WO2022225821A1 - Procédés de traitement d'une toxicité liée à une immunothérapie utilisant un antagoniste du gm-csf - Google Patents

Procédés de traitement d'une toxicité liée à une immunothérapie utilisant un antagoniste du gm-csf Download PDF

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WO2022225821A1
WO2022225821A1 PCT/US2022/025089 US2022025089W WO2022225821A1 WO 2022225821 A1 WO2022225821 A1 WO 2022225821A1 US 2022025089 W US2022025089 W US 2022025089W WO 2022225821 A1 WO2022225821 A1 WO 2022225821A1
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csf
hgm
antibody
car
cells
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Cameron DURRANT
Dale CHAPPELL
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Humanigen, Inc.
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411—Immunoglobulin superfamily
    • A61K39/464412—CD19 or B4
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    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/53—Colony-stimulating factor [CSF]
    • C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
    • 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
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    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/243—Colony Stimulating Factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • 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 A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 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 A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 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 A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • 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
    • 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

Definitions

  • this invention provides methods for delaying or preventing adverse immunotherapy-related neurologic events in a subject treated for cancer with anti-CD19 CAR-T cell therapy, the method comprising (a) administering a recombinant hGM-CSF antagonist to the subject, wherein the recombinant hGM-CSF antagonist is anti-hGM-CSF antibody lenzilumab; and (b) administering anti-CD19 CAR-T cells to the subject after administration of the anti-hGM- CSF antibody lenzilumab.
  • this invention provides methods for preventing/reducing immunotherapy-related toxicity, the method comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation or GM-CSF knockout (GM-CSF k/o CAR-T cells), wherein the GM-CSF gene is inactivated or knocked out by the methods described herein.
  • this invention provides methods for reducing blood-brain barrier disruption in a subject treated with immunotherapy, the methods comprising administering a recombinant GM-CSF antagonist to the subject.
  • a method of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject comprising a step of administering a recombinant hGM-CSF antagonist to the subject.
  • said immunotherapy comprises adoptive cell transfer, administration of monoclonal antibodies, administration of cytokines or chemokines, administration of a cancer vaccine, T cell engaging therapies, or any combination thereof.
  • the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14).
  • the CDR3 comprises RQRFPYYFDY (SEQ ID NO: 15) or RDRFPYYFDY (SEQ ID NO: 16).
  • the heavy chain variable region CDR1 or CDR2 can be a human germline VH1 sequence; or both the CDR1 and CDR2 can be human germline VH1.
  • the antibody comprises a heavy chain variable region CDR1 or CDR2, or both CDR1 and CDR2, as shown in a V H region set forth in Figure 1.
  • Figures 2A-2B illustrates binding of GM-CSF to Ab1 ( Figure 2A) or Ab2 ( Figure 2B) determined by surface plasmon resonance analysis at 37°C (Biacore 3000). Ab1 and Ab2 were captured on anti Fab polyclonal antibodies immobilized on the Biacore chip. Different concentrations of GM-CSF were injected over the surface as indicated. Global fit analysis was carried out assuming a 1:1 interaction using Scrubber2 software.
  • Figures 3A-3B illustrates binding of Ab1 and Ab2 to glycosylated ( Figure 3A) and non- glycosylated GM-CSF ( Figure 3B).
  • CAR-T produced GM-CSF recruits CCR2+ myeloid cells to the tumor site, which produce CCL2 (MCP1).
  • CCL2 positively reinforces its own production by CCR2+ myeloid cell recruitment.
  • IL-1 and IL-6 from myeloid cells form another positive feedback loop with CAR- T by inducing production of GM-CSF.
  • Phosphatidyl serine is exposed as a result of perforin and granzyme cell membrane destruction.
