WO2017103086A1 - Méthode pour prédire la réponse à une immunothérapie anticancéreuse de blocage du point de contrôle - Google Patents

Méthode pour prédire la réponse à une immunothérapie anticancéreuse de blocage du point de contrôle Download PDF

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WO2017103086A1
WO2017103086A1 PCT/EP2016/081399 EP2016081399W WO2017103086A1 WO 2017103086 A1 WO2017103086 A1 WO 2017103086A1 EP 2016081399 W EP2016081399 W EP 2016081399W WO 2017103086 A1 WO2017103086 A1 WO 2017103086A1
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antibodies
patients
immune
cancer
cancer immunotherapy
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Jérôme GALON
Bernhard Mlecnik
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Universite Pierre et Marie Curie
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
Universite Paris Diderot Paris 7
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Universite Pierre et Marie Curie
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
Universite Paris Diderot Paris 7
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a method for predicting the response of a patient to checkpoint blockade cancer immunotherapy.
  • Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors.
  • the present invention relates to a method for predicting the response of a patient suffering from cancer to a checkpoint blockade cancer immunotherapy, said method comprising the step of determining if a Fbxw7 gene is mutated in a tumour sample of said patient, wherein a mutation of the Fbxw7 gene is predictive of a response to the checkpoint blockade cancer immunotherapy.
  • the present invention also relates to a checkpoint blockade cancer immunotherapy agent for use in a method for treating a patient which has been selected to have a tumour cell which harbors a mutated ft>xw7 gene. The method is thus particularly suitable for discriminating responder from non responder.
  • the term "responder” in the context of the present disclosure refers to a patient that will achieve a response, i.e. a patient where the cancer is eradicated, reduced or improved.
  • the responders have an objective response and therefore the term does not encompass patients having a stabilized cancer such that the disease is not progressing after the immune checkpoint therapy.
  • a non-responder or refractory patient includes patients for whom the cancer does not show reduction or improvement after the immune checkpoint therapy.
  • the term "non responder” also includes patients having a stabilized cancer.
  • the present invention also relates to a method for treating a patient suffering from cancer, wherein said method comprises the steps of:
  • F-box protein FBXW7 is frequently mutated in many human cancers.
  • FBXW7 also known as Fbw7, Sel-10, hCdc4, or hAgo
  • SCF-type Skp1-Cul1-F-box protein-type ubiquitin ligase, in which it functions as a receptor responsible for substrate recognition.
  • Most of the substrates of FBXW7 are growth promoters, including c-MYC, NOTCH, cyclin E, c-JUN, KLF5, and mTOR, and FBXW7 is therefore thought to serve as a tumor suppressor (see Yumimoto et al., J Clin Invest.
  • FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of approximately 6%.
  • the highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31 %), endometrium (9%), colon (9%), and stomach (6%).
  • Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition (see for example Akhoondi S, et al.. Cancer Res. 2007;67(19):9006-9012).
  • the mutation of the Fbxw7 gene leads to the inactivation of FBXW7.
  • the present invention provides methods of determining whether or not a cancer patient has a mutated Fbxw7 gene (point mutations, deletions, or additions, including the absence of the gene by complete deletion and promoter silencing) and thereby determining whether or not the patient is a candidate for checkpoint blockade cancer immunotherapy.
  • the determination involves detecting Fbxw7 DNA, RNA, or protein and determining whether or not the molecule is mutated, thereby determining whether or not the gene is mutated.
  • PCR e.g., Taqman
  • sequencing techniques Southern, western, and northern blots
  • microarrays e.g., DNA sequencing techniques
  • immunohistochemical techniques e.g., ELISA
  • mass spectroscopy e.g., mass spectroscopy
  • the patient suffering from cancer is a mammalian, preferably a human.
  • the cancer may be a solid cancer or a cancer affecting the blood.
  • the cancer is a solid cancer affecting one of the following organs selected from the group consisting of uterus, endometrium, rectum, colon, cervix, esophagus, bladder, stomach, head and neck, liver, lung, bile duct, pancreas, eye, kidney, ovary, brain, breast and the thyroid gland.
  • the cancer is a solid cancer affecting one of the following organs selected from the group consisting of uterus, endometrium, rectum, colon, cervix, and esophagus.
  • the tumor sample of the patient may be obtained by biopsy or resection.
