EP4633647A1 - Induction de tolérance immunologique rétroactive (retardée) chez des patients avec des transplantations d'organes solides préexistants - Google Patents

Induction de tolérance immunologique rétroactive (retardée) chez des patients avec des transplantations d'organes solides préexistants

Info

Publication number
EP4633647A1
EP4633647A1 EP23904745.9A EP23904745A EP4633647A1 EP 4633647 A1 EP4633647 A1 EP 4633647A1 EP 23904745 A EP23904745 A EP 23904745A EP 4633647 A1 EP4633647 A1 EP 4633647A1
Authority
EP
European Patent Office
Prior art keywords
patient
cells
hematopoietic stem
organ
transplanted
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.)
Pending
Application number
EP23904745.9A
Other languages
German (de)
English (en)
Inventor
Jeffrey L. VEALE
Nima NASSIRI
Neil KOGUT
Erik LUM
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.)
University of California
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California
University of California Berkeley
University of California San Diego UCSD
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
Application filed by University of California, University of California Berkeley, University of California San Diego UCSD filed Critical University of California
Publication of EP4633647A1 publication Critical patent/EP4633647A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells

Definitions

  • Embodiments of the disclosure concern at least the fields of medicine, transplantation, immunology and pharmacology.
  • transplanted organs include heart, intestine, liver, lung, pancreas and kidney.
  • having medications to suppress the immune system is essential.
  • suppressing an individual's immune system places that individual at greater risk of infections, cancers, heart disease, diabetes, metabolic syndrome, gastrointestinal disorders, neurological disorders, dermatologic and cosmetic disorders, among others.
  • Recipients usually receive a mixture of three maintenance immunosuppressive drugs, including calcineurin inhibitors, antimetabolites, and steroids.
  • Alternative maintenance mediations can include inhibitors of the molecular target of rapamycin (mTOR) and co-stimulation blockade medications. These medications have their own set of detrimental side effects.
  • kidney transplant failure Ironically, calcineurin inhibitors cause nephrotoxicity from vasoconstriction and ultimately lead to kidney failure, resulting in the need for renal replacement therapy. A leading cause of kidney transplant failure is chronic kidney rejection. Immunosuppressive medications must be continued for the life of the transplanted organ. Even for widely available medications, these costs can be high, which can lead to medication non-adherence and once again, transplant failure.
  • Embodiments of the invention are designed to address problems observed in immunosuppression regimens used in organ transplant recipients, and include, for example, methods of modulating chimerism and/or immunological tolerance in a patient having a pre-existing transplanted organ (e.g., a transplanted kidney, heart, intestine, liver, pancreas or lung).
  • a pre-existing transplanted organ e.g., a transplanted kidney, heart, intestine, liver, pancreas or lung.
  • the invention disclosed herein includes therapeutic methods designed so that patients with a pre-existing, well-functioning kidney transplant from a living donor can be retroactively withdrawn from immunosuppressive medications without compromising allograft function.
  • hematopoietic progenitor stem cells CD34 +
  • T-cells CD3 +
  • hematopoietic progenitor stem cells CD34 +
  • T-cells CD3 +
  • gCSF granulocyte colony stimulating factor
  • hematopoietic progenitor stem cells (CD34 + ) and T-cells (CD3 + ) infusion in the patient is preceded by a conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti -thymocyte globulin (rATG), thereby avoiding the need for chemotherapy.
  • TLI total lymphoid irradiation
  • rATG rabbit anti -thymocyte globulin
  • graft function and chimerism can be evaluated in recipient whole blood and white blood cell subsets. As therapeutic milestones are then met in the recipient, immunosuppressive medications can be weaned/discontinued.
  • weaning of immunosuppressive agents such as calcineurin inhibitors can begin at 6 months with a goal of discontinuation by 12 months as long as the following conditions are met: (1) chimerism is detectable for at least 180 days after CD34 + and CD3 + cell infusion, (2) stable graft function (defined as eGFR >30 mL/min and no greater than sustained 30% change over 3 months from baseline function) without clinical rejection episodes is maintained, and (3) there is no evidence of graft versus host disease (GVHD).
  • immunosuppressive agents such as calcineurin inhibitors
  • inventions disclosed herein includes methods that provide patients living with a transplanted organ (e.g., a transplanted kidney, heart, intestine, liver, pancreas or lung) a means of delayed withdrawal from immunosuppressive drugs while maintaining normal organ function.
  • a transplanted organ e.g., a transplanted kidney, heart, intestine, liver, pancreas or lung
  • embodiments of the invention include methods of modulating immunological tolerance in a patient having a transplanted organ or the like.