  • Phosphatidyl-serine stimulates myeloid cell production of CCL2, IL-1, IL-6, and other inflammatory effectors.
  • FIG. 15A-15G illustrate that GM-CSF CRISPR knockout T-cells exhibit reduced expression of GM-CSF but similar levels of other cytokines and degranulation.
  • a. Generation of GM-CSF knockout CAR-Ts. See Example 6
  • Figures 16A-16J illustrate that GM-CSF neutralizing antibody in accordance with embodiments described herein does not inhibit CAR-T mediated killing, proliferation, or cytokine production but successfully neutralizes GM-CSF (See Example 7).
  • FIG. 33D depicts CD11b+ bright macrophages were decreased in the brains of mice receiving GM-CSF neutralization during CAR-T therapy compared to isotype control during CAR-T therapy as assayed by flow cytometry in brain hemispheres, 3 mice per group, mean+SEM.
  • Figures 34A(i)-34B illustrate the generation of GM-CSF k/o CART19 cells.
  • Figs. 34A(i) 34A(iv) show the experimental schema;
  • Fig 34B shows the gRNA sequence and primer sequences for generation of GM-CSF k/o CART19.
  • CRES is associated with elevated concentrations of circulating cytokines, as C-reactive protein, GM-CSF, IL-1, IL-2, sIL2R ⁇ , IL-5, IL-6, IL-8, IL-10, IP10, IL-15, MCP-1, MIG, MIP1 ⁇ , IFN ⁇ , CX3CR1, and TNF ⁇ .
  • cytokines as C-reactive protein, GM-CSF, IL-1, IL-2, sIL2R ⁇ , IL-5, IL-6, IL-8, IL-10, IP10, IL-15, MCP-1, MIG, MIP1 ⁇ , IFN ⁇ , CX3CR1, and TNF ⁇ .
  • the cytokine concentration gradient between serum and CSF observed in normal conditions is reduced or lost during CRES.
  • CAR T-cells and high protein concentrations are observed in the CSF of patients and is correlated with the severity of the condition. All this indicates a blood-brain barrier dysfunction following immunotherapy.
  • GM-CSF antagonists may act by reducing the amount of GM-CSF ligand available to bind the receptor (e.g., antibodies that once bound to GM-CSF increase the clearance rate of GM-CSF) or prevent the ligand from binding to its receptor either by binding to GM-CSF or the receptor (e.g., neutralizing antibodies).
  • GM-CSF antagonists may also include other peptide inhibitors, which may include polypeptides that bind GM-CSF or its receptor to partially or completely inhibit signaling.
  • a peptide GM-CSF antagonist can be, e.g., an antibody; a natural or synthetic GM-CSF receptor ligand that antagonizes GM-CSF, or other polypeptides.
  • binding specificity determinant refers to the minimum contiguous or non-contiguous amino acid sequence within a CDR region necessary for determining the binding specificity of an antibody. In the current invention, the minimum binding specificity determinants reside within a portion or the full-length of the CDR3 sequences of the heavy and light chains of the antibody.
  • anti-GM-CSF antibody or “GM-CSF antibody” are used interchangeably to refer to an antibody that binds to GM-CSF and inhibits GM-CSF receptor binding and activation.
  • the above-described treatment achieves an objective response rate of at least 80%.
  • the objective response rate is a complete response or partial response.
  • the anti-CD19 CAR-T cells are administered 2-24 hours after the administration of the anti-hGM-CSF antibody lenzilumab.
  • the tumor burden at four weeks after treatment is a complete response of no tumor detection compared to the baseline tumor burden.
  • the tumor burden at four weeks after treatment is a partial response of ⁇ 50 % reduction in SPD compared to the baseline tumor burden.
  • the anti-hGM- CSF antibody comprises a VH region that comprises a CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY, a J segment, and a V-segment, wherein the J-segment comprises at least 95% identity to human JH4 (YFD YWGQGTL VTVSS) and the V-segment comprises at least 90% identity to a human germ line VHl 1-02 or VHl 1-03 sequence; or a VH region that comprises a CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12).
  • the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14).
  • the VH has the sequence of VH#1, VH#2, VH#3 , VH#4, or VH#5 set forth in Figure 1.
  • the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK or FNR.
  • the anti-hGM-CSF antibody comprises a human germline JK4 region.
  • the VL region CDR3 comprises QQFN(K/R)SPLT (SEQ ID NO:17).
  • the anti- hGM-CSF antibody comprises a V L region that comprises a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18).
  • the refractory pediatric cancer or the relapsed pediatric cancer is neuroblastoma.
