WO2018153936A1 - Cellules stromales mésenchymateuses dérivées de tissu adipeux destinées à être utilisées dans le traitement d'une maladie du greffon contre l'hôte - Google Patents

Cellules stromales mésenchymateuses dérivées de tissu adipeux destinées à être utilisées dans le traitement d'une maladie du greffon contre l'hôte Download PDF

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WO2018153936A1
WO2018153936A1 PCT/EP2018/054309 EP2018054309W WO2018153936A1 WO 2018153936 A1 WO2018153936 A1 WO 2018153936A1 EP 2018054309 W EP2018054309 W EP 2018054309W WO 2018153936 A1 WO2018153936 A1 WO 2018153936A1
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mscs
product
use according
versus
graft
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PCT/EP2018/054309
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Manuel JURADO CHACÓN
Antonio RUÍZ GARCÍA
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Servicio Andaluz De Salud
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Adipose tissue-derived mesenchymal stromal cells for use in the treatment of graft- versus-host disease
  • the invention relates to the field of medical treatments, immunology and cell therapy, and more specifically to the treatment of patients with adipose tissue-derived mesenchymal stromal cells combined or not with immunosuppressive agents for the treatment of graft- versus-host disease.
  • Allogeneic hematopoietic stem cell transplantation is a well established procedure for curing several hematological malignancies.
  • Acute and chronic graft-versus-host disease (GvHD), still the main causes of non-relapse mortality (NRM), are objects of clinical research.
  • GvHD graft-versus-host disease
  • NPM non-relapse mortality
  • several methods have been developed; their controversial effects include a higher risk of relapse, delayed immune reconstitution, and infectious complications (1 -3).
  • new efforts have been made to better classify chronic GvHD (5,6). Meanwhile, little progress has been achieved in treating patients with aggressive GvHD.
  • MSC Mesenchymal stromal cells
  • the present invention demonstrate the safety and feasibility of two different doses of adipose tissue-derived mesenchymal stromal cells (AT-MSCs) in patients with chronic GvHD.
  • AT-MSCs adipose tissue-derived mesenchymal stromal cells
  • a first aspect of the invention refers to a product selected from the group consisting of a composition or a kit of parts wherein the product (the composition or the kit of parts) comprises an AT-MSCs and an immunosuppressive agent for use in the treatment, prevention or amelioration of GvHD.
  • the AT-MSCs are autologous or allogeneic. In a more preferred embodiment the AT-MSCs are autologous.
  • the amount of AT-MSCs is above 0.5x10 6 /Kg. In a more preferred embodiment the amount of AT-MSCs is comprised between approximately 0.5x10 6 /Kg and 5x10 6 /Kg. In a yet more preferred embodiment, the amount of AT-MSCs is comprised between approximately 1 x10 6 /Kg and 3x10 6 /Kg. In another preferred embodiment, the AT-MSCs expanded until a maximum of three cell passages.
  • the AT-MSCs are administered intravenously through a central line. In a more preferred embodiment, the AT-MSCs are administered intravenously through a central line in a maximum of 10 minutes ' time.
  • the immunosuppressive agent is selected from the list consisting of a glucocorticoid, cytostatic, antibody, cyclosporine, tracolimus, sirolimus, everolimus, interferon, opioid, TNF binding proteins, and mycophenolate agents, or combination thereof.
  • the glucocorticoid is prednisone.
  • the immunosuppressive agents are cyclosporine (CsA) and prednisone.
  • the cyclosporine is given at the dose of 3 mg/Kg/12h and tapered when the chronic GvHD is under control.
  • the prednisone is given at the dose of 1 mg/Kg/day and tapered when the clinical situation allows the discontinuation.
  • FIG. 1 Kaplan-Meier curve for complete remission of patients receiving AT-MSC. Ten patients (6 in group A and 4 in group B) were able to continue the protocol at week 20: 5 in complete remission (CR) and 5 in partial remission (PR); week 42: 6 in CR and 4 in PR; and week 56: 8 in CR and 2 in PR. The median time needed to achieve CR was 36.6 weeks.
