Jackson laboratory) were utilized for the in vivo study. Two different cancer cell lines (e.g. MDA-MB- 231(FR+) and HEK(NK1R+)) were implanted into separate flanks on the same mouse. Then, anti-FITC CAR T cell (10' cells) was introduced by intravenous injection when tumor volumes reached about 50-100mm . In addition, either a mixture of FITC-ligands (i.e.
  • FITC-PEG12- Folate 500nmole/kg
  • FITC-PEGl 1-NKlR 500nmole/kg
  • single FITC-PEGl 1-NK-lR 500nmole/kg
  • PBS PBS
  • both tumors i.e. MDA-MB-231 (MDA) and MDA.
  • HEK (NKIR) were eliminated by the same anti-FITC CAR T cell when both FITC-PEGl 1- NK1R and FITC-PEG12-Folate were introduced.
  • HEK (NKIR) tumor was eradicated in the mouse that was treated by only FITC-PEGl 1-NKlR.
  • MDA-MB-231 continued growing in the same mouse where only FITC- PEG11-NKlR was administered because FITC-PEG12-Folate was not administrated.
  • both tumors did not show any response when PBS was introduced.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Virology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Mycology (AREA)
  • Oncology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plant Pathology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)
PCT/US2017/026618 2016-04-08 2017-04-07 Methods and compositions for car t cell therapy Ceased WO2017177149A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP17779919.4A EP3439675A4 (en) 2016-04-08 2017-04-07 METHOD AND COMPOSITIONS FOR CAR-T CELL THERAPY
RU2018139101A RU2792653C2 (ru) 2016-04-08 2017-04-07 Способы и композиции для car-t-клеточной терапии
US16/092,054 US12144850B2 (en) 2016-04-08 2017-04-07 Methods and compositions for car T cell therapy
JP2018553142A JP7282521B2 (ja) 2016-04-08 2017-04-07 Ｃａｒ ｔ細胞療法のための方法および組成物
CA3019835A CA3019835A1 (en) 2016-04-08 2017-04-07 Methods and compositions for car t cell therapy
CN201780033995.3A CN109195611A (zh) 2016-04-08 2017-04-07 用于car t细胞疗法的方法和组合物
BR112018070580-2A BR112018070580B1 (pt) 2016-04-08 2017-04-07 Uso de uma célula t com receptor de antígeno quimérico (car)
JP2023081216A JP7631410B2 (ja) 2016-04-08 2023-05-17 Ｃａｒ ｔ細胞療法のための方法および組成物
US18/914,891 US20250171803A1 (en) 2016-04-08 2024-10-14 Methods and compositions for car t cell therapy
JP2025017467A JP2025084765A (ja) 2016-04-08 2025-02-05 Ｃａｒ ｔ細胞療法のための方法および組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662320183P 2016-04-08 2016-04-08
US62/320,183 2016-04-08
US201662323971P 2016-04-18 2016-04-18
US62/323,971 2016-04-18

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/092,054 A-371-Of-International US12144850B2 (en) 2016-04-08 2017-04-07 Methods and compositions for car T cell therapy
US18/914,891 Division US20250171803A1 (en) 2016-04-08 2024-10-14 Methods and compositions for car t cell therapy

Publications (2)

Publication Number Publication Date
WO2017177149A2 true WO2017177149A2 (en) 2017-10-12
WO2017177149A3 WO2017177149A3 (en) 2017-11-16

Family

ID=60001557

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/026618 Ceased WO2017177149A2 (en) 2016-04-08 2017-04-07 Methods and compositions for car t cell therapy

Country Status (6)

Country Link
US (2) US12144850B2 (https=)
EP (1) EP3439675A4 (https=)
JP (3) JP7282521B2 (https=)
CN (1) CN109195611A (https=)
CA (1) CA3019835A1 (https=)
WO (1) WO2017177149A2 (https=)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018160622A1 (en) * 2017-02-28 2018-09-07 Endocyte, Inc. Compositions and methods for car t cell therapy
CN109134467A (zh) * 2018-08-09 2019-01-04 中国医学科学院北京协和医院 用于控制嵌合抗原受体t细胞激活/抑制的连接臂及其应用
WO2019144091A1 (en) * 2018-01-22 2019-07-25 Endocyte, Inc. Methods of use for car t cells
WO2019165237A1 (en) * 2018-02-23 2019-08-29 Endocyte, Inc. Sequencing method for car t cell therapy
EP3429575A4 (en) * 2016-03-16 2019-10-23 Purdue Research Foundation AGAINST CARBOANHYDRASE-IX DRUGS AND METHODS
EP3620464A1 (en) * 2018-09-10 2020-03-11 Miltenyi Biotec GmbH Car cell having crosslinked disulfide bridge on antigen recognizing moiety
EP3429637A4 (en) * 2016-03-16 2020-03-11 Endocyte, Inc. CARBOANHYDRASE IX INHIBITOR CONJUGATES AND USES THEREOF
JPWO2019124468A1 (ja) * 2017-12-24 2021-01-21 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ−７、及びｃｃｌ１９を発現する免疫担当細胞
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
US20210393786A1 (en) * 2018-07-26 2021-12-23 Purdue Research Foundation Small molecule ligand-targeted drug conjugates for anti-influenza chemotherapy and immunotherapy
US11225520B2 (en) 2016-02-16 2022-01-18 Dana-Farber Cancer Institute, Inc. Immunotherapy compositions and methods
EP3833400A4 (en) * 2018-08-07 2022-06-15 Purdue Research Foundation REJUVENATION OF CAR-T CELLS
US20220340927A1 (en) * 2019-09-01 2022-10-27 Exuma Biotech Corp. Methods and compositions for the modification and delivery of lymphocytes
US11649288B2 (en) 2017-02-07 2023-05-16 Seattle Children's Hospital Phospholipid ether (PLE) CAR T cell tumor targeting (CTCT) agents
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
US12312416B2 (en) 2018-02-06 2025-05-27 Seattle Children's Hospital Fluorescein-specific cars exhibiting optimal t cell function against FL-PLE labelled tumors
US12466869B2 (en) 2018-06-28 2025-11-11 Dana-Farber Cancer Institute, Inc. Targeting of multiple antigens with multiplex CAR T cells in solid and liquid malignancies
US12570716B2 (en) 2020-02-04 2026-03-10 Seattle Children's Hospital Anti-dinitrophenol chimeric antigen receptors

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112262214A (zh) 2018-04-12 2021-01-22 优莫佳生物制药股份有限公司 病毒载体及包装细胞系
US20220249565A1 (en) * 2019-06-27 2022-08-11 Eutilex Co., Ltd. Chimeric antigen receptor with 4-ibb costimulatory domain
WO2022015754A2 (en) * 2020-07-13 2022-01-20 University Of Southern California Universal car-nk cell targeting various epitopes of hiv-1 gp160
EP4448729A1 (en) 2021-12-17 2024-10-23 Umoja Biopharma, Inc. Cytotoxic innate lymphoid cell and uses thereof
US20250382586A1 (en) 2022-05-17 2025-12-18 Umoja Biopharma, Inc. Manufacturing viral particles
US20250354118A1 (en) 2022-06-09 2025-11-20 Umoja Biopharma, Inc. Compositions and methods for nk cell differentiation
WO2023240282A1 (en) 2022-06-10 2023-12-14 Umoja Biopharma, Inc. Engineered stem cells and uses thereof
CA3263301A1 (en) 2022-07-27 2024-02-01 Umoja Biopharma, Inc. Differentiation of stem cells in suspension culture
TW202434621A (zh) 2022-11-04 2024-09-01 美商優莫佳生物製藥有限公司 多核苷酸構築體及相關病毒載體及方法
WO2024097992A2 (en) 2022-11-04 2024-05-10 Umoja Biopharma, Inc. Particles displaying adhesion-molecule fusions
WO2025129084A1 (en) 2023-12-13 2025-06-19 Umoja Biopharma, Inc. Engineered induced stem cell derived myeloid cells and methods of differentiating and using same
WO2025231174A1 (en) 2024-04-30 2025-11-06 Umoja Biopharma, Inc. Manufacturing viral particles