  • the refractory pediatric cancer or the relapsed pediatric cancer is a pediatric leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or an uncommon pediatric leukemia which is juvenile myelomonocytic leukemia or chronic myeloid leukemia.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • an uncommon pediatric leukemia which is juvenile myelomonocytic leukemia or chronic myeloid leukemia.
  • the refractory cancer or the relapsed cancer is a pediatric bone cancer.
  • the refractory cancer or the relapsed cancer is an adrenal cancer.
  • the refractory cancer or the relapsed cancer is a breast cancer.
  • adoptive cell transfer comprises administering tumor infiltrating lymphocytes (TIL).
  • adoptive cell transfer comprises administering chimeric antigen receptor (CAR)-modified NK cells.
  • CAR- modified NK cells comprise NK cells isolated from the patient or commercially available NK engineered to express a CAR that recognizes a tumor-specific protein.
  • adoptive cell transfer comprises administering dendritic cells.
  • immunotherapy comprises administering monoclonal antibodies.
  • monoclonal antibodies attach to specific proteins on cancer cells, thus flagging the cells for the immune system finding and destroying them.
  • the cancer vaccine is selected from a group comprising: sipuleucel-T, GVAX, ADXS11-001, ADXS31-001, ADXS31-164, ALVAC- CEA vaccine, AC Vaccine, talimogene laherparepvec, BiovaxID, Prostvac, CDX110, CDX1307, CDX1401, CimaVax-EGF, CV9104, DNDN, NeuVax, Ae-37, GRNVAC, tarmogens, GI-4000, GI-6207, GI-6301, ImPACT Therapy, IMA901, hepcortespenlisimut-L, Stimuvax, DCVax-L, DCVax-Direct, DCVax Prostate, CBLI, Cvac, RGSH4K, SCIB1, NCT01758328, and PVX-410.
  • the hGM-CSF antagonist may be administered once pathophysiological processes leading up to or attesting to the beginning of immunotherapy-related toxicity are detected. In one embodiment, the hGM-CSF antagonist can terminate the pathophysiological processes and avoid its sequelae.
  • the subject has IL-6 serum concentration above 12 pg/mL following immunotherapy administration. In some embodiments, the subject has IL-6 serum concentration above 14 pg/mL following immunotherapy administration. In some embodiments, the subject has IL-6 serum concentration above 16 pg/mL following immunotherapy administration. In some embodiments, the subject has IL-6 serum concentration above 18 pg/mL following immunotherapy administration. In some embodiments, the subject has IL-6 serum concentration above 20 pg/mL following immunotherapy administration. In some embodiments, the subject has IL-6 serum concentration above 22 pg/mL following immunotherapy administration. [0247] In some embodiments, the subject has an MCP-1 serum concentration above 200 pg/ml following immunotherapy administration.
  • Antibodies or antibodies fragments as described herein can be expressed in prokaryotic or eukaryotic microbial systems or in the cells of higher eukaryotes such as mammalian cells.
  • An antibody that is employed in the invention can be in any format.
  • the lymphocytes may be immunized in vitro.
  • the immunizing agent preferably includes human GM-CSF protein, fragments thereof, or fusion protein thereof.
  • Human monoclonal antibodies can be produced using various techniques known in the art, including phage display libraries (Hoogenboom & Winter, J. MoI. Biol.227:381 (1991); Marks et al, J. MoI. Biol. 222:581 (1991)). The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, p. 77 (1985) and Boerner et al., J.
  • the Vkappa segment may differ by not more than 18 residues from VKIIIA27 (SEQ ID NO: 21).
  • the V L region V-segment of an antibody of the invention has at least 85% identity, or at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the human kappa V-segment sequence of a V L region shown in Figure 1, for example, the V-segment sequence of VK#1 (SEQ ID NO: 6), VK#2 (SEQ ID NO: 7), VK#3 (SEQ ID NO: 8), or VK#4 (SEQ ID NO: 9).
  • the antibody has a V H region VH#1, VH#2, VH#3, VH#4, or VH#5 as shown in Figure 1; and a V L region VK#1, VK#2, VK#3, or VK#4 as shown in Figure 1, as described, e.g., in U.S. Patent Nos. 8,168,183 and 9,017, 674, each of which is incorporated herein by reference in its entirety.
  • An antibody may be tested to confirm that the antibody retains the activity of antagonizing hGM-CSF activity.
  • the antagonist activity can be determined using any number of endpoints, including proliferation assays.
  • Antibodies of the invention compete with c19/2 antibody for binding to hGM-CSF.