  • Figure 2. Kaplan-Meier curve for overall survival of patients receiving AT-MSC. Group A: Dose of AT-MSC infused of 1x10 6 /Kg. Group B: Dose of AT-MSC infused of 3x10 6 /Kg.
  • the problem addressed by the present invention is to provide patients suffering from graft- versus-host disease (GvHD), preferably patients with the diagnosis of moderate or severe chronic GvHD, according to the National Institutes of Health (NIH) consensus (5), with an improved therapeutic alternative.
  • GvHD graft- versus-host disease
  • NASH National Institutes of Health
  • Such therapeutic improved alternative is provided by the present invention in the form of adipose tissue-derived mesenchymal stromal cells (AT-MSCs) as defined by the aspects and preferred embodiments referred to below.
  • a first aspect of the invention refers to a product, hereinafter "product of the invention” selected from the group consisting of a composition or a kit of parts wherein the product comprises an AT-MSCs and an immunosuppressive agent for use in the treatment, prevention or amelioration of GvHD.
  • the AT-MSCs are autologous or allogeneic. In a more preferred embodiment the AT-MSCs are autologous. In another more preferred embodiment the AT- MSCs are allogeneic. In another preferred embodiment, the amount of AT-MSCs is above 0.5x10 6 /Kg. In a more preferred embodiment the amount of AT-MSCs is comprised between approximately 0.5x10 6 /Kg and 5x10 6 /Kg. In a yet more preferred embodiment, the amount of AT-MSCs is comprised between approximately 1 x10 6 /Kg and 3x10 6 /Kg.
  • the AT-MSCs expanded until a maximum of three cell passages.
  • the AT-MSCs are administered intravenously through a central line. In a more preferred embodiment, the AT-MSCs are administered intravenously through a central line in a maximum of 10 minutes ' time.
  • adipose tissue derived mesenchymal cells or "AT-MSCs”, as used herein, refers to mesenchymal stem cells that originate from adipose tissue.
  • MSC meenchymal stem cell
  • meenchymal stromal cell or “MSC” refers to a multipotent stroma cell, originated from the germinal layer mesodermal, which can differentiate into a variety of cell types.
  • the International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs.
  • a cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology.
  • MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex-vivo.
  • adipose tissue is meant any fat tissue.
  • the adipose tissue may be brown or white adipose tissue, derived from subcutaneous, omental/visceral, mammary, gonadal, or other adipose tissue site.
  • GvHD raft-versus-host disease
  • Immune cells white blood cells
  • the recipient the host
  • the transplanted immune cells then attack the host's body cells.
  • GvHD can also occur after a blood transfusion if the blood products used have not been irradiated or treated with an approved pathogen reduction system.
  • composition of the invention for use in the treatment, prevention or amelioration of GvHD, preferably is a pharmaceutical composition. More preferably, the composition of the invention comprises also a pharmaceutically acceptable carrier. In another preferred embodiment of this aspect of the invention, the composition of the invention comprises also another active ingredient In a preferred embodiment of this aspect the composition of the invention comprises also another active ingredient together with a pharmaceutically acceptable carrier.
  • active ingredients of biological origin include growth factors, hormones, and cytokines.
  • a variety of therapeutic agents are known in the art and may be identified by their effects. Certain therapeutic agents are capable of regulating cell proliferation and differentiation. Examples include chemotherapeutic nucleotides, drugs, hormones, non-specific (non-antibody) proteins, oligonucleotides (e.g., antisense oligonucleotides that bind to a target nucleic acid sequence (e.g., mRNA sequence)), peptides, and peptidomimetics.
  • chemotherapeutic nucleotides drugs, hormones, non-specific (non-antibody) proteins, oligonucleotides (e.g., antisense oligonucleotides that bind to a target nucleic acid sequence (e.g., mRNA sequence)), peptides, and peptidomimetics.
  • pharmaceutically acceptable excipient refers to the fact that it must be approved by a regulatory agency of the federal government or a national government or one listed in the United States Pharmacopoeia or the European Pharmacopoeia, or some other pharmacopoeia generally recognized for use in animals and in humans.
