WO2017129763A1

WO2017129763A1 - Methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer

Info

Publication number: WO2017129763A1
Application number: PCT/EP2017/051805
Authority: WO
Inventors: Marc POCARD; Philippe Dessen; Simon DERIEUX
Original assignee: INSERM (Institut National de la Santé et de la Recherche Médicale); Université Paris Diderot - Paris 7; Assistance Publique-Hôpitaux De Paris (Aphp); Centre National De La Recherche Scientifique (Cnrs)
Priority date: 2016-01-28
Filing date: 2017-01-27
Publication date: 2017-08-03

Abstract

The present disclosure relates to methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer. The present disclosure also relates to a method of treating signet ring cell gastric carcinoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one PD-1 inhibitor or at least one IGF1 R inhibitor.

Description

METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF SIGNET RING CELL GASTRIC CANCER

FIELD OF THE INVENTION:

The present invention relates to methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer.

BACKGROUND OF THE INVENTION:

Signet Ring Cell (SRC) carcinoma of the stomach is defined by a predominant component (> 50%) of independent cells. The incidence of SRC carcinoma of the stomach is increasing (1,2). These cancers display specific features compared with Gastric Adenocarcinoma (GA). They tend to be more aggressive at the time of diagnosis, with higher rates of lymph nodes involvement and peritoneal carcinomatosis (3), and are known to occur more frequently in female, and younger patients (4). Furthermore, perioperative chemotherapies failed to provide any survival benefits in patients diagnosed with SRC (5, 6, 7), either resulting in the involvement of chemoresistance mechanisms, or in the patient's general status.

This justifies the search for strategies based on targeted therapies, without cytotoxic chemotherapies, such as the combination of an immunotherapy and a targeted therapy against a major oncogenic pathway. These combinations are part of the new therapeutic approaches in the treatment of glioblastoma and melanoma (8, 9).

IGFIR is a molecular pathway associated with many malignancies (10, 11, 12). Binding to its ligands Insulin Growth Factor- like 1 (IGF-1) and 2 (IGF-2) is known to induce cell growth and apoptosis escape through activation of PI3K and RAS intracellular pathways (13). IGFIR might be involved in SRC cancerogenesis through activation of PI3K (14, 15), and might explain chemoresistance in SRC. Indeed, a preclinical study showed that xenograft transfection with an inactive IGFIR increases apoptosis induced by cytotoxic chemotherapy (16). Furthermore, a clinical study showed that tumours hyperexpressing IGFIR were more likely to relapse after chemotherapy (17). At least, unpublished preliminary data obtained in our laboratory showed hyperexpression of IGF-1 in SRC on a DNA chip, while the same gene was repressed in GA. Anti-IGFIR therapies are being abandoned because of a lack of efficiency that might be explained by the absence of selection of tumors on which anti-IGFIR therapies were tested. Indeed, several studies show that tumours hyperexpressing IGFIR were more likely to respond to an anti-IGFIR therapy (18, 19), supporting the idea that these therapies might be efficient on selected tumours.

PD-1 (Programmed Cell Death 1) is part of a complex mechanism known as immunitory inhibitory checkpoint. PD-1 is expressed on activated T lymphocytes. Binding of PD-1 to its ligands PD-L1 and PD-L2 shapes tumour micro-environment in increasing T-Cell Regulators (Tregs) infiltrates and in decreasing activated T-Cells infiltrates (20). These mechanisms lead to immune escape. Data support the evidence that PI3K pathway, activated downstream of IGF1R, is related to the expression of PD-L1, resulting in immune evasion that could be reversed with blockade of PI3K in glioblastoma (21). In gastric cancer, PD-L1 is expressed in 42% (22), and a first clinical trial, evaluating efficiency of an immunotherapy targeting PD-1 (Pembrolizumab) displayed a response rate of 31% (23). Though, the exact role of this inhibitory checkpoint in SRC remains to be elucidated.