  • the biopsy technique applied will depend on the tissue type to be evaluated, the size and type of the tumor, among other factors.
  • Representative biopsy techniques include, but are not limited to, excisional biopsy, incisional biopsy, needle biopsy, surgical biopsy, and bone marrow biopsy.
  • An "excisional biopsy” refers to the removal of an entire tumor mass with a small margin of normal tissue surrounding it.
  • An “incisional biopsy” refers to the removal of a wedge of tissue that includes a cross-sectional diameter of the tumor.
  • immune checkpoint protein has its general meaning in the art and refers to a molecule that is expressed by T cells in that either turn up a signal (stimulatory checkpoint molecules) or turn down a signal (inhibitory checkpoint molecules).
  • Immune checkpoint molecules are recognized in the art to constitute immune checkpoint pathways similar to the CTLA-4 and PD-1 dependent pathways (see e.g. Pardoll, 2012. Nature Rev Cancer 12:252-264; Mellman et al., 201 1 . Nature 480:480- 489).
  • inhibitory checkpoint molecules examples include A2AR, B7-H3, B7- H4, BTLA, CTLA-4, CD277, IDO, KIR, PD-1 , LAG-3, TIM-3 TIGIT and VISTA.
  • the Adenosine A2A receptor (A2AR) is regarded as an important checkpoint in cancer therapy because adenosine in the immune microenvironment, leading to the activation of the A2a receptor, is negative immune feedback loop and the tumor microenvironment has relatively high concentrations of adenosine.
  • B7-H3, also called CD276, was originally understood to be a co-stimulatory molecule but is now regarded as co- inhibitory.
  • B7-H4 also called VTCN1
  • VTCN1 B7-H4
  • B and T Lymphocyte Attenuator (BTLA) and also called CD272 has HVEM (Herpesvirus Entry Mediator) as its ligand.
  • HVEM Herpesvirus Entry Mediator
  • Surface expression of BTLA is gradually downregulated during differentiation of human CD8+ T cells from the naive to effector cell phenotype, however tumor-specific human CD8+ T cells express high levels of BTLA.
  • CTLA-4 Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152. Expression of CTLA-4 on Treg cells serves to control T cell proliferation.
  • IDO1 Indoleamine 2,3-dioxygenase 1
  • TDO tryptophan catabolic enzyme
  • Another important molecule is TDO, tryptophan 2,3-dioxygenase.
  • IDO1 is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumour angiogenesis.
  • KIR Killer-cell Immunoglobulin-like Receptor
  • LAG3, Lymphocyte Activation Gene-3 works to suppress an immune response by action to Tregs as well as direct effects on CD8+ T cells.
  • PD-1 Programmed Death 1 (PD-1 ) receptor
  • PD-L1 and PD-L2 This checkpoint is the target of Merck & Co.'s melanoma drug Keytruda, which gained FDA approval in September 2014.
  • An advantage of targeting PD-1 is that it can restore immune function in the tumor microenvironment.
  • TIM-3 short for T-cell Immunoglobulin domain and Mucin domain 3, expresses on activated human CD4+ T cells and regulates Th1 and Th17 cytokines.
  • TIM-3 acts as a negative regulator of Th1/Tc1 function by triggering cell death upon interaction with its ligand, galectin-9. VISTA.
  • VISTA Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on hematopoietic cells so that consistent expression of VISTA on leukocytes within tumors may allow VISTA blockade to be effective across a broad range of solid tumors.
  • TIGIT also called T cell immunoreceptor with Ig and ITIM domains
  • NK Natural Killer Cells
  • checkpoint blockade cancer immunotherapy agent or “immune checkpoint inhibitor” (both expressions will be used interchangeably) has its general meaning in the art and refers to any compound inhibiting the function of an immune inhibitory checkpoint protein. Inhibition includes reduction of function and full blockade.
  • Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. A number of immune checkpoint inhibitors are known and in analogy of these known immune checkpoint protein inhibitors, alternative immune checkpoint inhibitors may be developed in the (near) future.
  • the immune checkpoint inhibitors include peptides, antibodies, nucleic acid molecules and small molecules.
  • CD8+ T cells has its general meaning in the art and refers to a subset of T cells which express CD8 on their surface. They are MHC class l-restricted, and function as cytotoxic T cells. "CD8+ T cells” are also called CD8+ T cells are called cytotoxic T lymphocytes (CTL), T-killer cell, cytolytic T cells, CD8+ T cells or killer T cells.