Family Cites Families (398)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986004356A1 (en) 1985-01-28 1986-07-31 International Genetic Engineering, Inc. AraB PROMOTERS AND METHOD OF PRODUCING POLYPEPTIDES, INCLUDINN CECROPINS, BY MICROBIOLOGICAL TECHNIQUES
US4690915A (en) 1985-08-08 1987-09-01 The United States Of America As Represented By The Department Of Health And Human Services Adoptive immunotherapy as a treatment modality in humans
IN165717B (https=) 1986-08-07 1989-12-23 Battelle Memorial Institute
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5202238A (en) 1987-10-27 1993-04-13 Oncogen Production of chimeric antibodies by homologous recombination
US6004781A (en) 1988-01-22 1999-12-21 The General Hospital Corporation Nucleic acid encoding Ig-CD4 fusion proteins
IL86278A (en) 1988-05-04 2003-06-24 Yeda Res & Dev Endowing cells with antibody specificity using chimeric t cell receptor
US5906936A (en) 1988-05-04 1999-05-25 Yeda Research And Development Co. Ltd. Endowing lymphocytes with antibody specificity
US5225538A (en) 1989-02-23 1993-07-06 Genentech, Inc. Lymphocyte homing receptor/immunoglobulin fusion proteins
US6406697B1 (en) 1989-02-23 2002-06-18 Genentech, Inc. Hybrid immunoglobulins
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US5216132A (en) 1990-01-12 1993-06-01 Protein Design Labs, Inc. Soluble t-cell antigen receptor chimeric antigens
US20020004052A1 (en) 1990-05-08 2002-01-10 David Berd Composition comprising a tumor cell extract and method of using the composition
US5914109A (en) 1990-06-15 1999-06-22 New York University Heterohybridomas producing human monoclonal antibodies to HIV-1
DE69123241T2 (de) 1990-12-14 1997-04-17 Cell Genesys Inc Chimärische ketten zur transduktion von rezeptorverbundenen signalwegen
US6319494B1 (en) 1990-12-14 2001-11-20 Cell Genesys, Inc. Chimeric chains for receptor-associated signal transduction pathways
US6407221B1 (en) 1990-12-14 2002-06-18 Cell Genesys, Inc. Chimeric chains for receptor-associated signal transduction pathways
US20020111474A1 (en) 1990-12-14 2002-08-15 Capon Daniel J. Chimeric chains for receptor-associated signal transduction pathways
US5843728A (en) 1991-03-07 1998-12-01 The General Hospital Corporation Redirection of cellular immunity by receptor chimeras
US6004811A (en) 1991-03-07 1999-12-21 The Massachussetts General Hospital Redirection of cellular immunity by protein tyrosine kinase chimeras
NZ241855A (en) 1991-03-07 1994-04-27 Gen Hospital Corp Use of therapeutic cells to obtain cellular response to infection, tumours or autoimmune-generated cells, cells with chimaeric receptors (with binding component and destruction signal), dna encoding the receptor, vectors and antibodies to receptor
US6753162B1 (en) 1991-03-07 2004-06-22 The General Hospital Corporation Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells
US5912170A (en) 1991-03-07 1999-06-15 The General Hospital Corporation Redirection of cellular immunity by protein-tyrosine kinase chimeras
US7049136B2 (en) 1991-03-07 2006-05-23 The General Hospital Corporation Redirection of cellular immunity by receptor chimeras
US5851828A (en) 1991-03-07 1998-12-22 The General Hospital Corporation Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells
JPH06505396A (ja) 1991-03-08 1994-06-23 サイトメッド，インコーポレイテッド 可溶性ｃｄ２８タンパク質およびそれを用いる治療方法
US6582959B2 (en) 1991-03-29 2003-06-24 Genentech, Inc. Antibodies to vascular endothelial cell growth factor
CA2121487A1 (en) 1991-10-21 1993-04-29 Stephen A. Sherwin Combined cellular and immunosuppresive therapies
IL104570A0 (en) 1992-03-18 1993-05-13 Yeda Res & Dev Chimeric genes and cells transformed therewith
US8211422B2 (en) 1992-03-18 2012-07-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric receptor genes and cells transformed therewith
US5372930A (en) 1992-09-16 1994-12-13 The United States Of America As Represented By The Secretary Of The Navy Sensor for ultra-low concentration molecular recognition
ES2276390T3 (es) 1992-11-05 2007-06-16 Sloan-Kettering Institute For Cancer Research Antigeno de membrana especifico de la prostata.
US6953668B1 (en) 1992-11-05 2005-10-11 Sloan-Kettering Institute For Cancer Research Prostate-specific membrane antigen
US7105159B1 (en) 1992-11-05 2006-09-12 Sloan-Kettering Institute For Cancer Research Antibodies to prostate-specific membrane antigen
US5861156A (en) 1993-01-08 1999-01-19 Creative Biomolecules Methods of delivering agents to target cells
EP0693084A4 (en) 1993-04-06 1999-06-02 Hutchinson Fred Cancer Res CHIMERAL CYTOKINE RECEPTORS IN LYMPHOCYTE
US5834256A (en) 1993-06-11 1998-11-10 Cell Genesys, Inc. Method for production of high titer virus and high efficiency retroviral mediated transduction of mammalian cells
US6051427A (en) 1993-06-11 2000-04-18 Cell Genesys, Inc. Method for production of high titer virus and high efficiency retroviral mediated transduction of mammalian cells
US5525503A (en) 1993-09-28 1996-06-11 Dana-Farber Cancer Institute, Inc. Signal transduction via CD28
US5935818A (en) 1995-02-24 1999-08-10 Sloan-Kettering Institute For Cancer Research Isolated nucleic acid molecule encoding alternatively spliced prostate-specific membrane antigen and uses thereof
AU694222B2 (en) 1994-05-02 1998-07-16 Bernd Groner Bifunctional protein, preparation and use
US7354587B1 (en) 1994-07-06 2008-04-08 Immunomedics, Inc. Use of immunoconjugates to enhance the efficacy of multi-stage cascade boosting vaccines
US5798100A (en) 1994-07-06 1998-08-25 Immunomedics, Inc. Multi-stage cascade boosting vaccine
CA2204183A1 (en) 1994-11-01 1996-05-09 Andrew Lawrence Feldhaus Chimeric receptors for the generation of selectively-activatable th-independent cytotoxic t cells
US6077947A (en) 1995-02-02 2000-06-20 Cell Genesys, Inc. DNA encoding an intracellular chimeric receptor comprising Janus kinase
US5712149A (en) 1995-02-03 1998-01-27 Cell Genesys, Inc. Chimeric receptor molecules for delivery of co-stimulatory signals
US6103521A (en) 1995-02-06 2000-08-15 Cell Genesys, Inc. Multispecific chimeric receptors
ATE317435T1 (de) 1995-02-24 2006-02-15 Sloan Kettering Inst Cancer Prostataspezifisches membranes antigen und seine anwendungen
US5830755A (en) 1995-03-27 1998-11-03 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services T-cell receptors and their use in therapeutic and diagnostic methods
WO1997004752A1 (en) 1995-07-26 1997-02-13 Duramed Pharmaceuticals, Inc. Pharmaceutical compositions of conjugated estrogens and methods for their use
GB9526131D0 (en) 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Recombinant chimeric receptors
WO1997034634A1 (en) 1996-03-20 1997-09-25 Sloan-Kettering Institute For Cancer Research Single chain fv constructs of anti-ganglioside gd2 antibodies
US6261787B1 (en) 1996-06-03 2001-07-17 Case Western Reserve University Bifunctional molecules for delivery of therapeutics
US5969102A (en) 1997-03-03 1999-10-19 St. Jude Children's Research Hospital Lymphocyte surface receptor that binds CAML, nucleic acids encoding the same and methods of use thereof
US20020018783A1 (en) 1997-03-20 2002-02-14 Michel Sadelain Fusion proteins of a single chain antibody and cd28 and uses thereof
DE69838843D1 (de) 1997-06-11 2008-01-24 Univ New York Prenylcystein carboxyl methyl-transferase, dns, welche für selbige kodiert, und ein verfahren zur suche nach hemmstoffen
US6759243B2 (en) 1998-01-20 2004-07-06 Board Of Trustees Of The University Of Illinois High affinity TCR proteins and methods
US20090011984A1 (en) 1998-02-23 2009-01-08 Seppo Yla-Herttuala Biotin-binding receptor molecules
GB9809951D0 (en) 1998-05-08 1998-07-08 Univ Cambridge Tech Binding molecules
JP2002524081A (ja) 1998-09-04 2002-08-06 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ 前立腺−特異的膜抗原に特異的な融合受容体およびその使用
WO2000023573A2 (en) 1998-10-20 2000-04-27 City Of Hope Cd20-specific redirected t cells and their use in cellular immunotherapy of cd20+ malignancies
ES2293748T3 (es) 1998-10-21 2008-03-16 Altor Bioscience Corporation Moleculas de fijacion poliespecificas y usos de las mismas.
US7217421B1 (en) 1998-11-03 2007-05-15 Cell Genesys, Inc. Cancer-associated antigens and methods of their identification and use
AU3389700A (en) 1999-03-01 2000-09-21 Cell Genesys, Inc. Anti-neoplastic compositions and uses thereof
US7052906B1 (en) 1999-04-16 2006-05-30 Celltech R & D Limited Synthetic transmembrane components
US6699972B1 (en) 1999-06-25 2004-03-02 Academia Sinica Chimeric protein and method of controlling tumor growth using the protein
WO2001049318A1 (en) 2000-01-03 2001-07-12 Tr Associates, L.L.C. Novel chimeric proteins and methods for using the same
ATE360430T1 (de) 2000-02-14 2007-05-15 Univ California Impfstoff spezifisch gegen nierentumore, gerichtet gegen das antigen g-250 des nierentumors
US6770749B2 (en) 2000-02-22 2004-08-03 City Of Hope P53-specific T cell receptor for adoptive immunotherapy
PL211872B1 (pl) 2000-03-31 2012-07-31 Purdue Research Foundation Kompozycja farmaceutyczna
AU2001255580A1 (en) 2000-04-21 2001-12-11 Rutgers, The State University Of New Jersey Methods and compositions for the diagnosis of schizophrenia
US6524572B1 (en) 2000-06-26 2003-02-25 Rainbow Therapeutic Company Targeting recombinant virus with a bispecific fusion protein ligand in coupling with an antibody to cells for gene therapy
ES2304398T3 (es) 2000-07-31 2008-10-16 Green Peptide Co., Ltd. Antigeno de tumores.
US7666424B2 (en) 2001-10-17 2010-02-23 Sloan-Kettering Institute For Cancer Research Methods of preparing and using single chain anti-tumor antibodies
AU2001297703B2 (en) 2000-11-07 2006-10-19 City Of Hope CD19-specific redirected immune cells
US20020132983A1 (en) 2000-11-30 2002-09-19 Junghans Richard P. Antibodies as chimeric effector cell receptors against tumor antigens
US7723111B2 (en) 2001-03-09 2010-05-25 The United States Of America As Represented By The Department Of Health And Human Services Activated dual specificity lymphocytes and their methods of use
