WO2024112158A1 - Plateforme d'évaluation d'agent anticancéreux immunothérapeutique utilisant un système d'avatar imitant l'immunité d'un patient cancéreux - Google Patents

Plateforme d'évaluation d'agent anticancéreux immunothérapeutique utilisant un système d'avatar imitant l'immunité d'un patient cancéreux Download PDF

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WO2024112158A1
WO2024112158A1 PCT/KR2023/019128 KR2023019128W WO2024112158A1 WO 2024112158 A1 WO2024112158 A1 WO 2024112158A1 KR 2023019128 W KR2023019128 W KR 2023019128W WO 2024112158 A1 WO2024112158 A1 WO 2024112158A1
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clause
animal model
gastric cancer
cells
tumor
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PCT/KR2023/019128
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Korean (ko)
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송교영
조미라
전주연
이승윤
이건희
최정원
김소정
정윤주
우진석
한세경
조상희
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가톨릭대학교 산학협력단
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Priority claimed from KR1020230165729A external-priority patent/KR20240078385A/ko
Publication of WO2024112158A1 publication Critical patent/WO2024112158A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention relates to an immuno-anticancer drug evaluation platform using a cancer patient immunomimetic avatar system.
  • targeted anticancer drugs were developed that target genetic mutations that occur in each cancer type, and the side effects caused by existing chemical anticancer drugs were improved, but cancer cells adapt very quickly to the environment.
  • 100% continuous cancer treatment effect by targeted anticancer drugs cannot be expected because anticancer drug resistance is induced to escape the attack of targeted anticancer drugs.
  • research on anticancer drugs and the tumor microenvironment has been actively conducted, and immuno-anticancer drugs against various immune checkpoint inhibitors that regulate the patient's immunity while maintaining anticancer effects have been developed and are being used as treatments for patients.
  • treatment against PD-1/PD-L1 is known to show a high therapeutic response in patients with skin cancer, lung cancer, etc.
  • immuno-anticancer drugs have the function of inhibiting the proliferation of cancer cells and increasing the activity of immune cells by regulating the function of immune cells within the tumor microenvironment.
  • immunotherapy drugs do not show the same anticancer effect in all patients, biomarkers for immunotherapy drugs are not clearly identified, and anticancer drug resistance may occur due to JAK-STAT genetic mutation or autoimmune diseases may occur due to the characteristics of antibody compounds. There are problems such as high treatment costs.
  • tailored medicine is also called custom-made medicine or personalized medicine. It examines each patient's constitution or environment individually and determines a treatment appropriate for them. It means treatment method.
  • biomarkers for genomic diagnosis various genomic testing methods, and medical informatics that can analyze/integrate genomic information derived using the biomarkers or obtained by the testing methods are used.
  • Analysis methods and targeted treatment technologies that can apply the results analyzed by the above analysis methods must be developed in advance in a complementary manner. In other words, not only is it necessary to develop a technology that can select a treatment appropriate for a patient, but also a technology that can verify the selected treatment must be developed.
  • the present inventors injected peripheral blood mononuclear cells (PBMCs) from patients. Afterwards, the present invention, which can produce an effective gastric cancer avatar animal model, was completed by additionally transplanting gastric cancer cell lines.
  • PBMCs peripheral blood mononuclear cells
  • the purpose of the present invention is to provide a humanized gastric cancer animal model in which immunodeficient mice are injected with PBMC (Peripheral blood mononuclear cells) and gastric cancer cell lines derived from gastric cancer patients.
  • PBMC Peripheral blood mononuclear cells
  • Another object of the present invention is to inject PBMC (Peripheral blood mononuclear cells) isolated from gastric cancer patients into immunodeficient mice; and
  • To provide a method for producing a humanized gastric cancer animal model including the step of transplanting a gastric cancer cell line into a mouse injected with the PBMC.
  • Another object of the present invention is to provide a screening method for a gastric cancer treatment substance, comprising treating the humanized stomach cancer cell line with a candidate substance.
  • the present invention provides a humanized gastric cancer animal model in which immunodeficient mice are injected with PBMC (Peripheral blood mononuclear cells) and gastric cancer cell lines derived from gastric cancer patients.
  • PBMC Peripheral blood mononuclear cells
  • the present invention includes the steps of injecting PBMC (Peripheral blood mononuclear cells) isolated from gastric cancer patients into immunodeficient mice; and
  • a method for producing a humanized gastric cancer animal model including the step of transplanting a gastric cancer cell line into a mouse injected with the PBMC.