SUMMARY OF THE INVENTION:

The present invention relates to methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer. In particular, the present invention is defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION:

The aim of the inventors was to investigate the role of IGF1R pathway and PD-1 immunitory checkpoint in SRC, in order to propose a new therapeutic strategy in SRC: the combination of an anti-IGFIR therapy with an immunotherapy targeting PD-1. The inventors performed a RT-qPCR on 11 SRC and 11 GA gastrectomy samples to assess the expression of IGF1R pathway and PD-L1/PD-L2 genes. They also analysed protein expression of IGF1R pathway, PD-1 immune checkpoint, and immune infiltrates (CD4+, CD8+, FoxP3+) using immuno-histochemistry (IHC) on a TMA including 17 SRC and 12 GA. Higher levels of IGF-1 and IGF-2 expression was found in SRC compared with GA : IGF-1 (2,95 versus 0,56 ; p=0,004), IGF-2 (0,78 vs 0,28 ; p=0,007). IGF1R was also found to have a higher expression in SRC in comparison with GA (1,79 vs 1,34 ; p=0,018). IHC confirmed that IGF1R expression was higher in SRC than in GA (H-Score = 171 vs 110; p=0,032) and 14/17 SRC were IGF1R+ versus 4/12 GA (p=0,018). On qPCR, every tumour sample of the study expressed PD-L1 as well as PD-L2. PD-L2 was slightly more expressed in SRC peri-tumoral tissue than in GA peri-tumoral tissue (1,55 versus 0,85 ; p = 0,03). IHC data showed no significant differences in the expression of PD-L1 in SRC compared with GA. 51 ,7% patients had PD-L1+ tumour (9/17 SRC, 6/12 GA; p=n.s.). In conclusion the results suggest the implication of IGF1R pathway in SRC. These tumours display predictive factors for anti- IGF1R therapy success. Our results also show that PD-L1 is expressed in SRC as well as in GA, and that its expression shapes tumour microenvironment. These results support the idea of a new therapeutic approach in SRC, combining PD-1 inhibitors and IGF1R inhibitors.

Accordingly a first object of the present invention relates to a method of treating signet ring cell gastric carcinoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one PD-1 inhibitor or at least one IGF1R inhibitor.

As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).

As used herein, the term "PD-1" has its general meaning in the art and refers to programmed cell death protein 1 (also known as CD279). PD-1 acts as an immune checkpoint, which upon binding of one of its ligands, PD-L1 or PD-L2, inhibits the activation of T cells. Accordingly, the term "PD-1 inhibitor" as used herein refers to a compound, substance or composition that can inhibit the function of PD-1. For example, the inhibitor can inhibit the expression or activity of PD-1, modulate or block the PD-1 signaling pathway and/or block the binding of PD-1 to PD-L1 or PD-L2. Thus the term "PD-1 inhibitor" means any molecule that attenuates inhibitory signal transduction mediated by PD-1, found on the surface of T cells, B cells, natural killer (NK) cells, monocytes, DC, and macrophages. Such an antagonist includes a molecule that disrupts any inhibitory signal generated by a PD-1 molecule on a T cell. In specific examples of the invention, a PD-1 inhibitor is a molecule that inhibits, reduces, abolishes or otherwise reduces inhibitory signal transduction through the PD-1 receptor signaling pathway. Such decrease may result where: (i) the PD-1 inhibitor of the invention binds to a PD-1 receptor without triggering signal transduction, to reduce or block inhibitory signal transduction; (ii) the PD-1 inhibitor binds to a ligand (e.g. PD-L1 or PD-L2) of the PD-1 receptor, preventing its binding thereto; (iii) the PD-1 inhibitor binds to, or otherwise inhibits the activity of, a molecule that is part of a regulatory chain that, when not inhibited, has the result of stimulating or otherwise facilitating PD-1 inhibitory signal transduction; or (iv) the PD-1 inhibitor inhibits expression of a PD-1 receptor or expression ligand thereof, especially by reducing or abolishing expression of one or more genes encoding PD-1 or one or more of its natural ligands. Thus, a PD-1 inhibitor of the invention is a molecule that effects a decrease in PD-1 inhibitory signal transduction, thereby increasing T cell response to one or more antigens.