US7070995B2 (en) 2001-04-11 2006-07-04 City Of Hope CE7-specific redirected immune cells
US20090257994A1 (en) 2001-04-30 2009-10-15 City Of Hope Chimeric immunoreceptor useful in treating human cancers
US7514537B2 (en) 2001-04-30 2009-04-07 City Of Hope Chimeric immunoreceptor useful in treating human gliomas
US20030171546A1 (en) 2001-04-30 2003-09-11 City Of Hope Chimeric immunoreceptor useful in treating human cancers
US20070031438A1 (en) 2001-12-10 2007-02-08 Junghans Richard P Antibodies as chimeric effector cell receptors against tumor antigens
US7939059B2 (en) 2001-12-10 2011-05-10 California Institute Of Technology Method for the generation of antigen-specific lymphocytes
US20030170238A1 (en) 2002-03-07 2003-09-11 Gruenberg Micheal L. Re-activated T-cells for adoptive immunotherapy
US7446190B2 (en) 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
AU2003256912A1 (en) 2002-08-16 2004-03-03 Yeda Research And Development Co. Ltd. Tumor associated antigen, peptides thereof, and use of same as anti-tumor vaccines
US8809504B2 (en) 2002-09-03 2014-08-19 Vit Lauermann Inhibitor which is deactivatable by a reagent produced by a target cell
DE10244457A1 (de) 2002-09-24 2004-04-01 Johannes-Gutenberg-Universität Mainz Verfahren zur rationalen Mutagenese von alpha/beta T-Zell Rezeptoren und entsprechend mutierte MDM2-Protein spezifische alpha/beta T-Zell Rezeptoren
US20050129671A1 (en) 2003-03-11 2005-06-16 City Of Hope Mammalian antigen-presenting T cells and bi-specific T cells
US20060018878A1 (en) 2003-03-11 2006-01-26 City Of Hope Dual antigen specific T cells with trafficking ability
TWI353991B (en) 2003-05-06 2011-12-11 Syntonix Pharmaceuticals Inc Immunoglobulin chimeric monomer-dimer hybrids
US7348004B2 (en) 2003-05-06 2008-03-25 Syntonix Pharmaceuticals, Inc. Immunoglobulin chimeric monomer-dimer hybrids
US20050113564A1 (en) 2003-11-05 2005-05-26 St. Jude Children's Research Hospital Chimeric receptors with 4-1BB stimulatory signaling domain
US20130266551A1 (en) 2003-11-05 2013-10-10 St. Jude Children's Research Hospital, Inc. Chimeric receptors with 4-1bb stimulatory signaling domain
US7435596B2 (en) 2004-11-04 2008-10-14 St. Jude Children's Research Hospital, Inc. Modified cell line and method for expansion of NK cell
US8652484B2 (en) 2004-02-13 2014-02-18 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US7196062B2 (en) 2004-02-18 2007-03-27 Wisconsin Alumni Research Foundation Method for treating glaucoma
KR20070015518A (ko) 2004-03-02 2007-02-05 셀렉타, 엘엘씨 암의 진단 및 치료를 위한 포스포리피드 유사체
DE602005016683D1 (de) 2004-07-10 2009-10-29 Fox Chase Cancer Ct Genetisch modifizierte, menschliche, natürliche killerzellenlinien:
TWI309240B (en) 2004-09-17 2009-05-01 Hoffmann La Roche Anti-ox40l antibodies
US7994298B2 (en) 2004-09-24 2011-08-09 Trustees Of Dartmouth College Chimeric NK receptor and methods for treating cancer
AU2005336093B2 (en) 2004-10-08 2011-02-24 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Adoptive immunotherapy with enhanced T lymphocyte survival
EP1810035A4 (en) 2004-11-10 2010-03-17 Macrogenics Inc GENERATION OF FC ANTIBODY REGIONS FOR EFFECTOR FUNCTION
WO2007044033A2 (en) 2004-12-07 2007-04-19 University Of Pittsburgh Of The Commonwealth System Of Higher Education Therapeutic and diagnostic cloned mhc-unrestricted receptor specific for the muc1 tumor associated antigen
US20070036773A1 (en) 2005-08-09 2007-02-15 City Of Hope Generation and application of universal T cells for B-ALL
WO2007065027A2 (en) 2005-12-02 2007-06-07 Dana Farber Cancer Institute Carbonic anhydrase ix (g250) antibodies and methods of use thereof
US7919079B2 (en) 2006-03-31 2011-04-05 Biosante Pharmaceuticals, Inc. Cancer immunotherapy compositions and methods of use
WO2007146968A2 (en) 2006-06-12 2007-12-21 Trubion Pharmaceuticals, Inc. Single-chain multivalent binding proteins with effector function
US20080051380A1 (en) 2006-08-25 2008-02-28 Auerbach Alan H Methods and compositions for treating cancer
EP1900752A1 (en) 2006-09-15 2008-03-19 DOMPE' pha.r.ma s.p.a. Human anti-folate receptor alpha antibodies and antibody fragments for the radioimmunotherapy of ovarian carcinoma
US20100105136A1 (en) 2006-10-09 2010-04-29 The General Hospital Corporation Chimeric t-cell receptors and t-cells targeting egfrviii on tumors
US9334330B2 (en) 2006-10-10 2016-05-10 Universite De Nantes Use of monoclonal antibodies specific to the O-acetylated form of GD2 ganglioside for the treatment of certain cancers
JP2010509570A (ja) 2006-11-03 2010-03-25 パーデュー・リサーチ・ファウンデーション エクスビボフローサイトメトリーの方法および装置
US9217026B2 (en) 2006-11-13 2015-12-22 Sangamo Biosciences, Inc. Method of inactivating a glucocorticoid receptor gene in an isolated cell
US20080131415A1 (en) 2006-11-30 2008-06-05 Riddell Stanley R Adoptive transfer of cd8 + t cell clones derived from central memory cells
US8748405B2 (en) 2007-01-26 2014-06-10 City Of Hope Methods and compositions for the treatment of cancer or other diseases
US8946385B2 (en) 2007-01-30 2015-02-03 Chugai Seiyaku Kabushiki Kaisha Chimeric Fcγ receptor and method for determination of ADCC activity by using the receptor
EP2126054B1 (en) 2007-01-31 2016-07-06 Yeda Research And Development Company Limited Redirected, genetically-engineered t regulatory cells and their use in suppression of autoimmune and inflammatory disease
US8859229B2 (en) 2007-02-02 2014-10-14 Yale University Transient transfection with RNA
US8865169B2 (en) 2007-02-20 2014-10-21 Tufts University Methods and systems for multi-antibody therapies
CA2682527C (en) 2007-03-30 2017-07-11 Memorial Sloan-Kettering Cancer Center Constitutive expression of costimulatory ligands on adoptively transferred t lymphocytes
WO2009020094A1 (ja) 2007-08-09 2009-02-12 Daiichi Sankyo Company, Limited 疎水性分子で修飾した抗体
WO2009091826A2 (en) 2008-01-14 2009-07-23 The Board Of Regents Of The University Of Texas System Compositions and methods related to a human cd19-specific chimeric antigen receptor (h-car)
WO2009117117A1 (en) 2008-03-19 2009-09-24 Altor Bioscience Corporation T cell receptor fusions and conjugates and methods of use there of
US8450112B2 (en) 2008-04-09 2013-05-28 Maxcyte, Inc. Engineering and delivery of therapeutic compositions of freshly isolated cells
EP2365003A1 (en) 2008-04-11 2011-09-14 Emergent Product Development Seattle, LLC CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof
US20090324630A1 (en) 2008-04-21 2009-12-31 Jensen Michael C Fusion multiviral chimeric antigen
EP4032552B1 (en) 2008-08-26 2023-10-04 City of Hope Method and compositions for enhanced anti-tumor effector functioning of t cells
AU2009293140A1 (en) 2008-09-17 2010-03-25 Endocyte, Inc. Folate receptor binding conjugates of antifolates
CN104195227B (zh) 2008-11-07 2017-04-12 适应生物技术公司 通过序列分析监测状况的方法
US9283184B2 (en) 2008-11-24 2016-03-15 Massachusetts Institute Of Technology Methods and compositions for localized agent delivery
US8877199B2 (en) 2009-05-15 2014-11-04 The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services B cell surface reactive antibodies
US20100322909A1 (en) 2009-06-17 2010-12-23 The University Of Pittsburgh - Of The Commonwealth System Of Higher Education Th1-associated micrornas and their use for tumor immunotherapy
US8465743B2 (en) 2009-10-01 2013-06-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-vascular endothelial growth factor receptor-2 chimeric antigen receptors and use of same for the treatment of cancer
JP5816627B2 (ja) 2009-10-27 2015-11-18 イミュニカム・エイビイ 抗原特異的ｔ細胞の増殖のための方法
US9273283B2 (en) 2009-10-29 2016-03-01 The Trustees Of Dartmouth College Method of producing T cell receptor-deficient T cells expressing a chimeric receptor
WO2011059836A2 (en) 2009-10-29 2011-05-19 Trustees Of Dartmouth College T cell receptor-deficient t cell compositions
DK2496698T3 (en) 2009-11-03 2019-04-15 Hope City TRUNCATED EPIDERIMAL GROWTH FACTOR RECEPTOR (EGFRt) FOR TRUNCATED T-CELL SELECTION
US8956860B2 (en) 2009-12-08 2015-02-17 Juan F. Vera Methods of cell culture for adoptive cell therapy
US8809050B2 (en) 2009-12-08 2014-08-19 Wilson Wolf Manufacturing Methods of cell culture for adoptive cell therapy
DK2529020T3 (en) 2010-01-28 2018-08-06 Childrens Hospital Philadelphia SCALABLE PREPARATION PLATF FOR CLEANING VIRAL VECTORS AND CLEANED VIRAL VECTORS FOR USE IN GENTHERAPY
ES2724451T3 (es) 2010-02-04 2019-09-11 Univ Pennsylvania ICOS regula fundamentalmente la expansión y la función de linfocitos Th17 humanos inflamatorios
US8551715B2 (en) 2010-02-12 2013-10-08 Oncomed Pharmaceuticals, Inc. Methods for identifying and isolating cells expressing a polypeptide
SA111320200B1 (ar) 2010-02-17 2014-02-16 ديبيوفارم اس ايه مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة
EP2558128B1 (en) 2010-04-14 2016-12-21 Roger Williams Medical Center Methods and compositions for treating hiv
ES2686424T5 (es) 2010-05-04 2023-03-27 Yeda Res & Dev Inmunoterapia con células alogénicas redireccionadas
WO2011146862A1 (en) 2010-05-21 2011-11-24 Bellicum Pharmaceuticals, Inc. Methods for inducing selective apoptosis
US9242014B2 (en) 2010-06-15 2016-01-26 The Regents Of The University Of California Receptor tyrosine kinase-like orphan receptor 1 (ROR1) single chain Fv antibody fragment conjugates and methods of use thereof
US9163258B2 (en) 2010-07-23 2015-10-20 Fred Hutchinson Cancer Research Center Method for the treatment of obesity
DE102010036122A1 (de) 2010-09-01 2012-03-01 Nora Systems Gmbh Bodenbelag
US9487800B2 (en) 2010-09-08 2016-11-08 Chemotherapeutisches Forschunginstitut Georg-Speyer-Haus Interleukin 15 as selectable marker for gene transfer in lymphocytes
EP3467101A3 (en) 2010-09-08 2019-06-19 Baylor College of Medicine Immunotherapy of brain tumor using geneticially engineered gd2-specific t cells
ES2754394T3 (es) 2010-09-08 2020-04-17 Chemotherapeutisches Forschungsinstitut Georg Speyer Haus Receptores de antígenos quiméricos con una región bisagra optimizada
CN103124740B (zh) 2010-09-21 2015-09-02 美国卫生和人力服务部 抗-ssx-2t细胞受体和相关材料及使用方法