  • the present invention provides a screening method for a gastric cancer treatment material, comprising the step of treating the humanized gastric cancer cell line with a candidate material.
  • the avatar model simulating gastric cancer patients of the present invention accelerates the progression of gastric cancer by increasing the size of tumors engrafted by transplantation of gastric cancer cell lines following injection of patient-derived PBMC.
  • injection of patient-derived PBMC significantly increases the expression of IL-10 and PD-L1, which are markers of immunodeficiency, and increases the expression of NF- ⁇ B, which is a factor that increases PD-L1 and is an inflammatory factor, thereby reducing the risk of gastric cancer patients. It was confirmed that it well reflects the immune status of.
  • the patient's immune cells engrafted which could reflect the clinical stage of the gastric cancer patient, and that the expression of PD-L1 and PD-1, markers of immunosuppression, was increased. It was confirmed that it can be used for customized medical treatment for stomach cancer patients.
  • a gastric cancer treatment drug tumor growth is suppressed, the expression of immunosuppression markers and tumor factors is suppressed, and related cells can be controlled, which can be used to evaluate the therapeutic drug responsiveness of gastric cancer patients. It can be useful in animal models related to anticancer or drug screening, so it can be economically used in the non-clinical stage for immunotherapy drug development.
  • Figure 1 schematically illustrates the production process of an avatar animal model simulating a gastric cancer patient according to the present invention.
  • Figure 2 is a diagram confirming tumor growth following injection of patient-derived PBMC in the avatar animal model simulating a gastric cancer patient of the present invention (A: confirmation of tumor volume over time, B: quantification of tumor volume).
  • Figure 3 is a diagram confirming the expression of immunodeficiency markers IL-10 and PD-L1 following injection of patient-derived PBMCs by immunohistochemical staining in the avatar animal model simulating gastric cancer patients of the present invention (A: staining results, B: Quantification of staining results).
  • Figure 4 is a diagram confirming the expression of NF- ⁇ B, an inflammatory factor, following injection of patient-derived PBMC in an avatar animal model simulating a gastric cancer patient of the present invention by immunohistochemical staining (A: staining result, B: staining result quantification) .
  • Figure 5 is a diagram confirming human immune cell engraftment following injection of patient-derived PBMC using flow cytometry in the avatar animal model simulating a gastric cancer patient of the present invention.
  • Figure 6 is a diagram confirming that tumor proliferation specifically increases in patient-derived PBMC in the avatar animal model simulating gastric cancer patients of the present invention (A: confirmation of tumor proliferation by number of days, B: confirmation of tumor volume, C: visual observation of tumor growth check).
  • Figure 7 is a diagram confirming the expression of immunodeficiency markers following injection of patient-derived PBMCs by confocal analysis in the avatar animal model simulating gastric cancer patients of the present invention (A: confocal analysis results, B: quantification of analysis results).
  • Figure 8 is a diagram confirming tumor growth according to the clinical stage of the patient in the avatar animal model simulating a gastric cancer patient of the present invention.
  • Figure 9 is a diagram confirming tumor growth according to treatment drug treatment in the avatar animal model simulating gastric cancer patients of the present invention (A: confirmation of tumor growth by number of days, B: confirmation of tumor volume).
  • Figure 10 is a diagram confirming the expression of immunosuppression markers and tumor factors according to treatment drug treatment by immunohistochemical staining in the avatar animal model simulating gastric cancer patients of the present invention (A: staining result, B: staining result quantification).
  • Figure 11 is a diagram confirming the expression of cells related to immune decline according to treatment drug treatment in the avatar animal model simulating gastric cancer patients of the present invention by confocal analysis (A: confocal analysis results, B: quantification of analysis results).
  • Figure 12 is a diagram confirming the expression of tumor immune regulatory cells according to treatment drug treatment by flow cytometry in the avatar animal model simulating gastric cancer patients of the present invention (A: flow cytometry results, B: quantification of results).
  • the present invention provides a humanized gastric cancer animal model in which immunodeficient mice are injected with PBMC (Peripheral blood mononuclear cells) and gastric cancer cell lines derived from gastric cancer patients.
  • PBMC Peripheral blood mononuclear cells
  • the “avatar animal model” of the present invention refers to a patient-specific xenograft animal model produced by stereotactic xenografting of patient-derived cells or tissues into an immunodeficient animal, and the disease and morphological environment in the patient are identical. Or, it is similar, the genetic environment is the same or similar, and the expression characteristics of the marker protein of the disease are the same, so that conditions that directly reflect the patient's genetic, physiological, and environmental characteristics can be provided.