PD-1 antagonists are well known in the art and typically include antibodies or fragments thereof having specificity for PD-1 or its ligands (i.e. PD-L1 or PD-L2). Examples of PD-1 inhibitors 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, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699. In some embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of MDX-1106, Merck 3475 and CT-011. Nivolumab (MDX 1106, BMS 936558, ONO 4538), a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2 ant that is described in WO2006/121168. Lambrolizumab (MK-3475 or SCH 900475) is a humanized monoclonal IgG4 antibody against PD-1. CT-011, also known as hBAT or hB ATMs an anti-PD-1 antibody described in WO2009/101611

In some embodiments, the PD-1 inhibitor is anti-PD-Ll antibody. In some embodiments, the anti-PD-Ll binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A and MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-Ll antibody described in WO2007/005874. Antibody YW243.55.S70 is an anti- PD-Ll described in WO2010/077634. In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region of an immuglobulin (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342.

In some embodiments, the IGFIR inhibitor is an inhibitor of PD-1 expression.

As used herein the term "IGFIR" has its general meaning in the art and refers to Insulin- like growth factor 1 receptor. Accordingly the term "IGFIR inhibitor" refers to any substance that inhibits or decreases the expression, ligand binding (e.g., binding to IGF-1 and/or IGF-2), kinase activity (e.g., autophosphorylation activity) or any other biological activity of IGFIR (e.g., mediation of anchorage-independent cellular growth). Such IGFIR inhibitors include any agent that can block IGFIR activation or any of the downstream biological effects of IGFIR activation.

IGFIR inhibitors are well known in the art. Non- limiting examples of inhibitors can be found in, for example, U.S. Pat. No. 7,329,734, U.S. Pat. No. 7,173,005, U.S. Pat. No. 7,071,300, U.S. Pat. No. 7,020,563, U.S. Pat. No. 6,875,741; US Pat. App. Pub. No. US2007/0299010, US2007/0265189, US2007/0135340, US2007/0129399, US2007/0004634, US2005/0282761, US2005/0054638, US2004/0023887, US2003/0236190, US2003/0195147; PCT Pub. No. WO2007/099171, WO2007/099166, WO2007/031745, WO2007/029106, WO2007/029107, WO2007/004060, WO2006/074057, WO2006/069202, WO2006/017443, WO2006/012422, WO2006/009962, WO2006/009950, WO2006/009947, WO2006/009933, WO2005/097800, WO2005/082415, WO2005/037836, WO2003/070911, W01999/28347; European Pat. No. EP 1 732 898 Bl, EP 0 737 248 Bl, European Pat. App, No. EP 1 496 935 and EP 1 432 433, and D'ambrosio et al., 1996, Cancer Res. 56:4013-20, each of which is incorporated herein by reference in its entirety.

In some embodiments, IGFIR inhibitors may include, for example, imidazopyrazine IGFIR inhibitors, quinazoline IGFIR inhibitors, pyrido-pyrimidine IGFIR inhibitors, pyrimido-pyrimidine IGFIR inhibitors, pyrrolo-pyrimidine IGF inhibitors, pyrazolo- pyrimidine IGFIR inhibitors, phenylamino-pyrimidine IGFIR inhibitors, oxindole IGFIR inhibitors, indolocarbazole IGFIR inhibitors, phthalazine IGFIR inhibitors, isoflavone IGFIR inhibitors, quinalone IGFIR inhibitors, and tyrphostin IGFIR inhibitors, and all pharmaceutically acceptable salts and solvates of such IGFIR inhibitors, imidazopyrazine IGFIR inhibitors, pyrimidine-based IGF-1R inhibitors, cyclolignans, cyclolignans, pyrrolopyrimidines, pyrrolotriazine, pyrrolo[2,3-d], heteroaryl-aryl ureas, and the like.

