WO2018146148A1 - Procédé de prédiction de la réponse à une immunothérapie anticancéreuse par inhibition de points de contrôle - Google Patents

Procédé de prédiction de la réponse à une immunothérapie anticancéreuse par inhibition de points de contrôle Download PDF

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WO2018146148A1
WO2018146148A1 PCT/EP2018/053073 EP2018053073W WO2018146148A1 WO 2018146148 A1 WO2018146148 A1 WO 2018146148A1 EP 2018053073 W EP2018053073 W EP 2018053073W WO 2018146148 A1 WO2018146148 A1 WO 2018146148A1
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antibodies
met
cancer immunotherapy
checkpoint blockade
cells
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Jérôme GALON
Bernhard Mlecnik
Gabriela BINDEA
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Sorbonne Universite
Université Paris Diderot - Paris 7
Universite Paris Descartes
Assistance Publique Hopitaux De Paris
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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

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 MET gene is mutated in a tumor sample of said patient, wherein a mutation of the MET 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 tumor cell which harbors a mutated MET gene.
  • MET-mutated patients have a better adaptive immune response than non-MET-mutated patients. Accordingly, MET- mutated patients are more likely to respond to a checkpoint blockade cancer immunotherapy (i.e. they are good candidates for this type of therapy).
  • the method according to the present invention is thus particularly suitable for discriminating responder from non-responder.
  • responder refers to a patient that will achieve a response, i.e. a patient where the cancer is eradicated, reduced or stabilized.
  • a non-responder or refractory patient includes patients for whom the cancer does not show reduction or stabilization after the immune checkpoint therapy.
  • the present invention also relates to a method for treating a patient suffering from cancer, wherein said method comprises the steps of:
  • MET proto-oncogene, receptor tyrosine kinase.
  • MET is also known as HGFR; AUTS9; RCCP2; c-Met; or DFNB97.
  • the proto-oncogene MET product is the hepatocyte growth factor receptor.
  • MET is a tyrosine-kinase receptor.
  • the present invention provides methods of determining whether or not a cancer patient has a mutated MET 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 MET 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
  • enzymatic, binding or functional assays e.g., binding or functional assays, and the like.
  • 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.
  • the cancer is a solid cancer affecting one of the organs selected from the group consisting of colon, rectum, skin, endometrium, lung, uterus, liver, kidney, esophagus, stomach, bladder, pancreas, cervix, brain, ovary, breast, head and neck region, testis, prostate and the thyroid gland.
  • the cancer is a solid cancer affecting an organ selected from the group consisting of skin, endometrium, lung, uterus and liver.
  • These cancers are those in which MET mutations are the most frequently observed in patients; i.e., in which the percentage of MET-mutated patients among a cohort is higher than 3% (see Example below).
  • 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.
  • 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. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT Published Patent Application Nos: WO03042402, WO2008156712, WO201008941 1 , WO2010036959, WO201 1066342, WO201 1 159877, WO201 1082400, and WO201 1 161699.
  • 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.
  • CTLA4 blocking antibody such as Ipilimumab
  • PD-1 blocking antibody such as Nivolumab or Pembrolizumab
  • Figure 1 Analysis of the gene expression profile in patients displaying a MET mutation.
  • Figure 2 Influence of MET mutation on the expression of immune genes: the light grey bin categories represent the expression in MET mutants/ the white bin categories represent the expression in wild types (non-MET mutated).
  • Figure 3 Evaluation of immune cells infiltration in MET-mutant and non-MET mutant patients.
  • Figure 4 Mean intra-tumor expression of CXCL13 in MET-mutated and non-MET mutated patients.
  • Figure 5 Determination of the frequency of high densities of infiltrating T-cells in MET- mutated and non-MET mutated patients.
  • FIG. 6 In vitro stimulation of colorectal tumor cells (HCT1 16) with MET's ligand, hepatocellular growth factor (HGF) on several immune responsive factors (CXCL13, CX3CL1 , CCL26, IL-2, IL-1 b, CCL22, CXCL9 and IL-16).
  • HGF hepatocellular growth factor
  • Genomic DNA from 214 patients has been extracted from frozen tumors using QIAmp DNA mini kit (Qiagen, Courtaboeuf, France) or, if frozen samples were not available, from two 5um thick FFPE slides using QIAmp DNA FFPE kit (Qiagen). Quantity of double strand DNA have been evaluated using qubit 2.0 fluorometer (Invitrogen, life Technologies, Saint Aubin, France) and 10ng (or 20ng if FFPE) of extracted DNA were amplified using Ion AmpliSeq Cancer HotSpot Panel V2 (Ion Torrent, Life Technologies) according to manufacturer's protocol.