JP5719443B2 (ja) 2010-09-26 2015-05-20 ダ・ユー・エンタープライジズ、エルエルシー 組換え巨大分子製造方法
US9845362B2 (en) 2010-10-08 2017-12-19 The University Of North Carolina At Charlotte Compositions comprising chimeric antigen receptors, T cells comprising the same, and methods of using the same
WO2012054825A1 (en) 2010-10-22 2012-04-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-mage-a3 t cell receptors and related materials and methods of use
PH12013501201A1 (en) 2010-12-09 2013-07-29 Univ Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
WO2012076059A1 (en) 2010-12-09 2012-06-14 Stichting Het Nederlands Kanker Instituut Immune restricted peptides with increased efficacy
ES2791716T3 (es) 2010-12-14 2020-11-05 Univ Maryland Células T que expresan al receptor de antígeno quimérico antietiqueta universal y métodos para el tratamiento del cáncer
US9402865B2 (en) 2011-01-18 2016-08-02 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cancer
SG193023A1 (en) 2011-02-11 2013-10-30 Sloan Kettering Inst Cancer Hla-restricted, peptide-specific antigen binding proteins
CN110200997A (zh) 2011-03-23 2019-09-06 弗雷德哈钦森癌症研究中心 用于细胞免疫治疗的方法和组合物
EP2502934B1 (en) 2011-03-24 2018-01-17 Universitätsmedizin der Johannes Gutenberg-Universität Mainz Single chain antigen recognizing constructs (scARCs) stabilized by the introduction of novel disulfide bonds
KR20140033029A (ko) 2011-04-01 2014-03-17 메모리얼 슬로안-케터링 캔서 센터 에이치엘에이 에이2에 의해 제공된 더블유티1 펩타이드에 특이적인 티 세포 수용체 유사 항체
EP2694549B1 (en) 2011-04-08 2018-08-15 The United States of America, as represented by The Secretary, Department of Health and Human Services Anti-epidermal growth factor receptor variant iii chimeric antigen receptors and use of same for the treatment of cancer
EP2697367B1 (en) 2011-04-13 2018-12-19 Immunicum AB Method for proliferation of antigen-specific t cells
KR20140043340A (ko) 2011-04-13 2014-04-09 이뮤니쿰 에이비 T 세포의 프라이밍을 위한 방법
CN105968209B (zh) 2011-04-19 2021-08-03 美国政府(由卫生和人类服务部的部长所代表) 对磷脂酰肌醇蛋白聚糖3特异的人单克隆抗体及其用途
GB201108236D0 (en) 2011-05-17 2011-06-29 Ucl Business Plc Method
EP3549611B1 (en) 2011-07-29 2021-06-30 The Trustees of the University of Pennsylvania Switch costimulatory receptors
BR112014004168A2 (pt) 2011-08-23 2017-12-12 Roche Glycart Ag anticorpo biespecífico, composição farmacêutica, uso do anticorpo biespecífico, célula hospedeira procariótica ou eucariótica, método de produção de anticorpo e invenção
US9833476B2 (en) 2011-08-31 2017-12-05 The Trustees Of Dartmouth College NKP30 receptor targeted therapeutics
ES2834070T3 (es) 2011-09-15 2021-06-16 Us Health Receptores de células T que reconocen MAGE restringido por HLA-A1 o HLA-Cw7
WO2013040557A2 (en) 2011-09-16 2013-03-21 The Trustees Of The University Of Pennsylvania Rna engineered t cells for the treatment of cancer
EP3692794A1 (en) 2011-09-16 2020-08-12 Baylor College of Medicine Targeting the tumor microenvironment using manipulated nkt cells
US9708384B2 (en) 2011-09-22 2017-07-18 The Trustees Of The University Of Pennsylvania Universal immune receptor expressed by T cells for the targeting of diverse and multiple antigens
WO2013051718A1 (ja) 2011-10-07 2013-04-11 国立大学法人三重大学 キメラ抗原受容体
WO2013059593A1 (en) 2011-10-20 2013-04-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-cd22 chimeric antigen receptors
JP6074435B2 (ja) 2011-10-26 2017-02-01 ナショナル キャンサー センター 変異ｃｔｌａ４遺伝子移入ｔ細胞及びこれを含む抗がん免疫治療用組成物
WO2013063019A1 (en) 2011-10-28 2013-05-02 The Wistar Institute Of Anatomy And Biology Methods and compositions for enhancing the therapeutic effect of anti-tumor t cells
WO2013063419A2 (en) 2011-10-28 2013-05-02 The Trustees Of The University Of Pennsylvania A fully human, anti-mesothelin specific chimeric immune receptor for redirected mesothelin-expressing cell targeting
WO2013067492A1 (en) 2011-11-03 2013-05-10 The Trustees Of The University Of Pennsylvania Isolated b7-h4 specific compositions and methods of use thereof
WO2013070468A1 (en) 2011-11-08 2013-05-16 The Trustees Of The University Of Pennsylvania Glypican-3-specific antibody and uses thereof
KR102134932B1 (ko) 2011-11-11 2020-07-17 프레드 헛친슨 켄서 리서치 센터 암을 위한 사이클린 ａ１―표적화된 ｔ―세포 면역요법
PH12014501360B1 (en) 2011-12-16 2022-05-20 Targetgene Biotechnologies Ltd Compositions and methods for modifying a predetermined target nucleic acid sequence
JP2015502397A (ja) 2011-12-23 2015-01-22 ファイザー・インク 部位特異的コンジュゲーションのための操作された抗体定常領域、ならびにそのための方法および使用
US20140370012A1 (en) 2012-01-27 2014-12-18 Gliknik Inc. Fusion proteins comprising igg2 hinge domains
JP6850528B2 (ja) 2012-02-13 2021-03-31 シアトル チルドレンズ ホスピタル ドゥーイング ビジネス アズ シアトル チルドレンズ リサーチ インスティテュート 二重特異性キメラ抗原受容体およびその治療的使用
MX2014010185A (es) 2012-02-22 2014-11-14 Univ Pennsylvania Uso de dominio de señalizacion cd2 en receptores de antigeno quimericos de segunda generacion.
WO2013126726A1 (en) 2012-02-22 2013-08-29 The Trustees Of The University Of Pennsylvania Double transgenic t cells comprising a car and a tcr and their methods of use
CA3205751A1 (en) 2012-02-22 2013-08-29 The Trustees Of The University Of Pennsylvania Use of icos-based cars to enhance antitumor activity and car persistence
US9359447B2 (en) 2012-03-23 2016-06-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-mesothelin chimeric antigen receptors
EA033110B1 (ru) 2012-04-11 2019-08-30 Дзе Юнайтед Стейтс Оф Америка, Эз Репрезентед Бай Дзе Секретари, Департмент Оф Хелс Энд Хьюман Сёрвисез Химерный рецептор антигена, направленный на антиген созревания b-клеток, кодирующая его нуклеиновая кислота, соответствующие экспрессионный вектор, клетка-хозяин, применения и способы
US9156915B2 (en) 2012-04-26 2015-10-13 Thomas Jefferson University Anti-GCC antibody molecules
SG10201609210SA (en) 2012-05-03 2016-12-29 Hutchinson Fred Cancer Res Enhanced affinity t cell receptors and methods for making the same
ES2719495T5 (en) 2012-05-07 2025-09-10 Dartmouth College Anti-b7-h6 antibody, fusion proteins, and methods of using the same
CN104718188B (zh) 2012-05-22 2018-08-21 基因泰克公司 N-取代的苯甲酰胺类及其在治疗疼痛中的用途
JP6378172B2 (ja) 2012-05-22 2018-08-22 アメリカ合衆国 マウス抗ｎｙ−ｅｓｏ−１ｔ細胞受容体
KR102437522B1 (ko) 2012-05-25 2022-08-26 셀렉티스 면역요법을 위한 동종이형 및 면역억제제 저항성인 ｔ 세포의 조작 방법
SG11201407972RA (en) 2012-06-01 2015-01-29 Us Health High-affinity monoclonal antibodies to glypican-3 and use thereof
KR20150013935A (ko) 2012-06-08 2015-02-05 갓코 호진 긴키 다이가쿠 트랜스포터에 대한 항체 및 이의 용도
JP5863585B2 (ja) 2012-07-11 2016-02-16 三菱電機株式会社 大信号等価回路モデルを用いたトランジスタ特性計算装置
LT4461308T (lt) 2012-07-13 2025-06-10 The Trustees Of The University Of Pennsylvania Car priešnavikinio aktyvumo toksiškumo valdymas
KR20150029714A (ko) 2012-07-13 2015-03-18 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 이중특이적 항체의 공-도입에 의한 ｃａｒ 세포의 활성 증강
AU2013289979A1 (en) 2012-07-13 2015-01-22 The Trustees Of The University Of Pennsylvania Methods of assessing the suitability of transduced T cells for administration
CN104507537A (zh) 2012-07-13 2015-04-08 宾夕法尼亚大学董事会 用于调节car t细胞的组合物和方法
CN102775500A (zh) 2012-08-03 2012-11-14 郑骏年 嵌合抗原受体iRGD-scFv(G250)-CD8-CD28-CD137-CD3ζ及其用途
CA2881981A1 (en) 2012-08-20 2014-02-27 Fred Hutchinson Cancer Research Center Method and compositions for cellular immunotherapy
US9409992B2 (en) 2012-08-21 2016-08-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Mesothelin domain-specific monoclonal antibodies and use thereof
CN104769103B (zh) 2012-09-04 2018-06-08 塞勒克提斯公司 多链嵌合抗原受体和其用途
IL286786B (en) 2012-09-14 2022-09-01 The Us Secretary Department Of Health And Human Services Office Of Technology Transfer National Inst T cell receptors that recognize mhc mage–a3 are restricted type ii
CN104955845B (zh) 2012-09-27 2018-11-16 美国政府(由卫生和人类服务部的部长所代表) 间皮素抗体和引起有效的抗肿瘤活性的方法
WO2014055442A2 (en) 2012-10-01 2014-04-10 The Trustees Of The University Of Pennsylvania Compositions and methods for targeting stromal cells for the treatment of cancer
AU2013327136A1 (en) 2012-10-02 2015-04-16 Memorial Sloan-Kettering Cancer Center Compositions and methods for immunotherapy
US9598489B2 (en) 2012-10-05 2017-03-21 The Trustees Of The Univeristy Of Pennsylvania Human alpha-folate receptor chimeric antigen receptor
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
EP2906684B8 (en) 2012-10-10 2020-09-02 Sangamo Therapeutics, Inc. T cell modifying compounds and uses thereof
US20140120136A1 (en) 2012-10-12 2014-05-01 The Babraham Institute Mir-155 enhancement of cd8+ t cell immunity
UY35103A (es) 2012-10-29 2014-05-30 Glaxo Group Ltd Compuestos de cefem 2-sustituidos
EP2934532B1 (en) 2012-12-20 2019-10-23 Purdue Research Foundation Chimeric antigen receptor-expressing t cells as anti-cancer therapeutics
AU2013204922B2 (en) 2012-12-20 2015-05-14 Celgene Corporation Chimeric antigen receptors
WO2014099671A1 (en) 2012-12-20 2014-06-26 Bluebird Bio, Inc. Chimeric antigen receptors and immune cells targeting b cell malignancies
EP2948544A4 (en) 2013-01-28 2016-08-03 St Jude Childrens Res Hospital CHIMERIC RECEPTOR WITH NKG2D SPECIFICITY FOR CELL THERAPY AGAINST CANCER AND INFECTION DISEASES
SG11201507026WA (en) 2013-02-06 2015-10-29 Anthrogenesis Corp Modified t lymphocytes having improved specificity
JO3529B1 (ar) 2013-02-08 2020-07-05 Amgen Res Munich Gmbh مضاد التصاق خلايا الدم البيض من أجل التخفيف من الاثار السلبية الممكنة الناتجة عن مجالات ارتباط cd3- المحدد
EP4303232A3 (en) 2013-02-15 2024-04-17 The Regents of The University of California Chimeric antigen receptor and methods of use thereof
TW201446794A (zh) 2013-02-20 2014-12-16 Novartis Ag 利用抗－ｃｄ１２３嵌合抗原受體工程化ｔ細胞之初級人類白血病有效靶向
DK2958943T3 (da) 2013-02-20 2019-12-09 Univ Pennsylvania Behandling af cancer ved anvendelse af humaniseret anti-EGFRvIII kimær antigenreceptor
US9434935B2 (en) 2013-03-10 2016-09-06 Bellicum Pharmaceuticals, Inc. Modified caspase polypeptides and uses thereof
CN105283201B (zh) 2013-03-14 2019-08-02 斯克利普斯研究所 靶向剂抗体偶联物及其用途
WO2014151960A2 (en) 2013-03-14 2014-09-25 Bellicum Pharmaceuticals, Inc. Methods for controlling t cell proliferation
US9587237B2 (en) 2013-03-14 2017-03-07 Elwha Llc Compositions, methods, and computer systems related to making and administering modified T cells