  • vehicle or “carrier” relates to a diluent, excipient, carrier or adjuvant with which the stem cells, progenitor cells or differentiated cells of the invention, the immortalized cells of the invention, as well as the cells of the cell population of the invention, must be administered; obviously, said vehicle must be compatible with the cells.
  • Illustrative, non-limiting examples of said vehicle include any physiologically compatible vehicle, for example isotonic solutions (e.g. sterile saline solution (0.9% NaCI), phosphate -buffered saline solution (PBS), Ringer-lactate solution, etc.), optionally supplemented with serum, preferably with autologous serum; culture media (e.g.
  • DMEM fetal calf serum
  • RPMI RPMI
  • McCoy fetal calf serum
  • a solid, semisolid, gelatinous or viscous support medium such as collagen, collagen-glycosamine-glycan, fibrin, polyvinyl chloride, poly-amino acids, such as polylysine, or polyornithine, hydrogels, agarose, dextran sulphate silicone.
  • the support medium can, in special embodiments, contain growth factors or other agents. If the support is solid, semisolid, or gelatinous, the cells can be introduced in a liquid phase of the vehicle that is treated subsequently so that it is converted into a more solid phase.
  • said vehicle in some embodiments of the invention in which the vehicle has a solid structure, said vehicle can be configured according to the form of the lesion.
  • the pharmaceutical composition of the invention can, if desired, also contain, when necessary, additives for increasing and/or controlling the desired therapeutic effect of the cells, e.g. buffering agents, surface-active agents, preservatives, etc.
  • the pharmaceutically acceptable carrier may comprise a cell culture medium which supports the cells' viability.
  • the medium will generally be serum-free in order to avoid provoking an immune response in the recipient.
  • the carrier will generally be buffered and/or pyrogen free. Also, for stabilizing the cellular suspension, it is possible to add chelating agents of metals.
  • the stability of the cells in the liquid medium of the pharmaceutical composition of the invention can be improved by adding additional substances, such as, for example, aspartic acid, glutamic acid, etc.
  • Said pharmaceutically acceptable substances that can be used in the pharmaceutical composition of the invention are generally known by a person skilled in the art and are normally used in the production of cellular compositions. Examples of suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Additional information on said vehicles can be found in any manual of pharmaceutical technology (that is, galenical pharmacy).
  • the pharmaceutical composition of the invention will be administered in a suitable pharmaceutical form of administration.
  • the pharmaceutical composition of the invention will be formulated according to the chosen form of administration.
  • the formulation will be adapted to the method of administration.
  • the pharmaceutical composition is prepared in a liquid, solid or semisolid dosage form, e.g. in the form of suspension, in order to be administered by implanting, injection or infusion to the subject needing treatment.
  • a pharmaceutically acceptable excipient e.g. an isotonic solution, for example, phosphate-buffered saline solution (PBS), or any other suitable, pharmaceutically acceptable vehicle, for administration to a subject parenterally, although other routes of administration can also be used.
  • PBS phosphate-buffered saline solution
  • composition of the invention to the subject who needs it will be carried out using conventional means.
  • said pharmaceutical composition of the invention can be administered to the subject parenterally using suitable devices such as syringes, catheters, trocars, cannulas, etc.
  • the pharmaceutical composition of the invention will be administered using equipment, apparatus and devices suitable for the administration of cellular compositions and known by a person skilled in the art.
  • direct administration of the pharmaceutical composition of the invention to the site that is intended to benefit may be advantageous.
  • direct administration of the pharmaceutical composition of the invention to the desired organ or tissue can be achieved by direct administration (e.g. by injection, etc.) on the external surface of the affected organ or tissue by inserting a suitable device, e.g. a suitable cannula, by infusion (including reverse flow mechanisms) or by other means described in this patent or known in the art.
  • composition of the invention is administered intravenously through a central line.
  • AT-MSCs are administered intravenously through a central line in a maximum of 10 minutes time.
  • the pharmaceutical composition of the invention can be stored until the moment of its application by the conventional methods known by a person skilled in the art.