  • these methods comprise selecting a patient having a transplanted organ, wherein the transplanted organ is from an individual who is not genetically identical to the patient, and the patient is administrated an immunosuppressive agent to facilitate immunological tolerance of the transplanted organ.
  • transplantation conditioning regimen comprises the administration of rabbit anti -thymocyte globulin and total lymphoid irradiation, optionally with the administration of belumosudil (depending on HLA and eplet matching); and then further transfusing the patient with hematopoietic stem/progenitor cells; wherein the hematopoietic stem/progenitor cells are obtained from the same individual from which the transplanted organ was obtained.
  • the transplantation conditioning regimen comprises the administration of rabbit anti -thymocyte globulin and total lymphoid irradiation, optionally with the administration of belumosudil (depending on HLA and eplet matching)
  • belumosudil depending on HLA and eplet matching
  • Illustrative specific embodiments of the invention include methods that provide patients having a pre-existing, well-functioning kidney transplant a means of withdrawal from immunosuppressive drugs while maintaining normal renal function. This is accomplished through a transfusion of hematopoietic stem/progenitor cells (HSPCs) from the same donor who provided the original kidney transplant. Donor HSPCs are peripheralized using granulocyte colony stimulating factor and plerixafor, after which cells are collected, processed, and evaluated.
  • HSPCs hematopoietic stem/progenitor cells
  • Recipients undergo a conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti -thymocyte globulin (rATG) optionally with the administration of belumosudil (depending on HLA and eplet matching), after which a stem cell infusion is performed.
  • TLI total lymphoid irradiation
  • rATG rabbit anti -thymocyte globulin
  • immunosuppression can be discontinued within 12 months after HSPC transfusion if the following conditions are met: (1) chimerism is detectable for at least 180 days after CD34 + and CD3 + cell infusion, (2) stable graft function (defined as eGFR >30 mL/min and no greater than sustained 30% change over 3 months) without clinical rejection episodes is maintained, (3) there is lack of rejection and (4) there is no evidence of graft vs. host disease.
  • the purpose is to maximize allograft function, minimize comorbidities associated with immunosuppression, and minimize the need for re-transplantation.
  • embodiments of the invention include observing a physiological parameter in the patient for a period of time following transfusing the patient with hematopoietic stem/progenitor cells (e.g., for at least 3, 6, 9 or 12 months).
  • Illustrative physiological parameters includes at least one of: detectability of chimerism; estimated glomerular filtration rate (eGFR); and the presence of graft versus host disease.
  • Embodiments of the invention can also include the step of withdrawing the administration of the immunosuppressive agent when the patient exhibits an estimated glomerular filtration rate >30 mL/min and no greater than a 30% change in estimated glomerular filtration rate for at least 3 months.
  • the hematopoietic stem/progenitor cells are obtained by administering one or more mobilization agents to the donor, wherein the one or more mobilization agents comprise plerixafor, human granulocyte colony-stimulating factor (G-CSF), or a combination thereof.
  • the immunosuppressive agent can comprise various immunosuppressive agents.
  • the transplanted cells comprise at least 1, 2, 3, 4, 5 or 6 human leukocyte antigens that are mismatched with human leukocyte antigens present in the patient/recipient.
  • the HLA mismatches occur at least one of: HLA-A, HLA-B, HLA-C or HLA-DR.
  • the donor is HLA-identical.
  • the transplanted tissues or organs comprise at least one of: kidney cells, heart cells, intestinal cells, liver cells, lung cells or pancreatic cells.
  • the tissues or organs are obtained from a human lymphocyte antigen (HLA) single haplotype-matched donor.
  • HLA human lymphocyte antigen
  • the one or more genetically non-identical cells, tissues or organs are obtained from a 0-3 antigen HLA mismatched donor (e.g., 0-3 HLA mismatches occurring at least one of: HLA-A, HLA-B, HLA-C or HLA-DR).
  • Freeing patients from immunosuppression regimens will eliminate the toxicities associated with immunosuppression, decrease the risks for short and long-term infectious and cancerous complications, reduce or eliminate the risk of graft rejection, and increase allograft durability, potentially for life.
  • By optimizing allograft survivability the burden of re-transplantation is minimized, and challenges to the patient and the health care system as a result of graft failure/rej ection and repeat renal replacement are mitigated.
  • Methods that allow for increasing kidney allograft life-years consequently allows available kidneys to be allocated elsewhere; with kidneys that would be allocated to patients with graft failure instead being directed towards the transplant-naive patients. With such methods, chains of transplantations will be more efficacious and patients can move more rapidly up the deceased donation waiting list.