US9499855B2 (en) 2013-03-14 2016-11-22 Elwha Llc Compositions, methods, and computer systems related to making and administering modified T cells
US9402888B2 (en) 2013-03-14 2016-08-02 The Wistar Institute Of Anatomy And Biology Methods and compositions for treating cancer
US9393268B2 (en) 2013-03-15 2016-07-19 Thomas Jefferson University Cell-based anti-cancer compositions with reduced toxicity and methods of making and using the same
US9446105B2 (en) 2013-03-15 2016-09-20 The Trustees Of The University Of Pennsylvania Chimeric antigen receptor specific for folate receptor β
US9561291B2 (en) 2013-03-15 2017-02-07 Imre Kovesdi Methods of targeting T-cells to tumors
AU2014240083C1 (en) 2013-03-15 2019-10-24 Celgene Corporation Modified T lymphocytes
EP2970426B1 (en) 2013-03-15 2019-08-28 Michael C. Milone Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US9657105B2 (en) 2013-03-15 2017-05-23 City Of Hope CD123-specific chimeric antigen receptor redirected T cells and methods of their use
UY35468A (es) 2013-03-16 2014-10-31 Novartis Ag Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19
WO2014160627A1 (en) 2013-03-25 2014-10-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-cd276 polypeptides, proteins, and chimeric antigen receptors
EP3783098A1 (en) 2013-05-14 2021-02-24 Board Of Regents, The University Of Texas System Human application of engineered chimeric antigen receptor (car) t-cells
CN105683376A (zh) 2013-05-15 2016-06-15 桑格摩生物科学股份有限公司 用于治疗遗传病状的方法和组合物
AU2014268364A1 (en) 2013-05-24 2015-12-10 Board Of Regents, The University Of Texas System Chimeric antigen receptor-targeting monoclonal antibodies
ES2883131T3 (es) 2013-05-29 2021-12-07 Cellectis Métodos para la modificación de células T para inmunoterapia utilizando el sistema de nucleasa CAS guiado por ARN
WO2014191128A1 (en) 2013-05-29 2014-12-04 Cellectis Methods for engineering t cells for immunotherapy by using rna-guided cas nuclease system
CA2912172A1 (en) 2013-06-05 2014-12-11 Bellicum Pharmaceuticals, Inc. Methods for inducing partial apoptosis using caspase polypeptides
WO2014200891A1 (en) 2013-06-11 2014-12-18 THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTEMENT OF HEALTH & HUMAN SERVICES Her2-specific monoclonal antibodies and conjugates thereof
MX377858B (es) 2013-06-25 2025-03-11 Vaccinex Inc Combinación de moleculas inhibidoras de semaforina-4d con agentes inmunomoduladores y usos de los mismos.
KR102271498B1 (ko) 2013-08-30 2021-07-05 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 종양 치료를 위한 키누레닌 고갈 효소의 투여
US20150073154A1 (en) 2013-09-11 2015-03-12 Equip, Llc Discrete PEG Based Dyes
CN105813654B (zh) 2013-10-11 2019-05-31 美国政府(由卫生和人类服务部的部长所代表) Tem8抗体及其用途
KR102339240B1 (ko) 2013-10-15 2021-12-15 더 스크립스 리서치 인스티튜트 펩타이드 키메라 항원 수용체 t 세포 스위치 및 이의 용도
EP3057991B8 (en) * 2013-10-15 2019-09-04 The Scripps Research Institute Chimeric antigen receptor t cell switches and uses thereof
US10144770B2 (en) 2013-10-17 2018-12-04 National University Of Singapore Chimeric receptors and uses thereof in immune therapy
MX389160B (es) 2013-10-31 2025-03-20 Hutchinson Fred Cancer Res Células no t efectoras y madre/progenitoras hematopoyéticas modificadas y usos de estas.
US20160333108A1 (en) 2014-01-13 2016-11-17 Stephen J. Forman CHIMERIC ANTIGEN RECEPTORS (CARs) HAVING MUTATIONS IN THE FC SPACER REGION AND METHODS FOR THEIR USE
ES2701846T3 (es) 2014-01-14 2019-02-26 Cellectis Receptor de antígeno quimérico que usa dominios de reconocimiento de antígenos derivados de pez cartilaginoso
US9694033B2 (en) 2014-01-24 2017-07-04 The Cleveland Clinic Foundation IL-9 secreting CD8+ Tc9 cells and methods of treating cancer
US10934346B2 (en) 2014-02-14 2021-03-02 Bellicum Pharmaceuticals, Inc. Modified T cell comprising a polynucleotide encoding an inducible stimulating molecule comprising MyD88, CD40 and FKBP12
CA2939093A1 (en) 2014-02-14 2015-08-20 Immune Design Corp. Immunotherapy of cancer through combination of local and systemic immune stimulation
WO2015126548A1 (en) 2014-02-21 2015-08-27 Ibc Pharmaceuticals, Inc. Disease therapy by inducing immune response to trop-2 expressing cells
WO2015127548A1 (en) 2014-02-28 2015-09-03 The Royal Institution For The Advancement Of Learning / Mcgill University Tc-ptp inhibitors as apc activators for immunotherapy
KR101605421B1 (ko) 2014-03-05 2016-03-23 국립암센터 B 세포 림프종 세포를 특이적으로 인지하는 단일클론항체 및 이의 용도
GB201403875D0 (en) 2014-03-05 2014-04-16 Cantargia Ab Novel antibodies and uses thereof
CA2940460A1 (en) 2014-03-07 2015-09-11 Bellicum Pharmaceuticals, Inc. Caspase polypeptides having modified activity and uses thereof
EP3593812A3 (en) 2014-03-15 2020-05-27 Novartis AG Treatment of cancer using chimeric antigen receptor
US20170081411A1 (en) 2014-03-15 2017-03-23 Novartis Ag Regulatable chimeric antigen receptor
AU2015244039B2 (en) 2014-04-07 2021-10-21 Novartis Ag Treatment of cancer using anti-CD19 chimeric antigen receptor
WO2015157299A2 (en) 2014-04-09 2015-10-15 Seattle Children's Hospital (Dba Seattle Children's Research Institute Inhibition of lactate dehydrogenase 5 (ldh-5) binding, incorporation, internalization and/or endocytosis to immune cells
CA2945320A1 (en) 2014-04-10 2015-10-15 Seattle Children's Hospital (dba Seattle Children's Research Institute) Drug regulated transgene expression
KR20160145802A (ko) 2014-04-23 2016-12-20 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 요법에 사용하기 위한 키메라 항원 수용체 (car) 및 이의 제조 방법
WO2015167766A1 (en) 2014-04-29 2015-11-05 Seattle Children's Hospital (dba Seattle Children's Research Institute) Ccr5 disruption of cells expressing anti-hiv chimeric antigen receptor (car) derived from broadly neutralizing antibodies
US20170210818A1 (en) 2014-06-06 2017-07-27 The California Institute For Biomedical Research Constant region antibody fusion proteins and compositions thereof
US9885021B2 (en) 2014-06-12 2018-02-06 Children's National Medical Center Generation of broadly-specific, virus-immune cells targeting multiple HIV antigens for preventive and therapeutic use
KR20170037625A (ko) 2014-07-21 2017-04-04 노파르티스 아게 Cll-1 키메라 항원 수용체를 사용한 암의 치료
SG10201913765YA (en) 2014-07-21 2020-03-30 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
TWI750110B (zh) 2014-07-21 2021-12-21 瑞士商諾華公司 使用人類化抗-ｂｃｍａ嵌合抗原受體治療癌症
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
US11141494B2 (en) 2014-08-09 2021-10-12 Purdue Research Foundation Development of neurokinin-1 receptor-binding agent delivery conjugates
WO2016025454A2 (en) 2014-08-12 2016-02-18 Anthrogenesis Corporation Car-t lymphocytes engineered to home to lymph node b cell zone, skin, or gastrointestinal tract
ES2791248T3 (es) 2014-08-19 2020-11-03 Novartis Ag Receptor antigénico quimérico (CAR) anti-CD123 para su uso en el tratamiento del cáncer
US10888608B2 (en) 2014-09-02 2021-01-12 Bellicum Pharmaceuticals, Inc. Costimulation of chimeric antigen receptors by MyD88 and CD40 polypeptides
CN107002084B (zh) 2014-09-19 2021-09-10 希望之城公司 靶向IL13Rα2的共刺激嵌合抗原受体T细胞
WO2016054520A2 (en) 2014-10-03 2016-04-07 The California Institute For Biomedical Research Engineered cell surface proteins and uses thereof
DK3204399T3 (da) 2014-10-09 2025-02-24 Seattle Childrens Hospital Dba Seattle Childrens Res Inst Lange poly (a)-plasmider og fremgangsmåder til indføring af lange poly (a)-sekvenser i plasmidet
WO2016061133A1 (en) 2014-10-14 2016-04-21 Riptide Bioscience, Inc. Peptides having anti-inflammatory properties
JP7523203B2 (ja) 2014-10-31 2024-07-26 マサチューセッツ インスティテュート オブ テクノロジー 生体分子の免疫細胞への送達
AU2015343013B2 (en) 2014-11-05 2020-07-16 Board Of Regents, The University Of Texas System Gene modified immune effector cells and engineered cells for expansion of immune effector cells
US9879087B2 (en) 2014-11-12 2018-01-30 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
WO2016077761A1 (en) 2014-11-14 2016-05-19 Massachusetts Institute Of Technology Disruption and field enabled delivery of compounds and compositions into cells
CN107708702A (zh) 2014-11-17 2018-02-16 塞勒克塔生物科学有限公司 磷脂醚类似物作为靶向癌症的药物载体
SG10202103475XA (en) 2014-12-02 2021-05-28 Prospect Chartercare Rwmc Llc Methods and compositons for treating cancer
BR112017011893A2 (pt) 2014-12-05 2018-07-24 City Of Hope células t modificadas no receptor de antígeno quimérico direcionado para cs1
CA2966234A1 (en) 2014-12-15 2016-06-23 Bellicum Pharmaceuticals, Inc. Methods for controlled elimination of therapeutic cells
HK1245827B (en) 2014-12-15 2020-06-19 Board Of Regents Of The University Of Texas System Methods for controlled activation or elimination of therapeutic cells
EP4400516A1 (en) 2014-12-15 2024-07-17 The Regents of the University of California Bispecific or-gate chimeric antigen receptor responsive to cd19 and cd20
US20190054117A1 (en) 2014-12-19 2019-02-21 Novartis Ag Dimerization switches and uses thereof
KR102376244B1 (ko) 2014-12-24 2022-03-21 오토러스 리미티드 세포
CA3197849A1 (en) 2014-12-29 2016-07-07 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
US20180021378A1 (en) 2014-12-31 2018-01-25 Anthrogenesis Corporation Methods of treating hematological disorders, solid tumors, or infectious diseases using natural killer cells
US9765330B1 (en) 2015-01-09 2017-09-19 Nant Holdings Ip, Llc Compositions and methods for reduction of allograft recognition and rejection
US11512289B2 (en) 2015-02-18 2022-11-29 Enlivex Therapeutics Rdo Ltd Combination immune therapy and cytokine control therapy for cancer treatment
WO2016138034A1 (en) 2015-02-24 2016-09-01 The Regents Of The University Of California Binding-triggered transcriptional switches and methods of use thereof
KR102133857B1 (ko) 2015-03-02 2020-07-20 이노베이티브 셀룰러 테라퓨틱스 코퍼레이션 리미티드 Ｐｄ－ｌ１에 의해 유도된 면역관용의 감소
WO2016149254A1 (en) 2015-03-17 2016-09-22 Chimera Bioengineering, Inc. Smart car devices, de car polypeptides, side cars and uses thereof
CA2984624A1 (en) 2015-03-18 2016-09-22 Baylor College Of Medicine Her2/erbb2 chimeric antigen receptor