  • CTL cytotoxic T lymphocytes
  • T-killer cell cytolytic T cells
  • CD8 antigens are members of the immunoglobulin supergene family and are associative recognition elements in major histocompatibility complex class l-restricted interactions.
  • the ability of the immune checkpoint inhibitor to enhance T CD8 cell killing activity may be determined by any assay well known in the art.
  • said assay is an in vitro assay wherein CD8+ T cells are brought into contact with target cells (e.g. target cells that are recognized and/or lysed by CD8+ T cells).
  • the immune checkpoint inhibitor of the present invention can be selected for the ability to increase specific lysis by CD8+ T cells by more than about 20%, preferably with at least about 30%, at least about 40%, at least about 50%, or more of the specific lysis obtained at the same effector: target cell ratio with CD8+ T cells or CD8 T cell lines that are contacted by the immune checkpoint inhibitor of the present invention, Examples of protocols for classical cytotoxicity assays are conventional.
  • the checkpoint blockade cancer immunotherapy agent is an agent which blocks an immunosuppressive receptor expressed by activated T lymphocytes, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1 , best known as PD-1 ), or by NK cells, like various members of the killer cell immunoglobulin-like receptor (KIR) family, or an agent which blocks the principal ligands of these receptors, such as PD-1 ligand CD274 (best known as PD-L1 or B7-H1 ).
  • CTL4 cytotoxic T lymphocyte-associated protein 4
  • PDCD1 programmed cell death 1
  • NK cells like various members of the killer cell immunoglobulin-like receptor (KIR) family, or an agent which blocks the principal ligands of these receptors, such as PD-1 ligand CD274 (best known as PD-L1 or B7-H1 ).
  • the checkpoint blockade cancer immunotherapy agent is an antibody.
  • the checkpoint blockade cancer immunotherapy agent is an antibody selected from the group consisting of anti-CTLA4 antibodies, anti-PD1 antibodies, anti-PDL1 antibodies, anti-PDL2 antibodies, anti-TIM-3 antibodies, anti- LAG3 antibodies, anti-IDO1 antibodies, anti-TIGIT antibodies, anti-B7H3 antibodies, anti-B7H4 antibodies, anti-BTLA antibodies, and anti-B7H6 antibodies.
  • anti-CTLA-4 antibodies examples include anti-CTLA-4 antibodies, and anti-CTLA-4 antibodies.
  • One anti-CDLA-4 antibody is tremelimumab, (ticilimumab, CP-675,206).
  • the anti-CTLA-4 antibody is ipilimumab (also known as 10D1 , MDX- D010) a fully human monoclonal IgG antibody that binds to CTLA-4.
  • PD-1 and PD-L1 antibodies are described in US Patent Nos.
  • the PD-1 blockers include anti-PD-L1 antibodies.
  • the PD-1 blockers include anti-PD-1 antibodies and similar binding proteins such as nivolumab (MDX 1 106, BMS 936558, ONO 4538), a fully human lgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-LI and PD-L2; lambrolizumab (MK-3475 or SCH 900475), a humanized monoclonal lgG4 antibody against PD-1 ; CT-01 1 a humanized antibody that binds PD-1 ; AMP-224 is a fusion protein of B7-DC; an antibody Fc portion; BMS-936559 (MDX- 1 105-01 ) for PD-L1 (B7- H1 ) blockade.
  • nivolumab MDX 1 106, BMS 936558, ONO 4538
  • a fully human lgG4 antibody that binds to and blocks the activation of PD-1 by its ligands
  • lymphocyte activation gene-3 (LAG-3) inhibitors such as IMP321 , a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179:4202-421 1 ).
  • immune-checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors.
  • B7 inhibitors such as B7-H3 and B7-H4 inhibitors.
  • MGA271 the anti-B7-H3 antibody MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834).
  • TIM3 T-cell immunoglobulin domain and mucin domain 3 inhibitors
  • TIM-3 has its general meaning in the art and refers to T cell immunoglobulin and mucin domain-containing molecule 3.
  • the natural ligand of TIM-3 is galectin 9 (Gal9).
  • TIM-3 inhibitor refers to a compound, substance or composition that can inhibit the function of TIM-3.
  • the inhibitor can inhibit the expression or activity of TIM- 3, modulate or block the TIM-3 signaling pathway and/or block the binding of TIM-3 to galectin-9.