  • the potential impact on increasing the pool of organ donors increases substantially with any advancements in immunological tolerance.
  • Figure 1 Cartoon schematic showing a retroactive tolerance protocol (adapted from the Stanford simultaneous tolerance protocol).
  • the donor’s stem cells are mobilized using a combination of granulocyte colony stimulating factor and plerixafor. The cells are separated, processed, and cryopreserved.
  • the recipient who has already recovered from the kidney transplant, undergoes conditioning with rabbit antithymocyte globulin and total lymphoid irradiation, after which the donor-derived stem cells are infused.
  • Serial chimerism testing guides weaning of immunosuppression, with eventual full withdrawal within one year after stem cell infusion.
  • kidney transplants are performed in the United States annually. Although kidney transplantation prolongs survival and improves the quality of life of patients with end-stage renal disease, it has two major limitations: the risk of graft rejection and the need for lifelong immunosuppression.
  • Conventional immunosuppression following kidney transplantation is associated with serious, longterm complications, including infection, secondary malignancies, hypertension, hyperlipidemia, diabetes, and cardiovascular disease. Calcineurin inhibitors may damage kidney function and contribute to graft failure.
  • the intensive and complicated pharmaceutical regimen adversely affects quality of life and leads to a risk of medication non-adherence.
  • the costs of conventional immunosuppression are high, and ironically contribute to long-term graft failure.
  • Embodiments of the invention are designed to address problems observed in immunosuppression regimens, and include, for example, methods of modulating chimerism and/or immunological tolerance in a patient having a pre-existing transplanted organ (e.g. a transplanted kidney, heart, intestine, liver, pancreas or lung).
  • a pre-existing transplanted organ e.g. a transplanted kidney, heart, intestine, liver, pancreas or lung.
  • the one or more genetically nonidentical cells, tissues or organs comprise at least one human leukocyte antigen that is mismatched with a human leukocyte antigen present in the patient.
  • these methods include the steps of first selecting a patient having a transplanted organ, wherein the transplanted organ is from an individual who is not genetically identical to the patient and the patent is administrated an immunosuppressive agent to facilitate immunological tolerance of the transplanted organ; and then performing a transplantation conditioning regimen on the patient, wherein the transplantation conditioning regimen comprises the administration of rabbit anti -thymocyte globulin and total lymphoid irradiation; and further transfusing the patient with donor hematopoietic stem/progenitor cells and T cells; wherein the donor hematopoietic stem/progenitor and T cells are obtained from the individual from which the transplanted organ was obtained.
  • the transplanted organ/cells comprise at least 1, 2, 3, 4, 5 or 6 human leukocyte antigens that are mismatched with human leukocyte antigens present in the patient.
  • the HLA mismatches occur at least one of: HLA-A, HLA-B, HLA-C or HLA-DR.
  • the donor is HLA-identical.
  • the hematopoietic stem/progenitor cells used in the methods are obtained by administering one or more mobilization agents to the donor, wherein the one or more mobilization agents comprise plerixafor, human granulocyte colony-stimulating factor (G-CSF), or a combination thereof.
  • G-CSF human granulocyte colony-stimulating factor
  • Embodiments of the invention can include the step of further observing a physiological parameter in the patient for a period of time following transfusing the patient with hematopoietic stem/progenitor cells, wherein the physiological parameter includes at least one of: detectability of chimerism; estimated glomerular filtration rate (eGFR); and the presence of graft versus host disease.
  • the period of time is at least 3, 6, 9 or 12 months.
  • Embodiments of the invention can further include the step then withdrawing the administration of the immunosuppressive agent when the patient exhibits a selected physiological profile such as an estimated glomerular filtration rate >30 mL/min and no greater than a 30% change in estimated glomerular filtration rate for at least 3 months.
  • the immunosuppressive agent comprises an antibody (e.g., Daclizumab and Basiliximab), a calcineurin inhibitor (e.g. cyclosporine, tacrolimus), an antimetabolite (e.g. mycophenolate mofetil, azathioprine), an mTORi (e.g. sirolimus, everolimus), and/or a steroid (e.g. prednisone).
  • an antibody e.g., Daclizumab and Basiliximab
  • a calcineurin inhibitor e.g. cyclosporine, tacrolimus
  • an antimetabolite e.g. mycophenolate mofetil, azathioprine
  • an mTORi e.g. sirolimus, everolimus
  • a steroid e.g. prednisone
  • Certain embodiments of the invention focus on patients transplanted with an organ less than 30 days (e.g., less than 3, 2 or 1 week(s)) prior to performing a transplantation conditioning regimen on the patient and then transfusing the patient with hematopoietic stem/progenitor cells and T cells.