  • xenotransplantation refers to a method of transplanting organs, tissues, cells, etc., such as the liver, heart, and kidney, of a different species of animal.
  • the xenotransplantation can be understood as a method of transplanting PBMC or human-derived gastric cancer cell lines isolated from a patient into an immunodeficient animal, but is not particularly limited thereto.
  • immunodeficiency animal in the present invention refers to an animal model manufactured by artificially damaging some components of the immune system at the genetic level to prevent the development of a disease, thereby preventing the development of a normal immune system.
  • the immunodeficient animal may be an animal with a formed nervous system, preferably an immunodeficient mammal, and more preferably an immunodeficient rodent such as a mouse, rat, hamster, or guinea pig engineered to be immunodeficient.
  • nude mice can be, and most preferably, nude mice, NSG (NOD scid gamma) mice, NOD (non-obese diabetic) mice, SCID (severe combined immunodeficiency) mice, NOD-SCID mice, NOG (NOD/SCID Il2rg-/ -) It may be a mouse, etc., but is not particularly limited thereto.
  • Particularly useful immunodeficient mouse strains include NOD, Cg-PrkdcscidIl2rgtml Wjl/SzJ, generally referred to as NOD scid gamma (NSG) mouse, as described in detail in Shultz et al., J Immunol, 174: 6477-6489, 2005. and NOD.Cg-Rag1tmlMomIl2rgtml Wjl/SzJ, generally referring to NRG mice (Shultz et al, Clin Exp Immunol, 154(2):270-284, 2008).
  • the term "tailored medicine” in the present invention is also referred to as ordered-made medicine or personalized medicine, and determines the appropriate treatment by individually examining each patient's constitution or environment. It means a method of doing something or a method of treatment.
  • the gastric cancer patient-derived PBMC may be injected at a concentration of 1 to 5 x 10 6
  • the gastric cancer cell line may be injected at a concentration of 1 to 5 x 10 6 .
  • the animal model may have increased tumor growth compared to the baseline value of the control group, and the tumor growth may be an increase in tumor volume.
  • the animal model may have increased expression of immunodeficiency markers compared to the baseline value of the control group, and the immunodeficiency markers include IL-10, PD-L1, PD-1, and It may be a factor selected from the group consisting of GDF-15.
  • PD-L1 or PD-1 may be a therapeutic target of an immunotherapy agent.
  • the animal model may have increased expression of inflammatory factors or tumor factors compared to the baseline value of the control group, and the inflammatory factors or tumor factors are NF- ⁇ B, STAT3, or VEGF. It may be.
  • the animal model may be one in which human immune cells have engrafted in the spleen, and the human immune cells may be Th1 or Th17.
  • the animal model may have increased expression of tumor immunocompromised cells compared to the baseline value of the control group, and the tumor immunocompromised cells include CD8 PD-L1 positive cells; CD8 + CD69 + PD-1 + cells; mCD68 PD-L1 positive cells; and mCD68 IL-10 positive cells; it may be a cell selected from the group consisting of.
  • the animal model may have reduced expression of INF- ⁇ positive CD8 T cells, which are tumor immune regulatory cells, compared to the baseline value of the control group.
  • the animal model may reflect the clinical stage of the patient, and the reflection of the clinical stage may mean that tumor growth increases as the clinical stage increases.
  • the present invention includes the steps of injecting PBMC (Peripheral blood mononuclear cells) isolated from gastric cancer patients into immunodeficient mice; and
  • a method for producing a humanized gastric cancer animal model including the step of transplanting a gastric cancer cell line into a mouse injected with the PBMC.
  • the step of injecting the PBMC may be performed 1 to 5 times over 0 to 4 weeks, and the step of transplanting the gastric cancer cell line may be performed 1 to 5 times over 0 to 4 weeks. It may be.
  • the present invention provides a screening method for a gastric cancer treatment material, comprising the step of treating the humanized gastric cancer cell line with a candidate material.
  • the candidate substance may reduce tumor volume compared to the baseline value of the control group.
  • the candidate substance may reduce the expression of an immunodeficiency marker compared to the baseline value of the control group.
  • the candidate substance may reduce the expression of inflammatory factors or tumor factors compared to the baseline value of the control group.
  • the candidate substance may reduce the expression of tumor immunocompromised cells compared to the baseline value of the control group, and increase the expression of INF- ⁇ positive CD8 T cells, which are tumor immune regulatory cells. It may be to do so.