  • Antibodies having specificity for TIM-3 are well known in the art and typically those described in WO201 1 155607, WO2013006490 and WO20101 17057.
  • the immune checkpoint inhibitor is an Indoleamine 2,3-dioxygenase (IDO) inhibitor, preferably an IDO1 inhibitor. Examples of IDO inhibitors are described in WO 2014150677.
  • IDO inhibitors include without limitation 1 -methyl- tryptophan (IMT), ⁇ - (3-benzofuranyl)-alanine, -(3-benzo(b)thienyl)-alanine), 6-nitro- tryptophan, 6- fluoro-tryptophan, 4-methyl-tryptophan, 5 -methyl tryptophan, 6-methyl- tryptophan, 5-methoxy-tryptophan, 5 -hydroxy-tryptophan, indole 3-carbinol, 3,3'- diindolylmethane, epigallocatechin gallate, 5-Br-4-CI-indoxyl 1 ,3-diacetate, 9- vinylcarbazole, acemetacin, 5-bromo-tryptophan, 5-bromoindoxyl diacetate, 3- Amino- naphtoic acid, pyrrolidine dithiocarbamate, 4-phenylimidazole a brassinin derivative, a thiohydantoin
  • the IDO inhibitor is selected from 1 -methyl-tryptophan, ⁇ -(3- benzofuranyl)-alanine, 6- nitro-L-tryptophan, 3-Amino-naphtoic acid and ⁇ -[3- benzo(b)thienyl] -alanine or a derivative or prodrug thereof.
  • the immune checkpoint inhibitor is an anti-TIGIT (T cell immunoglobin and ITIM domain) antibody.
  • the checkpoint blockade cancer immunotherapy agent is a CTLA4 blocking antibody, such as Ipilimumab, or a PD-1 blocking antibody, such as Nivolumab or Pembrolizumab, or a combination thereof.
  • the expression of the 48 cancer genes was investigated in relation to the presence of synchronous metastasis for cohort 1 . Surprisingly, the majority of genes had similar expression levels regardless of M0 or M1 status, and only BRAF, EGFR, JAK2 and SRC reached statistically significant differences between M1 and M0 patients. To validate this observation, the cancer genes were analyzed by Affymetrix arrays in cohort 1
  • JAK2 was the only gene differentially expressed in both cohorts.
  • JAK2 was the only gene differentially expressed in both cohorts.
  • the expression of cancer genes known to be involved in metastasis process, tumor progression and WNT pathway was investigated in cohort 1 .
  • the majority of metastasis related genes had similar expression levels regardless of MO or M1 status, and only PTP4A3, PTPRC, CXCR4 and VEGFA reached statistically significant differences between M1 and MO patients.
  • the tumor-related genes were analyzed by real- time qPCR in cohort 3. The qPCR results confirmed the gene expression results from cohort 1 , and showed no difference in tumor-related gene expression between MO and M1 patients, except for two genes; CSF1 and MMP9.
  • JAK2, SMAD2 and FZD1 were slightly decreased in tumors with synchronous metastases while DKK1 and TCF7 levels were increased, however these change in expression levels did not reach statistical significance.
  • Equivalent results were obtained for genes known to be associated with the tumor progression as well as a larger panel of genes involved in the WNT pathway also analyzed by qPCR in cohort 3. Strikingly, most genes had similar expression in tumors with and without metastases and were therefore not considered to be associated with the presence of metastasis.
  • RNAseq expression data from primary tumors from cohort 1 was performed to identify differentially expressed genes.
  • Lymphatic vessel density within the invasive margin and immune cytotoxicity are decreased in patients with distant metastases
  • Hallmarks of the metastatic process progression are the combined decrease of PDPN+ lymphatic vessels and immune cytotoxicity
  • Immunoscore The quantification of T cells and cytotoxic T cells (CD3 and CD8) in the CT and IM of CRC tumors has been defined as the Immunoscore (J. Galon et al., Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 232, 199-209 (2014)). Immunoscore stratifies patients based on immune cell densities and locations in the primary tumor on a scale of I0-I4, where patients with high densities of all markers in all locations are scored as I4 and patients with low densities for all markers in all locations are I0. Immunoscore low (I0) tumors were significantly overrepresented in M1 compared to M0 patients.
  • Immunoscore significantly identifies patients with the longest overall survival (I4: 65% OS at 5 years).