US9717745B2 (en) 2015-03-19 2017-08-01 Zhejiang DTRM Biopharma Co. Ltd. Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases
WO2016154621A1 (en) 2015-03-26 2016-09-29 The California Institute For Biomedical Research SWITCHABLE NON-scFv CHIMERIC RECEPTORS, SWITCHES, AND USES THEREOF
WO2016154628A1 (en) 2015-03-26 2016-09-29 Xiuli Wang Bi-specific targeted chimeric antigen receptor t cells
GB201505305D0 (en) 2015-03-27 2015-05-13 Immatics Biotechnologies Gmbh Novel Peptides and combination of peptides for use in immunotherapy against various tumors
WO2016168773A2 (en) 2015-04-15 2016-10-20 The California Institute For Biomedical Research Optimized pne-based chimeric receptor t cell switches and uses thereof
WO2016168769A1 (en) 2015-04-15 2016-10-20 The California Institute For Biomedical Research Chimeric receptor t cell switches for her2
PT3294764T (pt) 2015-05-15 2021-02-15 Hope City Composições de recetores de antigénios quiméricos
CA2985087C (en) 2015-05-19 2021-02-16 Morphogenesis, Inc. Cancer vaccine comprising mrna encoding a m-like-protein
IL295224B2 (en) 2015-05-28 2025-07-01 Kite Pharma Inc Methods of conditioning patients for t cell therapy
CN107708741A (zh) 2015-06-12 2018-02-16 免疫医疗公司 用嵌合抗原受体(car)构建体和表达car构建体的t细胞(car‑t)或nk细胞(car‑nk)进行的疾病疗法
US9663756B1 (en) 2016-02-25 2017-05-30 Flodesign Sonics, Inc. Acoustic separation of cellular supporting materials from cultured cells
WO2016210447A1 (en) 2015-06-26 2016-12-29 University Of Southern California Masking chimeric antigen receptor t cells for tumor-specific activation
GB201514328D0 (en) 2015-08-12 2015-09-23 Sigmoid Pharma Ltd Compositions
GB201514875D0 (en) 2015-08-20 2015-10-07 Autolus Ltd Receptor
GB201514874D0 (en) 2015-08-20 2015-10-07 Autolus Ltd Cell
WO2017035362A1 (en) 2015-08-26 2017-03-02 Achillion Pharmaceuticals, Inc. Use of complement pathway inhibitor compounds to mitigate adoptive t-cell therapy associated adverse immune responses
CN108243607A (zh) 2015-09-09 2018-07-03 西雅图儿童医院（Dba西雅图儿童研究所） 用于免疫疗法的巨噬细胞的遗传工程
US9790467B2 (en) 2015-09-22 2017-10-17 Qt Holdings Corp Methods and compositions for activation or expansion of T lymphocytes
CN117070468A (zh) 2015-10-05 2023-11-17 精密生物科学公司 包含经修饰的人T细胞受体α恒定区基因的经遗传修饰的细胞
BR112018006991A2 (en) 2015-10-06 2018-10-16 City Of Hope psca-targeted chimeric antigen receptors
GB201518817D0 (en) 2015-10-23 2015-12-09 Autolus Ltd Cell
GB201518816D0 (en) 2015-10-23 2015-12-09 Autolus Ltd Receptor
US20180320133A1 (en) 2015-11-05 2018-11-08 City Of Hope Methods for preparing cells for adoptive t cell therapy
WO2017083274A1 (en) 2015-11-09 2017-05-18 Seattle Children's Hospital (dba Seattle Children's Research Institute) Novel rna-based vector system for transient and stable gene expression
TWI734715B (zh) 2015-11-19 2021-08-01 美商卡默森屈有限公司 趨化因子受體調節劑
TWI724056B (zh) 2015-11-19 2021-04-11 美商卡默森屈有限公司 Ｃｘｃｒ２抑制劑
JP2019506143A (ja) 2015-12-14 2019-03-07 ベリカム ファーマシューティカルズ， インコーポレイテッド 治療用細胞の活性化及び排除のための二重コントロール
US9849092B2 (en) 2015-12-21 2017-12-26 Gholam A. Peyman Early cancer detection and enhanced immunotherapy
AU2016382512A1 (en) 2015-12-30 2018-07-12 Novartis Ag Immune effector cell therapies with enhanced efficacy
JP7068169B2 (ja) 2016-01-08 2022-05-16 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 条件付活性ヘテロ二量体ポリペプチド及びその使用方法
WO2017123559A2 (en) 2016-01-11 2017-07-20 The Board Of Trustees Of The Leland Stanford Junior University Chimeric proteins and methods of regulating gene expression
WO2017123548A1 (en) 2016-01-14 2017-07-20 Seattle Children's Hospital (dba Seattle Children's Research Institute) Tumor-specific ifna secretion by car t-cells to reprogram the solid tumor microenvironment
ES2879700T3 (es) 2016-02-05 2021-11-22 Hope City Administración de células T genomanipuladas para el tratamiento de cánceres en el sistema nervioso central
GB201602563D0 (en) 2016-02-12 2016-03-30 Autolus Ltd Signalling system
GB201602571D0 (en) 2016-02-12 2016-03-30 Autolus Ltd Signalling system
JP2019508036A (ja) 2016-02-16 2019-03-28 ダナ−ファーバー キャンサー インスティテュート，インコーポレイテッド 免疫療法組成物及び方法
EP3416690A4 (en) 2016-02-19 2020-02-19 City of Hope SPECIFIC APTAMER
IL261713B2 (en) 2016-03-19 2023-09-01 F1 Oncology Inc Methods and preparations for the transfer of lymphocytes and their regulated expansion
US11111505B2 (en) 2016-03-19 2021-09-07 Exuma Biotech, Corp. Methods and compositions for transducing lymphocytes and regulating the activity thereof
KR20190021200A (ko) 2016-03-22 2019-03-05 시애틀 칠드런즈 호스피탈 디/비/에이 시애틀 칠드런즈 리서치 인스티튜트 독성을 예방 또는 경감시키기 위한 조기 개재 방법
JP7282521B2 (ja) 2016-04-08 2023-05-29 パーデュー・リサーチ・ファウンデイション Ｃａｒ ｔ細胞療法のための方法および組成物
EP3443001B1 (en) 2016-04-11 2025-04-30 Obsidian Therapeutics, Inc. REGULATED BIOCIRCUIT SYSTEMS
KR20250084978A (ko) 2016-06-06 2025-06-11 시티 오브 호프 Baff-r 표적 키메라 항원 수용체-변형된 t 세포 및 그 용도
CN116041514A (zh) 2016-06-06 2023-05-02 希望之城 Baff-r抗体及其用途
GB201610515D0 (en) 2016-06-16 2016-08-03 Autolus Ltd Cell
GB201610512D0 (en) 2016-06-16 2016-08-03 Autolus Ltd Chimeric antigen receptor
US9567399B1 (en) 2016-06-20 2017-02-14 Kymab Limited Antibodies and immunocytokines
CN115404196A (zh) 2016-07-13 2022-11-29 哈佛学院院长等 抗原呈递细胞模拟支架及其制备和使用方法
WO2018031694A1 (en) 2016-08-09 2018-02-15 City Of Hope Chimeric poxvirus compositions and uses thereof
US9642906B2 (en) 2016-09-16 2017-05-09 Baylor College Of Medicine Generation of HPV-specific T-cells
CN110267982B (zh) 2016-10-19 2024-02-23 斯克利普斯研究所 具有人源化靶向部分和/或经过优化的嵌合抗原受体相互作用结构域的嵌合抗原受体效应细胞开关以及其用途
EP3529353A4 (en) 2016-10-19 2020-05-13 City of Hope USE OF TRIPLEX-CMV VACCINE IN CAR-T-CELL THERAPY
WO2018075813A1 (en) 2016-10-19 2018-04-26 City Of Hope Use of endogenous viral vaccine in chimeric antigen receptor t cell therapy
US10617720B2 (en) 2016-10-20 2020-04-14 Miltenyi Biotech, GmbH Chimeric antigen receptor specific for tumor cells
CN110139675B (zh) 2016-10-31 2023-09-29 西雅图儿童医院（Dba西雅图儿童研究所） 用具有工程化稳定的内源性foxp3基因表达的cd4t细胞治疗自身免疫疾病的方法
WO2018102761A1 (en) 2016-12-02 2018-06-07 City Of Hope Methods for manufacturing and expanding t cells expressing chimeric antigen receptors and other receptors
CN110291200B (zh) 2016-12-12 2024-05-14 西雅图儿童医院（Dba西雅图儿童研究所） 对哺乳动物细胞中转基因表达的药剂配体诱导具有增大的灵敏度的嵌合转录因子变异体
JP7206214B2 (ja) 2016-12-13 2023-01-17 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） インビトロ及びインビボで操作された細胞において発現された化学誘導シグナル伝達複合体の外因性薬物活性化の方法
EP3336107A1 (en) 2016-12-15 2018-06-20 Miltenyi Biotec GmbH Immune cells expressing an antigen binding receptor and a chimeric costimulatory receptor
US11590214B2 (en) 2016-12-21 2023-02-28 Danmarks Tekniskte Universitet Antigen presenting scaffolds for immune-cell manipulation
CN110612119B (zh) 2017-02-07 2024-10-29 西雅图儿童医院（Dba西雅图儿童研究所） 磷脂醚(ple)car t细胞肿瘤靶向(ctct)剂
CN110662839A (zh) 2017-02-17 2020-01-07 珀杜研究基金会 用于细胞疗法的基于靶向性配体-有效负载的药物递送
JP7178355B2 (ja) 2017-02-28 2022-11-25 エンドサイト・インコーポレイテッド Ｃａｒ ｔ細胞療法のための組成物および方法
WO2018165194A1 (en) 2017-03-06 2018-09-13 University Of Washington Engineered cells and agent compositions for therapeutic agent delivery and treatments using same
US20200405881A1 (en) 2017-03-06 2020-12-31 University Of Washington Cell based methods and compositions for therapeutic agent delivery and treatments using same
US11939594B2 (en) 2017-03-16 2024-03-26 Seattle Children's Hospital Engraftable cell-based immunotherapy for long-term delivery of therapeutic proteins
AU2018240111A1 (en) 2017-03-20 2019-10-10 City Of Hope CS1 targeted chimeric antigen receptor-modified T cells for treatment of AL amyloidosis
CN118147137A (zh) 2017-05-17 2024-06-07 西雅图儿童医院（Dba西雅图儿童研究所） 生成哺乳动物t细胞活化诱导型合成启动子(syn+pro)以改善t细胞疗法
KR20200038490A (ko) 2017-08-01 2020-04-13 시티 오브 호프 항-il1rap 항체
WO2019033050A1 (en) 2017-08-11 2019-02-14 City Of Hope BISPECIFIC MOLECULE FOR BINDING TO ANTIGEN
JP7549303B2 (ja) 2018-01-22 2024-09-11 エンドサイト・インコーポレイテッド Ｃａｒ ｔ細胞の使用方法
SG11202007426XA (en) 2018-02-06 2020-09-29 Seattle Childrens Hospital Dba Seattle Childrens Res Inst Fluorescein-specific cars exhibiting optimal t cell function against fl-ple labelled tumors
CN112105382A (zh) 2018-02-23 2020-12-18 恩多塞特公司 用于car t细胞疗法的顺序方法
CN112262214A (zh) 2018-04-12 2021-01-22 优莫佳生物制药股份有限公司 病毒载体及包装细胞系
CA3091490A1 (en) 2018-04-27 2019-10-31 Seattle Children's Hospital (dba Seattle Children's Research Institute) Rapamycin resistant cells
KR20210074274A (ko) 2018-08-06 2021-06-21 시애틀 칠드런즈 호스피탈 디/비/에이 시애틀 칠드런즈 리서치 인스티튜트 합텐 표지된 세포로의 키메라 항원 수용체 t 세포의 자극을 위한 방법 및 조성물
KR20210042125A (ko) 2018-08-07 2021-04-16 퍼듀 리서치 파운데이션 Car t 세포의 회생
WO2020106992A1 (en) 2018-11-21 2020-05-28 Umoja Biopharma, Inc. Multicistronic vector for surface engineering lentiviral particles
CN114340643A (zh) 2019-07-05 2022-04-12 普渡研究基金会 用于car-t细胞治疗的脂质-荧光素缀合物的设计和有效合成
WO2021055641A1 (en) 2019-09-17 2021-03-25 Purdue Research Foundation Fibroblast activation protein (fap)-targeted imaging and therapy of cancers and other fibrotic and inflammatory diseases
US20240122978A1 (en) 2019-10-16 2024-04-18 Umoja Biopharma, Inc. Retroviral vector for univeral receptor therapy
US20230348624A1 (en) 2020-01-30 2023-11-02 Umoja Biopharma, Inc. Bispecific transduction enhancer
IL295074A (en) 2020-02-04 2022-09-01 Seattle Childrens Hospital Dba Seattle Childrens Res Inst Methods and compositions for stimulation of t cells with a chimeric receptor receptor by hapten-labeled cells
AU2021217003A1 (en) 2020-02-04 2022-09-15 Seattle Children's Hospital (dba Seattle Children's Research Institute) Anti-dinitrophenol chimeric antigen receptors
US20240058458A1 (en) 2020-03-06 2024-02-22 Purdue Research Foundation Methods, compounds, and compositions for modifying car-t cell activity
WO2022015955A1 (en) 2020-07-16 2022-01-20 Umoja Biopharma, Inc. Gated adapter targeting receptor
CA3199588A1 (en) 2020-11-20 2022-05-27 Andrew Scharenberg Vector system for delivery of multiple polynucleotides and uses thereof
MX2023008831A (es) 2021-01-27 2023-10-19 Umoja Biopharma Inc Lentivirus para generar células que expresan receptores de antígeno quimérico anti-cd19.
US20250354118A1 (en) 2022-06-09 2025-11-20 Umoja Biopharma, Inc. Compositions and methods for nk cell differentiation