  • the pharmaceutical composition of the invention can be stored at or below room temperature in a sealed container, supplemented or not with a nutrient solution.
  • Medium-term storage (less than 48 hours) is preferably carried out at 2-8[deg.]C, and the pharmaceutical composition of the invention includes, in addition, an iso-osmotic, buffered solution in a container made of or lined with a material that prevents cellular adhesion.
  • Longer- term storage is preferably carried out by means of suitable cryopreservation and storage in conditions that promote the retention of cellular function.
  • composition of the invention consists in AT-MSCs and an immunosuppressive agent, and optionally, a pharmaceutically acceptable excipient and/or carrier.
  • kit of parts may comprise separate formulations of AT-MSCs and immunosuppressive agent.
  • the separate formulations of AT-MSCs and immunosuppressive agent may be administered sequentially, separately and/or simultaneously (optionally repeatedly).
  • the two active ingredients can be administered either as a part of the same composition (pharmaceutical composition) or in separate compositions (pharmaceutical compositions).
  • AT-MSCs can be administered prior to, at the same time as, or subsequent to administration of immunosuppressive agent, or in some combination thereof.
  • kits of parts means that the components of the combined preparation need not be present as an union (the components in the combination did not enter into direct interaction with each other), for example in a composition, to be available for use separately or sequentially.
  • juxtaposed means that is not necessarily true combination, in view of the physical separation of the components.
  • kit of parts of the invention consists in: a) AT-MSCs and
  • an immunosuppressive agent b) an immunosuppressive agent, and optionally, a pharmaceutically acceptable excipient and/or carrier.
  • the terms “treat”, “treatment” and “treating” refer to the amelioration, cure or remedy of GvHD, which results from the administration of the pharmaceutical composition or the kit of parts provided by the present invention comprising AT-MSCs and an immunosuppressive agent to a subject in need of said treatment.
  • isolated applied to a cell population refers to a cell population, isolated from the human or animal body, which is substantially free of one or more cell populations that are associated with said cell population in vivo or in vitro.
  • the immunosuppressive agent is selected from the list consisting of a glucocorticoid, cytostatic, antibody, cyclosporine, tracolimus, sirolimus, everolimus, interferon, opioid, TNF binding proteins, and mycophenolate agents, or combination thereof.
  • the glucocorticoid is prednisone.
  • the immunosuppressive agents are cyclosporine (CsA) and prednisone.
  • the cyclosporine is given at the dose of 3 mg/Kg/12h and tapered when the chronic GvHD is under control.
  • the prednisone is given at the dose of 1 mg/Kg/day and tapered when the clinical situation allows the discontinuation.
  • the prednisone dose is tapered 2 weeks, then is tapered at weeks 7 and 20 (1 mg/Kg and 0.5 mg/Kg every other day, respectively); from week 42 onward, prednisone is reduced until stopping at week 46 as long as the clinical situation allowed the discontinuation.
  • Immunosuppressive agents or Immunosuppressive drugs are active principles that inhibit or prevent activity of the immune system.
  • active ingredient means any component that potentially provides a pharmacological activity or another different effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or that affect the structure and function of the human body and of other animals.
  • active pharmaceutical ingredient means any component that potentially provides a pharmacological activity or another different effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or that affect the structure and function of the human body and of other animals.
  • the term includes those components that promote a chemical change in the elaboration of the medicament and that are present in the same in a predicted modified form that provides the specific activity or the effect.
  • Adipose tissue was obtained from a third party by surgical excision, from patients undergoing abdominoplasty or liposuction under sterile conditions. Donor suitability was ensured by a study of medical history plus laboratory tests to exclude the transmission of infectious agents (serology and PCR: HIV, HBV, HCV). Depending on the fat reservoir, 400 to 1000 grams of tissue were removed from the donor in the operating room and transferred in physiological serum to the Cell Production Unit. Production and packaging operations were performed in a biosafety cabinet (Class A) in the cleanrooms (Class B). Facilities and methods met good manufacturing practice requirements and were authorized by the Spanish Medical Agency. The tissue was mechanically disintegrated, digested with collagenase, centrifuged and filtered.