  • Other embodiments of the invention focus on patients transplanted with an organ more than 30 days prior to performing a transplantation conditioning regimen on the patient and then transfusing the patient with hematopoietic stem/progenitor cells and T cells.
  • some embodiments of the invention focus on patients transplanted with an organ more than 1 year, 2 years, 3 years, 4 years or 5 years prior to performing a transplantation conditioning regimen on the patient and then transfusing the patient with hematopoietic stem/progenitor cells and T cells obtained from the organ donor.
  • Chimerism analysis is a well-established method for monitoring the state of hematopoietic stem cell transplantation (HSCT) over time by analyzing peripheral blood or bone marrow samples of the recipient. See, e.g., Tozzo et al., Diagnostics (Basel). 2021 Apr; 11(4): 621.
  • Embodiments of the invention include chimerism analyses. For example, certain embodiments of the invention observed chimerism detectable in the patient for at least 180 days after hematopoietic stem/progenitor cells and T cell infusion. In certain of these methods, the patient exhibits a chimerism of at least 5%, 10%, 20% or 40% following the hematopoietic stem/progenitor cells and T cell infusion. Typically in these methods, chimerism is observed when donor leukocytes comprise at least 5%, 10%, 20% or 40% of peripheral blood leukocytes obtained from the patient.
  • Embodiments of the invention can further include the step of weaning a patient off of the immunosuppressive agent when at least one of the following conditions are met: (1) chimerism is detectable for at least 180 days after hematopoietic stem/progenitor cells and T cell transfusion, (2) stable graft function (defined as eGFR >30 mL/min and no greater than sustained 30% change over 3 months from baseline function) without clinical rejection episodes is maintained, and (3) there is no evidence of graft versus host disease (GVHD).
  • weaning the patient off of the immunosuppressive agent occurs over at least 20, 30, 40 or 50 weeks.
  • the Rock-2 inhibitor belumosudil (KD025) demonstrates several properties which make it an attractive agent for use in certain embodiments of the invention.
  • Embodiments of the invention include methods for administering the drug belumosudil to patients who have undergone tissue and/or organ transplantation.
  • these methods for administering belumosudil comprise the steps of selecting a patient for belumosudil administration, wherein the patent is selected as one having undergone a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and then administering belumosudil to the patient.
  • the administration of belumosudil to the patient occurs in conjunction with a transplantation conditioning regimen comprising anti -thymocyte globulin (rATG) administration and total lymphoid irradiation (TLI).
  • rATG anti -thymocyte globulin
  • TLI total lymphoid irradiation
  • Belumosudil increases regulatory T-cell number and function and shifts the balance of effector/regulatory T cells towards the latter.
  • Belumosudil reduces IL- 17 and IL-21 through reduction in stat 3 phosphorylation.
  • These inflammatory cytokines may play a role in graft rejection.
  • Belumosudil down-regulates key fibrotic processes in preclinical models, including profibrotic gene transcription, stress fiber formation, myofibroblast activation and collagen deposition. Interstitial fibrosis is a prominent histological feature of chronic graft rejection.
  • Belumosudil has been given a breakthrough drug designation by the FDA for the treatment of chronic graft versus host disease (GVHD).
  • Embodiments of the present invention utilize pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of belumosudil formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • therapeutically-effective amount means that amount of a compound, material, or composition comprising belumosudil of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in a patient at a reasonable benefit/risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc, magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Actual dosage levels of belumosudil in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level can depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical belumosudil composition used (e.g., 200 mg QD, 200 mg BID, and 400 mg QD).
  • the physician or provider could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a dose of a compound or a composition is administered to a subject every day, every other day, every couple of days, every third day, once a week, twice a week, three times a week, or once every two weeks.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • a dose(s) of a compound or a composition is administered for 2 days, 3 days, 5 days, 7 days, 14 days, or 21 days.
  • a dose of a compound or a composition is administered for 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or more.
  • the methods of the invention can be used in a variety of transplantation procedures, including but not limited to kidney transplantation.