  • hotspot regions of 50 oncogenes or tumour suppressor genes, including MET were amplified using a panel of 207 primer pairs in a 17 cycles PCR reaction (20 cycles for FFPE samples). Amplicon were then digested with FuPa Reagent and samples were separately barcoded with Ion Xpress Barcodes. lonAmpliSeq Adapters were then added to each sample. DNA banks were then purified using Agencourt AMPure XP Reagent (Beckman Coulter, Villepinte, France) and purified library obtained were amplified using Platinum PCR supermix High fidelity enzyme and purified again with Agencourt process, following the manufacturer's instructions (Ion AmpliSeq Library kit 2.0, Ion Torrent, Life Technologies).
  • MET mutation is correlated with an increase in the expression of Th1 , cytotoxic T-celis and chemokines - associated genes
  • the data was analyzed using the SDS Software v2.2 (Applied Biosystems).
  • the t-test and the Wilcoxon-Mann-Whitney test were the parametric and non-parametric tests used to identify markers with a significantly different expression among patient groups. P-value smaller than 0.05 was considered as significant.
  • MET mutation significantly increases the density of tumor-infiitrating memory T c-cells (CD45RO+), cytotoxic T-cell (CD8), FoxP3+ and PD1 + cells, and decreases the density of infiltrating immature dendritic cells (CD1a)
  • Envision+ system enzyme-conjugated polymer backbone coupled to secondary antibodies
  • DAB-chromogen were applied (Dako, Glostrup, Denmark).
  • Double stainings were revealed with phosphate-conjugated secondary antibodies and FastBlue-chromogen.
  • tissue sections were counterstained with Harris hematoxylin (Sigma Aldrich Saint Louis, MO). Isotype- matched mouse monoclonal antibodies were used as negative controls. Slides were analyzed using an image analysis workstation (Spot Browser, Excilone, Elancourt, France).
  • Polychromatic high-resolution spot-images (740x540 pixel, 1 .181 ⁇ /pixel resolution) were obtained (x200 fold magnification). The density was recorded as the number of positive cells per unit tissue surface area. The t-test and the Wilcoxon-Mann-Whitney test were the parametric and non-parametric tests used to identify markers with a significantly different cell density among patient groups. P-value smaller than 0.05 was considered as significant.
  • patients displaying a MET mutation present a significantly increased density of infiltrating memory T-cells (CD45RO+), cytotoxic T-cell (CD8), FoxP3+ and PD1 + cells within the tumor and a decreased density of infiltrating- immature dendritic cells (CD1 a).
  • MET-mutated patients present an increased expression of CXCL13 (see Figure 4).
  • the t-test and the Wilcoxon-Mann-Whitney test were the parametric and non-parametric tests used to identify markers with a significantly different expression among patient groups. P-value smaller than 0.05 was considered as significant.
  • Immunoscore I0 is when a patient has low density for two markers in both tumor regions, Immunosocores 10-1 -2 and I3-4 represent low and high Immunoscore patients, respectively ⁇ Galon, Med Sci (Paris). 2014 Apr;30(4):439-44 ⁇ .
  • HCT116 colorectal tumor cells
  • HGF hepatocellular growth factor
  • CXCL13, CX3CL1 , CCL26, IL-2, IL-1 b, CCL22, CXCL9 and IL-16 levels were quantified in colorectal tumor cell (HCT1 16) culture supernatant using a multiplex human chemokine/cytokine magnetic bead panel (EMD Millipore, Billerica, MA, USA) according to the manufacturer's instructions.
  • EMD Millipore multiplex human chemokine/cytokine magnetic bead panel
  • HGF hepatocellular growth factor
  • a detection antibody was added, followed by streptadavin-phycoerythrin acting as a reporter molecule.
  • Data were acquired using the Luminex 200 system (Luminex, Austin, TX, USA ) and analyzed with Bio-Plex Manager software (Bio-Rad Laboratories, Hercules, CA, USA).
  • TCGA somatic mutations compiled from all cohorts with somatic mutation calls available (UCSC Xena, TCGA_PANCAN_mutation_xena_gene dataset) was used.
  • TCGA pan-cancer somatic mutation data was compiled from all cohorts with mutation calls available.
  • Non-silent somatic mutations nonsense, missense, frame-shift indeis, splice site mutations, shif codon readthroughs
  • TCGA PANCAN strictly filtered maf files downloaded from Synapse, processed into gene by sample matrix at UCSC into eg Data repository (TCGA PANCAN AWG, TCGA_PANCAN_mutation dataset) were investigated. Details on the TCGA data processing were previously described (Kandoth et al., 2013). In the same time, clinical information was downloaded for all cohorts included in the Pan-Cancer dataset.
  • the number and the percentage of patients with and without mutations were calculated for each cancer type from the Pan-Cancer dataset.
  • Kandoth C et al. Mutational landscape and significance across 12 major cancer types., Nature. 2013 Oct 17;502(7471 ):333-9.