  • the candidate substance may include an immuno-anti-cancer agent
  • the immuno-anti-cancer agent may be a PD-L1 or PD-1 targeting anti-cancer agent.
  • An avatar model simulating a stomach cancer patient according to the present invention was created. Specifically, to produce the gastric cancer patient avatar animal model of the present invention, 6-8 week old immunodeficient mice (NSG) were intravascularly injected with PBMC (Peripheral blood mononuclear cells) derived from gastric cancer patients at 5x10 6 /mice. One week after PBMC injection, 5x10 6 of the AGS cell line, a gastric cancer cell line, was mixed with 200 ul of Matrigel and injected subcutaneously to create an avatar model (AGS+PBMC) simulating a gastric cancer patient ( Figure 1).
  • NSG immunodeficient mice
  • a group administered only AGS (AGS only) was used as a control group.
  • AGS AGS only
  • the size of the tumor was measured three times every week using calipers, and the lengths of the long axis and short axis of the tumor were substituted into Equation 1 below to determine the tumor volume ( Tumor volume) was calculated.
  • mice from each group in Example 1 were humanely sacrificed at the end of the experiment, and then tumor tissues were obtained. Afterwards, the obtained tumor tissue was sectioned, and the expression of IL-10 and PD-L1, which are immunosuppression markers, was confirmed by immunohistochemical staining.
  • mice from each group in Example 1 were humanely sacrificed at the end of the experiment, and then tumor tissues were obtained. Afterwards, the obtained tumor tissue was sectioned, and the expression of NF- ⁇ B, an inflammatory factor, was confirmed by immunohistochemical staining.
  • the gastric cancer patient avatar model of the present invention reflects the patient's immune status
  • the effect of immune cell engraftment was confirmed. Specifically, spleen tissue was obtained from the mouse sacrificed in Example 2-2, and the expression of CD8 positive and CD4 positive cells was confirmed by flow cytometry.
  • gastric cancer patient avatar model of the present invention promoted tumor growth specifically in gastric cancer patient PBMC.
  • a gastric cancer patient PBMC injection model was prepared in the same manner as in Example 1, and as a control group, a group injected with only AGS, a gastric cancer cell line (AGS only), and a group injected with PBMC from normal people (AGS+HC) +PBMC) tumor growth was compared.
  • the tumor volume in the group injected with gastric cancer patient-derived PBMC (AGS+GC PBMC) group decreased with time after tumor transplantation. It was confirmed that the tumor volume increased significantly at the time of sacrifice.
  • the avatar model simulating gastric cancer patients of the present invention increases the expression of immunosuppression markers. Specifically, in the tumor tissues obtained from the AGS+GC PBMC group and the AGS only group among the groups of mice sacrificed in Example 3, the expression of PD-L1 and PD-1, which are immunosuppression markers, was analyzed confocally.
  • PBMC injection according to the clinical stage of gastric cancer patient affects tumor growth. Specifically, while creating an avatar model replicating a gastric cancer patient in the same manner as in Example 1, PBMCs derived from patients with stage 1 and early stage 2 gastric cancer (1, 2A) and late stage 2 and stage 3 stomach cancer (2B, 3) Patient-derived PBMCs were injected and tumor growth was confirmed.
  • tumor growth was increased in the group injected with patient-derived PBMC compared to the AGS only group, and in particular, compared to the group injected with PBMC derived from patients 1 and 2A, patients 2B and 3 had increased tumor growth. It was confirmed that tumor growth was significantly increased in the group injected with derived PBMC, and it was confirmed that the avatar model simulating gastric cancer patients of the present invention also reflects the clinical stage of gastric cancer patients.
  • the avatar model simulating a stomach cancer patient of the present invention responsiveness to a stomach cancer treatment drug was confirmed. Specifically, in an avatar model simulating gastric cancer patients, 200 mg/kg of butyric acid, a therapeutic drug with a confirmed PD-1 inhibitory effect, was orally administered daily (Butyric acid group). As control groups, the Vehicle group and the AGS only group administered the same amount of solvent were used. Then, at the end of the experiment, the mice in each group were humanely sacrificed and the tumor volume was checked.
  • the expression of immunodeficiency markers and tumor factors according to drug responsiveness was confirmed. Specifically, tumor tissues were obtained from each group of mice sacrificed in Example 6-1, and immunosuppression markers IL-10, PD-L1, and GDF-15, and tumor factors NF- ⁇ B, STAT3, and VEGF were examined. The expression of was confirmed by immunohistochemical staining.