  • the one or more genetically non-identical cells, tissues or organs comprises at least one of: kidney cells, heart cells, intestinal cells, liver cells, lung cells or pancreatic cells.
  • certain embodiments of the invention are used in vascular composite allografts.
  • Vascular composite allografts involve the transplantation of multiple structures that may include skin, bone, muscles, blood vessels, nerves and connective tissue. Face, uterine, and hand transplants are the most well-known types of vascular composite allografts.
  • the use of vascular composite allografts transplantation is increasing as this technology matures and further includes, for example, the transplantation of reproductive organs. Retroactive tolerance may be applicable in this setting as well.
  • Immunological tolerance based on the Stanford University Protocol combines simultaneous hematopoietic stem cells with kidney transplantation in a prospective fashion to liberate patients from immunosuppression.
  • patients who have been transplanted in the past also desire the opportunity to be freed from the side effects of anti -rejection medications.
  • Donor stem cells were infused into the recipient 417 days following kidney transplantation. This resulted in successful engraftment, without producing a profound antibody mediated response or rejection of the recipient’s renal transplant once the donor antigens were reintroduced.
  • the recipient underwent a conditioning regimen of rabbit anti-thymocycte globulin and total lymphoid irradiation (Figure 1). After conditioning, the donor’s cryopreserved stem cells were thawed and infused through a peripherally-inserted central catheter. The recipient received immunosuppression as depicted in Figure 1. All components of this delayed tolerance protocol were completed on an outpatient basis.
  • donor-derived stem cells A major concern with this delayed tolerance approach is the administration of donor-derived stem cells is that it reintroduces donor antigens. This sensitizing event can result in a profound recipient response, one that may trigger rejection and even the devastating loss of the living donor transplant. This process did not occur in our case.
  • Successful engraftment of stem cells and durable chimerism was achieved with rabbit anti -thymocyte globulin and total lymphoid irradiation, allowing for tolerance and complete removal of maintenance immunosuppression.
  • a second patient has undergone our protocol and has also exhibited successful engraftment and durable chimerism, and is currently in the process of tapering immunosuppression.
  • the delayed tolerance approach has several benefits for transplant recipients. As seen in this case, withdrawal of tacrolimus results in improvement in renal allograft function. Calcineurin inhibitors are known nephrotoxins which result in progressive allograft deterioration and return to dialysis. Achieving tolerance and withdrawal of immunosuppression can increase the life of a transplant, preventing the need for retransplantation and permitting one transplant for life.
  • Delayed tolerance may allow for tolerance trials to other solid organ transplant recipients.
  • Heart, lung, and liver transplant recipients are often critically ill at the time of transplantation and may not be suitable for conditioning therapy immediately following organ transplantation.
  • a delayed tolerance approach would permit adequate time for recovery and rehabilitation prior to undergoing the condition regimen. All donor and recipient components of this protocol were conducted in an outpatient setting.
  • conditioning regimens for simultaneous tolerance require prolonged admission to the hospital. Performing tolerance in the outpatient setting takes the strain off of the operating rooms, medical staff, hospital bed capacity, and is much more cost effective.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Developmental Biology & Embryology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Transplantation (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention divulguée propose des procédés et des matériaux conçus pour améliorer les résultats de greffe d'organe. Des modes de réalisation de l'invention comprennent des procédés conçus pour fournir à des patients présentant une greffe d'organe solide fonctionnelle préexistante un moyen de retrait de médicaments immunosuppresseurs tout en maintenant une fonction normale. Dans des modes de réalisation de l'invention, ceci est accompli par une transfusion de cellules souches/progénitrices hématopoïétiques (HSPC) et de cellules T provenant du même donneur qui a fourni l'organe solide d'origine au patient, les procédés comprenant un régime de conditionnement effectué sur le patient.
EP23904745.9A 2022-12-16 2023-12-18 Induction de tolérance immunologique rétroactive (retardée) chez des patients avec des transplantations d'organes solides préexistants Pending EP4633647A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202263433059P 2022-12-16 2022-12-16
US202363504844P 2023-05-30 2023-05-30
PCT/US2023/084521 WO2024130234A1 (fr) 2022-12-16 2023-12-18 Induction de tolérance immunologique rétroactive (retardée) chez des patients avec des transplantations d'organes solides préexistants