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Abstract

L'inhibition de points de contrôle immunitaires est l'une des approches les plus prometteuses pour activer l'immunité antitumorale thérapeutique. Cependant, les avantages globaux de l'immunothérapie anticancéreuse par inhibition de points de contrôle varient selon les individus. Les présents inventeurs ont en effet mis en évidence que les patients ayant subi une mutation MET présentent une meilleure réponse immunitaire adaptative que les patients n'ayant pas subi de mutation MET. En conséquence, les patients ayant subi une mutation MET sont plus susceptibles de répondre à une immunothérapie anticancéreuse par inhibition de points de contrôle. En conséquence, la présente invention concerne un procédé de prédiction de la réponse d'un patient souffrant d'un cancer à une immunothérapie anticancéreuse par inhibition de points de contrôle, en déterminant si le gène MET est muté dans un échantillon de tumeur dudit patient, une mutation du gène MET étant prédictive d'une réponse à l'immunothérapie anticancéreuse par inhibition de points de contrôle.
PCT/EP2018/053073 2017-02-07 2018-02-07 Procédé de prédiction de la réponse à une immunothérapie anticancéreuse par inhibition de points de contrôle WO2018146148A1 (fr)

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CN110055327A (zh) * 2019-03-26 2019-07-26 南通大学 用于预测癌症免疫治疗效果的内皮细胞标记物与试剂盒

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US5855887A (en) 1995-07-25 1999-01-05 The Regents Of The University Of California Blockade of lymphocyte down-regulation associated with CTLA-4 signaling
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6207157B1 (en) 1996-04-23 2001-03-27 The United States Of America As Represented By The Department Of Health And Human Services Conjugate vaccine for nontypeable Haemophilus influenzae
WO2003042402A2 (fr) 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents modulant l'activite de cellules immunes et procedes d'utilisation associes
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
WO2008156712A1 (fr) 2007-06-18 2008-12-24 N. V. Organon Anticorps dirigés contre le récepteur humain de mort programmée pd-1
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
WO2010036959A2 (fr) 2008-09-26 2010-04-01 Dana-Farber Cancer Institute Anticorps anti-pd-1, pd-l1, et pd-l2 humains et leurs utilisations
WO2010089411A2 (fr) 2009-02-09 2010-08-12 Universite De La Mediterranee Anticorps pd-1 et anticorps pd-l1 et leurs utilisations
WO2010117057A1 (fr) 2009-04-10 2010-10-14 協和発酵キリン株式会社 Procédé pour le traitement d'une tumeur sanguine utilisant un anticorps anti-tim-3
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
WO2011082400A2 (fr) 2010-01-04 2011-07-07 President And Fellows Of Harvard College Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
WO2011155607A1 (fr) 2010-06-11 2011-12-15 協和発酵キリン株式会社 Anticorps anti-tim-3
WO2011159877A2 (fr) 2010-06-18 2011-12-22 The Brigham And Women's Hospital, Inc. Anticorps di-spécifiques anti-tim-3 et pd-1 pour immunothérapie dans des états pathologiques immuns chroniques
WO2011161699A2 (fr) 2010-06-25 2011-12-29 Aurigene Discovery Technologies Limited Composés modulateurs de l'immunosuppression
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2013006495A2 (fr) * 2011-07-01 2013-01-10 Dana-Farber Cancer Institute, Inc. Méthodes de pronostic prédictif du cancer
WO2013006490A2 (fr) 2011-07-01 2013-01-10 Cellerant Therapeutics, Inc. Anticorps se liant spécifiquement à tim3
WO2014150677A1 (fr) 2013-03-15 2014-09-25 Bristol-Myers Squibb Company Inhibiteurs de l'indoléamine 2,3-dioxygénase (ido)
WO2015112534A2 (fr) * 2014-01-21 2015-07-30 Medimmune, Llc Compositions et procédés pour moduler et réorienter des réponses immunitaires
WO2015116868A2 (fr) * 2014-01-29 2015-08-06 Caris Mpi, Inc. Profilage moléculaire de modulateurs immunitaires
WO2016100975A1 (fr) * 2014-12-19 2016-06-23 Massachsetts Institute Ot Technology Biomarqueurs moléculaires pour l'immunothérapie d'un cancer