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12150981B2 (en) 2012-12-20 2024-11-26 Purdue Research Foundation Chimeric antigen receptor-expressing T cells as anti-cancer therapeutics
US11225520B2 (en) 2016-02-16 2022-01-18 Dana-Farber Cancer Institute, Inc. Immunotherapy compositions and methods
EP3429637A4 (en) * 2016-03-16 2020-03-11 Endocyte, Inc. CARBOANHYDRASE IX INHIBITOR CONJUGATES AND USES THEREOF
EP3429575A4 (en) * 2016-03-16 2019-10-23 Purdue Research Foundation AGAINST CARBOANHYDRASE-IX DRUGS AND METHODS
US11925696B2 (en) 2016-03-16 2024-03-12 Purdue Research Foundation Carbonic anhydrase IX targeting agents and methods
US12144850B2 (en) 2016-04-08 2024-11-19 Purdue Research Foundation Methods and compositions for car T cell therapy
US11649288B2 (en) 2017-02-07 2023-05-16 Seattle Children's Hospital Phospholipid ether (PLE) CAR T cell tumor targeting (CTCT) agents
WO2018160622A1 (en) * 2017-02-28 2018-09-07 Endocyte, Inc. Compositions and methods for car t cell therapy
CN110582288B (zh) * 2017-02-28 2024-09-20 恩多塞特公司 用于car t细胞疗法的组合物和方法
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
CN110582288A (zh) * 2017-02-28 2019-12-17 恩多塞特公司 用于car t细胞疗法的组合物和方法
JP2024086826A (ja) * 2017-12-24 2024-06-28 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ－７、及びｃｃｌ１９を発現する免疫担当細胞
JP7475088B2 (ja) 2017-12-24 2024-04-26 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ－７、及びｃｃｌ１９を発現する免疫担当細胞
JPWO2019124468A1 (ja) * 2017-12-24 2021-01-21 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ−７、及びｃｃｌ１９を発現する免疫担当細胞
JP7233720B2 (ja) 2017-12-24 2023-03-07 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ－７、及びｃｃｌ１９を発現する免疫担当細胞
JP2023053328A (ja) * 2017-12-24 2023-04-12 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ－７、及びｃｃｌ１９を発現する免疫担当細胞
JP7696658B2 (ja) 2017-12-24 2025-06-23 ノイルイミューン・バイオテック株式会社 ヒトメソセリンを特異的に認識する細胞表面分子、ｉｌ－７、及びｃｃｌ１９を発現する免疫担当細胞
JP2021511826A (ja) * 2018-01-22 2021-05-13 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 Ｃａｒ ｔ細胞の使用方法
JP2024174886A (ja) * 2018-01-22 2024-12-17 エンドサイト・インコーポレイテッド Ｃａｒ ｔ細胞の使用方法
AU2019209428B2 (en) * 2018-01-22 2025-06-26 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
AU2019209432B2 (en) * 2018-01-22 2026-01-08 Seattle Children's Hospital (dba Seattle Children's Research Institute) Methods of use for CAR T cells
CN112055595B (zh) * 2018-01-22 2024-12-17 恩多塞特公司 Car t细胞的使用方法
WO2019144091A1 (en) * 2018-01-22 2019-07-25 Endocyte, Inc. Methods of use for car t cells
EP3743082A4 (en) * 2018-01-22 2021-11-03 Seattle Children's Hospital (DBA Seattle Children's Research Institute) METHOD OF USE FOR CAR-T CELLS
IL276131B1 (en) * 2018-01-22 2026-01-01 Seattle Childrens Hospital D/B/A Seattle Childrens Res Institute Methods of using CAR T cells
US11779602B2 (en) 2018-01-22 2023-10-10 Endocyte, Inc. Methods of use for CAR T cells
US11311576B2 (en) 2018-01-22 2022-04-26 Seattle Children's Hospital Methods of use for CAR T cells
JP7417542B2 (ja) 2018-01-22 2024-01-18 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） Ｃａｒ ｔ細胞の使用方法
JP2021512147A (ja) * 2018-01-22 2021-05-13 エンドサイト・インコーポレイテッドＥｎｄｏｃｙｔｅ， Ｉｎｃ． Ｃａｒ ｔ細胞の使用方法
CN112055595A (zh) * 2018-01-22 2020-12-08 恩多塞特公司 Car t细胞的使用方法
US12312416B2 (en) 2018-02-06 2025-05-27 Seattle Children's Hospital Fluorescein-specific cars exhibiting optimal t cell function against FL-PLE labelled tumors
CN112105382A (zh) * 2018-02-23 2020-12-18 恩多塞特公司 用于car t细胞疗法的顺序方法
JP2021514003A (ja) * 2018-02-23 2021-06-03 エンドサイト・インコーポレイテッドＥｎｄｏｃｙｔｅ， Ｉｎｃ． Ｃａｒ ｔ細胞療法のための配列決定法
WO2019165237A1 (en) * 2018-02-23 2019-08-29 Endocyte, Inc. Sequencing method for car t cell therapy
US12240870B2 (en) 2018-02-23 2025-03-04 Purdue Research Foundation Sequencing method for CAR T cell therapy
US12466869B2 (en) 2018-06-28 2025-11-11 Dana-Farber Cancer Institute, Inc. Targeting of multiple antigens with multiplex CAR T cells in solid and liquid malignancies
US20210393786A1 (en) * 2018-07-26 2021-12-23 Purdue Research Foundation Small molecule ligand-targeted drug conjugates for anti-influenza chemotherapy and immunotherapy
AU2019317278B2 (en) * 2018-08-07 2025-05-22 Purdue Research Foundation Rejuvenation of CAR T cell
EP3833400A4 (en) * 2018-08-07 2022-06-15 Purdue Research Foundation REJUVENATION OF CAR-T CELLS
CN109134467B (zh) * 2018-08-09 2022-01-21 中国医学科学院北京协和医院 用于控制嵌合抗原受体t细胞激活/抑制的连接臂及其应用
CN114805356A (zh) * 2018-08-09 2022-07-29 中国医学科学院北京协和医院 用于控制嵌合抗原受体t细胞激活/抑制的连接臂及其应用
CN109134467A (zh) * 2018-08-09 2019-01-04 中国医学科学院北京协和医院 用于控制嵌合抗原受体t细胞激活/抑制的连接臂及其应用
EP3620464A1 (en) * 2018-09-10 2020-03-11 Miltenyi Biotec GmbH Car cell having crosslinked disulfide bridge on antigen recognizing moiety
US20220340927A1 (en) * 2019-09-01 2022-10-27 Exuma Biotech Corp. Methods and compositions for the modification and delivery of lymphocytes
US12570716B2 (en) 2020-02-04 2026-03-10 Seattle Children's Hospital Anti-dinitrophenol chimeric antigen receptors
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