  • the ability of an antibody described herein to block or compete with c19/2 antibody for binding to hGM-CSF indicates that the antibody binds to the same epitope c19/2 antibody or to an epitope that is close to, e.g., overlapping, with the epitope that is bound by c19/2 antibody.
  • an antibody described herein e.g., an antibody comprising a V H and V L region combination as shown in the table provided in Figure 1, can be used as a reference antibody for assessing whether another antibody competes for binding to hGM-CSF.
  • the antibody is an IgG , e.g., having an f-allotype, that has a VH selected from VH#1, VH#2, VH#3, VH#4, or VH#5 ( Figure 1), and a VL selected from VK#1, VK#2, VK#3, or VK#4 ( Figure 1).
  • the antibodies of the invention inhibit hGM-CSF receptor activation, e.g., by inhibiting hGM-CSF binding to the receptor, and exhibit high affinity binding to hGM-CSF, e.g., 500 pM.
  • the antibody has a dissociation constant of about 10 -4 per sec or less.
  • the antibodies of the invention are in the form of a Fab' fragment.
  • a full-length light chain is generated by fusion of a V L -region to human kappa or lambda constant region. Either constant region may be used for any light chain; however, in typical embodiments, a kappa constant region is used in combination with a Vkappa variable region and a lambda constant region is used with a Vlambda variable region.
  • the heavy chain of the Fab′ is a Fd′ fragment generated by fusion of a V H -region of the invention to human heavy chain constant region sequences, the first constant (CH1) domain and hinge region.
  • the hGM-CSF antagonist may be a peptide.
  • an hGM- CSF peptide antagonist may be a peptide designed to structurally mimic the positions of specific residues on the B and C helices of human GM-CSF that are implicated in receptor binding and bioactivity (e.g., Monfardini et al, J. Biol. Chem 271 :2966-2971, 1996).
  • treating comprises therapeutic treatment and “preventing” comprises prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove.
  • treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or a combination thereof.
  • “treating,” “ameliorating,” and “alleviating” refer inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
  • CAR-T cell activity should be preserved or improved if possible.
  • the experimental design tests the effects of GM-CSF blockade with anti-GM-CSF antibody (lenzilumab) on CAR-T cell effector functions, CAR-T efficacy in a tumor xenograft model, development of CRS in a CRS xenograft model and the development of NT using MRI imaging and volumetric analysis to quantify the neuro-inflammation seen with CAR-T cell therapy.
  • CAR-T +/- lenzilumab both in the presence and absence of human PBMCs were studied. (see Examples 9 and 10, Figs. 19 and 20a- 20b).
  • EXAMPLE 19 GM-CSF neutralization in vivo enhances CAR-T cell anti-tumor activity in xenograft models Xenograft Mouse Models [0410] Male and female 8-12 week old NOD-SCID-IL2r ⁇ ⁇ / ⁇ (NSG) mice were bred and cared for within the Department of Comparative Medicine at the Mayo Clinic under a breeding protocol approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC). Mice were maintained in an animal barrier space that is approved by the IBC for BSL2+ level experiments.
  • IACUC Mayo Clinic Institutional Animal Care and Use Committee
  • EXAMPLE 23 Administration of an anti-GM-CSF monoclonal antibody (Lenzilumab) significantly reduced neuro-inflammation caused by CAR-T therapy and maintained the integrity of the blood-brain-barrier in a xenograft model [0433]
  • This preclinical study was designed to closely replicate the findings observed in CAR-T clinical trials and utilized human acute lymphoblastic leukemia (ALL), human CD19 targeted CAR-T (CART19), and human peripheral blood mononuclear cells (PBMCs) and conducted in mice.
  • ALL acute lymphoblastic leukemia
  • CART19 human CD19 targeted CAR-T
  • PBMCs peripheral blood mononuclear cells
  • TALENS are similar to ZFNs in that they comprise a Fok1 nuclease domain fused to a sequence specific DNA-binding domain. The targeted nuclease then makes a double-strand break in the DNA and error-prone repair creates a mutated target gene.
  • TALENS can be easily designed using a simple protein-DNA code that uses DNA binding TALE (transcriptional-activator –like effectors) repeat domains to individual bases in a binding site. The robustness of TALEN means that genome editing is a reliable and facile process (Reyon D., et al., 2012 Nat Biotechnol. 2012 May;30(5):460-5.