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5855887A (en) 1995-07-25 1999-01-05 The Regents Of The University Of California Blockade of lymphocyte down-regulation associated with CTLA-4 signaling
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6207157B1 (en) 1996-04-23 2001-03-27 The United States Of America As Represented By The Department Of Health And Human Services Conjugate vaccine for nontypeable Haemophilus influenzae
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
WO2003042402A2 (fr) 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents modulant l'activite de cellules immunes et procedes d'utilisation associes
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
WO2008156712A1 (fr) 2007-06-18 2008-12-24 N. V. Organon Anticorps dirigés contre le récepteur humain de mort programmée pd-1
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
WO2010036959A2 (fr) 2008-09-26 2010-04-01 Dana-Farber Cancer Institute Anticorps anti-pd-1, pd-l1, et pd-l2 humains et leurs utilisations
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2010089411A2 (fr) 2009-02-09 2010-08-12 Universite De La Mediterranee Anticorps pd-1 et anticorps pd-l1 et leurs utilisations
WO2010117057A1 (fr) 2009-04-10 2010-10-14 協和発酵キリン株式会社 Procédé pour le traitement d'une tumeur sanguine utilisant un anticorps anti-tim-3
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
WO2011082400A2 (fr) 2010-01-04 2011-07-07 President And Fellows Of Harvard College Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci
WO2011155607A1 (fr) 2010-06-11 2011-12-15 協和発酵キリン株式会社 Anticorps anti-tim-3
WO2011159877A2 (fr) 2010-06-18 2011-12-22 The Brigham And Women's Hospital, Inc. Anticorps di-spécifiques anti-tim-3 et pd-1 pour immunothérapie dans des états pathologiques immuns chroniques
WO2011161699A2 (fr) 2010-06-25 2011-12-29 Aurigene Discovery Technologies Limited Composés modulateurs de l'immunosuppression
WO2013006495A2 (fr) * 2011-07-01 2013-01-10 Dana-Farber Cancer Institute, Inc. Méthodes de pronostic prédictif du cancer
WO2013006490A2 (fr) 2011-07-01 2013-01-10 Cellerant Therapeutics, Inc. Anticorps se liant spécifiquement à tim3
WO2014150677A1 (fr) 2013-03-15 2014-09-25 Bristol-Myers Squibb Company Inhibiteurs de l'indoléamine 2,3-dioxygénase (ido)
WO2015112534A2 (fr) * 2014-01-21 2015-07-30 Medimmune, Llc Compositions et procédés pour moduler et réorienter des réponses immunitaires
WO2015116868A2 (fr) * 2014-01-29 2015-08-06 Caris Mpi, Inc. Profilage moléculaire de modulateurs immunitaires
WO2016100975A1 (fr) * 2014-12-19 2016-06-23 Massachsetts Institute Ot Technology Biomarqueurs moléculaires pour l'immunothérapie d'un cancer

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BRIGNONE ET AL., J. IMMUNOL., vol. 179, 2007, pages 4202 - 4211
FOURCADE ET AL., J. EXP. MED., vol. 207, 2010, pages 2175 - 86
GALON, MED SCI (PARIS, vol. 30, no. 4, April 2014 (2014-04-01), pages 439 - 44
KANDOTH C ET AL.: "Mutational landscape and significance across 12 major cancer types", NATURE, vol. 502, no. 7471, 17 October 2013 (2013-10-17), pages 333 - 9
LOO ET AL., CLIN. CANCER RES., vol. 15, no. 18, July 2012 (2012-07-01), pages 3834
MELLMAN ET AL., NATURE, vol. 480, 2011, pages 480 - 489
PARDOLL, NAT REV CANCER, vol. 12, no. 4, 22 March 2012 (2012-03-22), pages 252 - 64
PARDOLL, NATURE REV CANCER, vol. 12, 2012, pages 252 - 264
SAKUISHI ET AL., J. EXP. MED., vol. 207, 2010, pages 2187 - 94

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110055327A (zh) * 2019-03-26 2019-07-26 南通大学 用于预测癌症免疫治疗效果的内皮细胞标记物与试剂盒
CN110055327B (zh) * 2019-03-26 2023-03-10 南通大学 用于预测癌症免疫治疗效果的内皮细胞标记物与试剂盒

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