Also Published As

Publication number Publication date
WO2017177149A3 (en) 2017-11-16
RU2018139101A3 (https=) 2021-02-24
US20190091308A1 (en) 2019-03-28
JP2023113693A (ja) 2023-08-16
BR112018070580A2 (pt) 2019-02-05
RU2018139101A (ru) 2020-05-12
JP7631410B2 (ja) 2025-02-18
US12144850B2 (en) 2024-11-19
JP2019513764A (ja) 2019-05-30
CN109195611A (zh) 2019-01-11
EP3439675A4 (en) 2019-12-18
US20250171803A1 (en) 2025-05-29
JP2025084765A (ja) 2025-06-03
CA3019835A1 (en) 2017-10-12
JP7282521B2 (ja) 2023-05-29
EP3439675A2 (en) 2019-02-13

Similar Documents

Publication Publication Date Title
US20250171803A1 (en) Methods and compositions for car t cell therapy
US12269862B2 (en) Methods of use for CAR T cells
US11759480B2 (en) Compositions and methods for CAR T cell therapy
US20250230216A1 (en) Sequencing method for car t cell therapy
US20240058458A1 (en) Methods, compounds, and compositions for modifying car-t cell activity
RU2792653C2 (ru) Способы и композиции для car-t-клеточной терапии
RU2854956C1 (ru) Способы, соединения и композиции для модификации активности car-t-клеток
BR112018070580B1 (pt) Uso de uma célula t com receptor de antígeno quimérico (car)
BR122025000107A2 (pt) Uso de uma célula t com receptor de antígeno quimérico (car), célula t car, ácido nucleico, polipeptídeo do receptor de antígeno quimérico, vetor, composição, combinação e conjugado

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 3019835

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2018553142

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112018070580

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 2017779919

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017779919

Country of ref document: EP

Effective date: 20181108

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17779919

Country of ref document: EP

Kind code of ref document: A2

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17779919

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 112018070580

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20181005