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Abstract

L'invention concerne des procédés de neutralisation et/ou d'élimination du GM-CSF humain chez un sujet en ayant besoin, consistant à administrer au sujet des cellules CAR-T présentant une invalidation génique de GM-CSF (cellules CAR-T à GM-CSFk/o). L'invention concerne également des procédés d'inactivation génique de GM-CSF ou d'invalidation de GM-CSF (KO) dans une cellule comprenant une édition génomique ciblée ou un silençage génique de GM-CSF. L'invention concerne également des procédés de prévention/traitement de toxicité liée à une immunothérapie, consistant à administrer au sujet des cellules CAR-T présentant une inactivation génique de GM-CSF ou une invalidation de GM-CSF (cellules CAR-T à GM-CSFk/o), le gène GM-CSF étant inactivé ou invalidé et/ou étant un antagoniste de GM-CSF recombinant. L'invention concerne également des procédés de réduction d'un niveau d'une cytokine ou d'une chimiokine autre que GM-CSF chez un sujet présentant une toxicité liée à une immunothérapie, consistant à administrer au sujet un antagoniste de hGM-CSF recombinant. L'invention concerne également des procédés de traitement ou de prévention de toxicité liée à une immunothérapie chez un sujet, consistant à administrer au sujet des cellules T exprimant un récepteur d'antigène chimérique (cellules CAR-T), les cellules CAR-T présentant une invalidation génique de GM-CSF (cellules CAR-T à GM-CSFk/o). L'invention concerne également des procédés de prévention ou de réduction de la rupture de la barrière hémato-encéphalique chez un sujet traité par immunothérapie, le procédé consistant à administrer des cellules CAR-T présentant une invalidation génique de GM-CSF (cellules CAR-T à GM-CSFk/o) au sujet.
PCT/US2022/025089 2021-04-19 2022-04-15 Procédés de traitement d'une toxicité liée à une immunothérapie utilisant un antagoniste du gm-csf WO2022225821A1 (fr)

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Citations (1)

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US20190322735A1 (en) * 2017-10-02 2019-10-24 Humanigen, Inc. Methods of treating immunotherapy-related toxicity using a gm-csf antagonist

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US20190322735A1 (en) * 2017-10-02 2019-10-24 Humanigen, Inc. Methods of treating immunotherapy-related toxicity using a gm-csf antagonist

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BEZERRA EVANDRO D., REONA SAKEMURA, JAMES GIRSCH, CARLI M. STEWART, GUNJAN A AWATRAMANI, CLAUDIA MANRIQUEZ-ROMAN, KENDALL J. SCHIC: "Optimized Inhibition of GM-CSF in Preclinical Models of Anti- CD 19 Chimeric Antigen Receptor T Cell Therapy", BLOOD, vol. 138, no. Suppl. 1, 23 November 2021 (2021-11-23), pages 2777, XP093000031 *
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