  • the expression of cells related to gastric cancer immunity according to drug responsiveness was regulated. Specifically, spleen tissue was obtained from each group of mice sacrificed in Example 6-1, and the expression of immune cells related to tumor immunity was analyzed confocally. In addition, the expression of INF- ⁇ positive CD8 T cells, which are tumor immune regulatory cells, was analyzed by flow cytometry.
  • INF- ⁇ positive CD8 T cells which are tumor immune regulatory cells, were confirmed to have significantly increased in the Drug group compared to the Vehicle group, and the avatar animal model simulating gastric cancer patients of the present invention was found to be effective in improving the patient's immunity following drug administration. It was confirmed that cell reactivity could be evaluated (FIG. 12).
  • the avatar model simulating a gastric cancer patient of the present invention accelerates the progression of gastric cancer by increasing the size of the tumor engrafted by transplantation of the gastric cancer cell line upon injection of patient-derived PBMC.
  • injection of patient-derived PBMCs significantly increased the expression of IL-10 and PD-L1, which are immunosuppression markers, and increased the expression of NF- ⁇ B, an inflammatory factor, reflecting the immune status of gastric cancer patients well.
  • IL-10 and PD-L1 which are immunosuppression markers
  • NF- ⁇ B an inflammatory factor

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Abstract

La présente invention concerne une plateforme d'évaluation d'agent anticancéreux immunothérapeutique utilisant un système d'avatar imitant l'immunité d'un patient cancéreux. Il a été découvert que le modèle d'avatar imitant un patient cancéreux gastrique de la présente invention accélère la progression du cancer gastrique en augmentant la taille de tumeurs greffées par la transplantation de lignées cellulaires cancéreuses gastriques, après l'injection de PBMC dérivées du patient. En outre, il a été découvert que l'injection de PBMC dérivées du patient a considérablement augmenté l'expression des marqueurs immunosuppresseurs IL-10 et PD-L1 et a régulé à la hausse l'expression du marqueur inflammatoire NF-κB, reflétant ainsi précisément l'état immunitaire de patients atteints d'un cancer gastrique. Il a également été observé que les cellules immunitaires du patient ont été greffées, que le stade clinique du cancer gastrique pourrait être réfléchi, et que l'expression des marqueurs immunosuppresseurs PD-L1 et PD-1 a été régulée à la hausse. Cette découverte indique l'utilisation potentielle du système de médicaments préparés en fonction des commandes pour des patients atteints d'un cancer gastrique. De plus, il s'est avéré que l'administration de médicaments thérapeutiques contre le cancer gastrique inhibe la prolifération tumorale, supprime l'expression de marqueurs immunosuppresseurs et de facteurs tumoraux, et régule des cellules associées de telle sorte que le système peut être utilisé pour évaluer la réactivité médicamenteuse de patients atteints d'un cancer gastrique. Par conséquent, le système peut être avantageusement appliqué pour cribler des modèles ou des médicaments vétérinaires associés à l'immunothérapie, et est économiquement viable pour des stades précliniques dans le développement de médicaments anticancéreux immunothérapeutiques.
PCT/KR2023/019128 2022-11-25 2023-11-24 Plateforme d'évaluation d'agent anticancéreux immunothérapeutique utilisant un système d'avatar imitant l'immunité d'un patient cancéreux WO2024112158A1 (fr)

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KR1020230165729A KR20240078385A (ko) 2022-11-25 2023-11-24 암환자 면역모사 아바타 시스템을 이용한 면역항암제 평가플랫폼

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220127639A1 (en) * 2015-06-23 2022-04-28 The Jackson Laboratory Non-hla matched humanized nsg mouse model with patient-derived xenograft

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US20220127639A1 (en) * 2015-06-23 2022-04-28 The Jackson Laboratory Non-hla matched humanized nsg mouse model with patient-derived xenograft

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BARATI TAHEREH, HADDADI MAHNAZ; SADEGHI FATEMEH; MUHAMMADNEJAD SAMAD; MUHAMMADNEJAD AHAD; HEIDARIAN RONAK; ARJOMANDNEJAD MOTAHAREH: "AGS cell line xenograft tumor as a suitable gastric adenocarcinoma model: growth kinetic characterization and immunohistochemistry analysis", IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES, vol. 21, 1 January 2018 (2018-01-01), pages 678 - 681, XP093174907, DOI: 10.22038/IJBMS.2018.22938.5835 *
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