  • Class A biosafety cabinet
  • Class B cleanrooms
  • the cells obtained were seeded in culture flasks and expanded until obtaining a maximum of three cell passages.
  • Adipose tissue-derived mesenchymal stromal cells were recovered and packaged with DMSO for cryopreservation (29,30).
  • the AT-MSCs were kept in quarantine until the results of quality control met acceptance criteria (Table 1 ).
  • AT-MSCs were thawed and seeded into culture flasks to select viable cells and remove any traces of DMSO. Recovered cells were resuspended in a solution of Ringer lactate/Albumin, and bagged for intravenous infusion. The finished product was tested for sterility, mycoplasma and endotoxin absence.
  • AT-MSCs The infusion of AT-MSCs was administered intravenously through a central line in a maximum of 10 minutes ' time. Since neither febrile nor allergic reactions are described in the literature, no prophylactic medication was used. Before and after infusion, vital signs (temperature, blood pressure, oxygen saturation) were measured.
  • Cyclosporine was given at the dose of 3 mg/Kg/12h and adjusted to maintain trough levels of 100 to 200 ng/mL.
  • Prednisone at the dose of 1 mg/Kg/day was tapered at weeks 7 and 20 (1 mg/Kg and 0.5 mg/Kg every other day, respectively); from week 42 onward, prednisone was reduced until stopping at week 46 as long as the clinical situation allowed the discontinuation.
  • CsA was also tapered, finishing at week 56.
  • Patients were evaluated following NIH consensus for diagnosis (5) with computed tomography (CT), pulmonary function tests (PFT), Schirmer test (ST), physical evaluation, endoscopy as required, blood cell counts and chemistry at the time of inclusion.
  • CT, PFT and ST were also repeated in order to assess the grade of response using the NIH consensus for treatment (31 ).
  • Example 3 Study endpoints The main endpoint was to analyze the safety (unexpected outcome) and feasibility (assessing the potential of this new procedure) of the infusion of expanded AT-MSCs as part of therapy in patients with moderate or severe chronic GvHD. Secondary endpoints included assessment of efficacy as the clinical response (partial and complete) at weeks 20, 42 and 56; the percentage of patients who were able to reduce the dose of prednisone at weeks 7, 20 and 42; and the proportion of patients who were off immunosuppressive therapy at week 56.
  • OS overall survival
  • IL-2 pro-inflammatory
  • TNF-a TNF-a
  • IFN- ⁇ inhibitory
  • IL-4 IL-5
  • I L-10 lymphocyte subsets
  • week 56 all patients were off steroids, although 9 out of 10 remained on CsA.
  • Lymphocyte subpopulations CD45, CD3, CD19, CD4, CD8, CD56, CD16
  • IL-2, TNF-a, IFN- ⁇ pro-inflammatory
  • IL-4, IL-5 and IL-10 inhibitory
  • cytokines were analyzed using flow cytometry in both groups of patients.
  • both CD19 and NK cells showed significant increases globally, and particularly at weeks 7, 20 and 42; there were also higher median CD4 levels at week 42 compared to baseline.
  • Maccario R Podesta M, Moretta A, Cometa A, Comoli P, Montagna D et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005;90:516-25.( 1 1 . Le Blanc K, Ringden O. Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Curr Opin Immunol 2006; 18:586-91 . (
  • Subbanna PK Mesenchymal stem cells for treating GVHD: in-vivo fate and optimal dose. Med Hypotheses 2007;69:469-70.
  • Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft- versus-host disease. Stem Cells 2006; 24:2582-91 .

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Abstract

La présente invention concerne l'utilisation d'un produit choisi dans le groupe constitué par une composition et un kit de pièces, le produit comprenant des AT-MSC et un agent immunosuppresseur pour le traitement, la prévention ou l'amélioration de la GvHD.
PCT/EP2018/054309 2017-02-21 2018-02-21 Cellules stromales mésenchymateuses dérivées de tissu adipeux destinées à être utilisées dans le traitement d'une maladie du greffon contre l'hôte WO2018153936A1 (fr)

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