Publications (1)

Publication Number Publication Date
EP4633647A1 true EP4633647A1 (fr) 2025-10-22

Family

ID=91486209

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23904745.9A Pending EP4633647A1 (fr) 2022-12-16 2023-12-18 Induction de tolérance immunologique rétroactive (retardée) chez des patients avec des transplantations d'organes solides préexistants

Country Status (2)

Country Link
EP (1) EP4633647A1 (fr)
WO (1) WO2024130234A1 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6305443B2 (ja) * 2013-02-26 2018-04-04 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー 移植片の移植寛容のための組み合わされた臓器及び造血細胞
WO2020047236A1 (fr) * 2018-08-30 2020-03-05 The Regents Of The University Of California Mobilisation et collecte de cellules souches hématopoïétiques de sang périphérique à partir de donneurs décédés
WO2020077267A1 (fr) * 2018-10-11 2020-04-16 Northwestern University Biomarqueur d'insuffisance rénale chronique chez des receveurs de transplantation hépatique
JP2023543863A (ja) * 2020-09-30 2023-10-18 ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー ドナー造血細胞キメリズム並びに臓器及び組織移植並びに自己免疫寛容
US20250114360A1 (en) * 2022-02-03 2025-04-10 The Regents Of The University Of California Novel regimen for augmenting and extending transplant tolerance

Also Published As

Publication number Publication date
WO2024130234A1 (fr) 2024-06-20

Similar Documents

Publication Publication Date Title
MORRIS et al. A controlled trial of cyclosporine in renal transplantation with conversion to azathioprine and prednisolone after three months
US12559720B2 (en) Mobilization and collection of peripheral blood hematopoietic stem cells and lymphocytes from deceased donors
KR20250048489A (ko) 줄기 세포 이식을 위한 방법
US20250114360A1 (en) Novel regimen for augmenting and extending transplant tolerance
Menahem et al. Native kidney BK nephropathy post cardiac transplantation
EP4633647A1 (fr) Induction de tolérance immunologique rétroactive (retardée) chez des patients avec des transplantations d'organes solides préexistants
Boghossian et al. Laparoscopic nephrectomy donor death due to cerebral gas embolism in a specialized transplant center: risk zero does not exist
US20210346317A1 (en) Treatment of hematopoietic stem cell transplant patients
Zakerinia et al. Bone marrow transplantation in thalassemia major patients using “short” anti-thymocyte globulin therapy in Shiraz, Southern Iran
Burdese et al. Sirolimus and ACE-inhibitors: a note of caution
CA2292734A1 (fr) Utilisation de composes de la vitamine d pour eviter les rejets de greffes
Akalin et al. Intravenous immunoglobulin treatment in a kidney transplant patient with chronic allograft nephropathy
Leventhal et al. Long-term follow-up of a phase 2 clinical trial to induce tolerance in living donor renal transplant recipients
Patel Organ transplant medicine
US20240238301A1 (en) Compositions and methods for reduced toxicity in transplantation using janus kinase (jak) inhibitors
JPH11343242A (ja) 造血幹細胞移植用剤
JP2010509360A (ja) 幹細胞移植を補助するためにＡＬＤＨｂｒ細胞を使用する方法
Rzhevskaya et al. Optimization of immunosuppressive therapy during the third kidney transplant in the early postoperative period. Clinical observation
Wang et al. UroToday International Journal
Kazory et al. Cytomegalovirus and thromboembolism in renal transplantation
SETYA et al. SUN-358 INDICATIONS, EFFICACY AND SAFETY OF THERAPEUTIC APHERESIS IN NEPHROLOGY PATIENTS
Davidson et al. Renal replacement therapy in the highly sensitised patient: Case Study
Goyal et al. Association of Infection Rate in Heart Transplant Recipients with Combined Tacrolimus and Sirolimus at High versus Low Concentration
Carbajal et al. Cyclosporine and low-dose ketoconazole in renal transplant recipients: a single center experience
Tan et al. Hypophosphatemia and the live liver donor

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250527

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)