  • FBXW7 F-box protein FBXW7 inhibits cancer metastasis in a non-cell- autonomous manner. J Clin Invest 125, 621 -635 (2015)).
  • FBXW7a also attenuated inflammatory signaling by downregulating C/ ⁇ and its target gene Tlr4, and FBXW7 depletion alone was sufficient to augment pro-inflammatory signaling in vivo (K. Balamurugan et al., FBXW7alpha attenuates inflammatory signalling by downregulating C/EBPdelta and its target gene Tlr4. Nat Commun 4, 1662 (2013)).
  • FBWX7 mutation could increase T-cell proliferation and antigen presentation functions. This could be one of the mechanisms leading to increase adaptive immunity and protection against metastasis.
  • lymphocyte densities CD3, GZMB, CD8, T-Bet, CD57, CD45RO
  • Cohort 1 includes CRC patients from the TCGA project (Cancer Genome Atlas Network, 2012).
  • Gene expression was tested using Affymetrix microarrays and Low-density array (LDA) Real- Time Taqman qPCR on samples from cohort 2.
  • Tissue microarrays (TMA) were constructed for 107 samples from cohort 2 and 415 samples from cohort 3.
  • TME.db A secure Web-based database, TME.db was built for the management of the patient data from cohorts 2 and 3 (B. Mlecnik et al., Data integration and exploration for the identification of molecular mechanisms in tumor-immune cells interaction. BMC Genomics 11 Suppl 1 , S7 (2010)). Ethical, Legal and Social Implications were approved by ethical review board. The observation time in the cohorts was the interval between diagnosis and last contact (death or last follow-up). Data were censored at the last follow-up for patients without relapse, or death. Time to recurrence or disease-free time was defined as the interval from the date of surgery to confirmed tumor relapse date for relapsed patients, and from the date of surgery to the date of last follow-up for disease-free patients.

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Abstract

La présente invention concerne une méthode qui permet de prédire la réponse d'un patient à une immunothérapie anticancéreuse de blocage du point de contrôle.
PCT/EP2016/081399 2015-12-18 2016-12-16 Méthode pour prédire la réponse à une immunothérapie anticancéreuse de blocage du point de contrôle Ceased WO2017103086A1 (fr)

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Cited By (16)

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US11783478B2 (en) 2017-07-24 2023-10-10 Ventana Medical Systems, Inc. Methods and systems for evaluation of immune cell infiltrate in tumor samples
US12154275B2 (en) 2017-07-24 2024-11-26 Ventana Medical Systems, Inc. Methods and systems for evaluation of immune cell infiltrate in tumor samples
US11250566B2 (en) 2017-07-24 2022-02-15 Ventana Medical Systems, Inc. Methods and systems for evaluation of immune cell infiltrate in tumor samples
US11852631B2 (en) 2018-01-19 2023-12-26 Dana-Farber Cancer Institute, Inc. Biomarkers predictive of anti-immune checkpoint response
WO2019143880A1 (fr) * 2018-01-19 2019-07-25 Dana-Farber Cancer Institute, Inc. Biomarqueurs permettant de prédire une réponse de point de contrôle anti-immunitaire
US12422435B2 (en) 2018-01-31 2025-09-23 Ventana Medical Systems, Inc. Methods and systems for evaluation of immune cell infiltrate in stage III colorectal cancer
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JP7728817B2 (ja) 2019-02-05 2025-08-25 ヴェンタナ メディカル システムズ， インク． ステージｉｖの結腸直腸がんにおける免疫細胞浸潤の評価のための方法及びシステム
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WO2021028326A1 (fr) * 2019-08-14 2021-02-18 Eberhard Karls Universität Tübingen Medizinische Fakultät Procédé de classification de la réponse d'un patient à une thérapie par inhibiteur du point de contrôle immunitaire
EP3778923A1 (fr) * 2019-08-14 2021-02-17 Eberhard Karls Universität Tübingen Medizinische Fakultät Procédé de classification de la réactivité d'un patient à une thérapie par inhibiteur de point de contrôle immunitaire
EP4397776A3 (fr) * 2019-08-14 2024-12-25 Eberhard Karls Universität Tübingen (Medizinische Fakultät) Procédé de classification de la réactivité d'un patient à une thérapie par inhibiteur de point de contrôle immunitaire

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