Specific examples of such molecules include OSI-906 (OSI Pharmaceuticals, Melvilee, N.Y.), BMS 536924 (Wittman et al, 2005, J Med Chem. 48:5639-43; Bristol Myers Squibb, New York, N.Y.), XL228 (Exelexis, South San Francisco, Calif), INSM-18, NDGA, and rhIGFBP-3 (Insmed, Inc., Richmond, Va.; Breuhahn et al, 2002006, Curr Cancer Ther Rev. 2: 157-67; Youngren et al, 2005, Breast Cancer Res Treatment 94:37-46; U.S. Pat. No. 6,608,108), each of which reference is incorporated herein by reference in its entirety. Additional, specific examples of suitable IGFIR inhibitors include h7C10 (Centre de Recherche Pierre Fabre), an IGF-1 antagonist; EM- 164 (ImmunoGen Inc.), an IGFIR modulator; CP-751871 (Pfizer Inc.), an IGF-1 antagonist; lanreotide (Ipsen), an IGF-1 antagonist; IGFIR oligonucleotides (Lynx Therapeutics Inc.); IGF-1 oligonucleotides (National Cancer Institute); IGFIR protein-tyrosine kinase inhibitors in development by Novartis (e.g., NVP-AEW541, Garcia-Echeverria, C. et al. (2004) Cancer Cell 5:231-239; or NVP-ADW742, Mitsiades, C. S. et al. (2004) Cancer Cell 5:221-230); IGFIR protein- tyrosine kinase inhibitors (Ontogen Corp); AG- 1024 (Camirand, A. et al. (2005) Breast Cancer Research 7:R570-R579 (DOI 10.1186/bcr 1028); Camirand, A. and Pollak, M. (2004) Brit. J. Cancer 90: 1825-1829; Pfizer Inc.), an IGF-1 antagonist; the tyrphostins-AG-538 and I-OMe-AG 538; BMS-536924, a small molecule inhibitor of IGF1R; PNU-145156E (Pharmacia & Upjohn SpA), an IGF-1 antagonist; BMS 536924, a dual IGF1R and IR kinase inhibitor (Bristol-Myers Squibb); AEW541 (Novartis); GSK621659A and GSK1838705 (Glaxo Smith-Kline); INSM-18 (Insmed); linsitinib (OSI); BMS 754807 (Bristol-Myers Squibb); AXL-1717 (Axelar); NVP-ADW742 (Novartis); ANT-429 (Antyra); A-928605 (Abbott); AZD4253 (AstraZeneca); TAE226 (Novartis); AG1024 (Merck); KW-2450 (Kyowa); and XL-228 (Exelixis).

In some embodiments, the IGF1R inhibitor is an antibody or antibody fragment that can partially or completely block IGF1R activation by its natural ligand. Antibody-based IGF1R inhibitors also include any anti-IGF-1 antibody or antibody fragment that can partially or completely block IGF1R activation. Non- limiting examples of antibody-based IGF1R inhibitors include those described in Larsson, O. et al (2005) Brit. J. Cancer 92:2097-2101 and Ibrahim, Y. H. and Yee, D. (2005) Clin. Cancer Res. l l :944s-950s; or being developed by Imclone (e.g., IMC-A12), or ganitumab, an anti-IGFIR antibody (Amgen), as described in "RECOMMENDED International Nonproprietary Names: List 65," published by the World Health Organization, Avenue Appia 2, 1211 Geneva 27, Switzerland; R1507, an anti-IGFIR antibody (Genmab/Roche); AVE- 1642, an anti-IGFIR antibody (Immunogen/Sanofi- Aventis); MK 0646 or h7C10, an anti-IGFIR antibody (Merck); or antibodies being develop by Schering-Plough Research Institute (e.g., SCH 717454 or 19D12; or as described in US Patent Application Publication Nos. US 2005/0136063 Al and US 2004/0018191 Al). The IGF1R inhibitor can be a monoclonal antibody, or an antibody or antibody fragment having the binding specificity thereof. In some embodiments, the IGF1R inhibitor is an antibody that binds specifically to the human IGF1R. More preferably, the antibody is ganitumab.

In some embodiments, the IGF1R inhibitor is an inhibitor of IGF1R expression. As used herein, the term "antibody" is thus used to refer to any antibody-like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP ("small modular immunopharmaceutical" scFv-Fc dimer; DART (ds-stabilized diabody "Dual Affinity ReTargeting"); small antibody mimetics comprising one or more CDRs and the like. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art (see Kabat et al., 1991, specifically incorporated herein by reference). Diabodies, in particular, are further described in EP 404, 097 and W093/1 1 161 whereas linear antibodies are further described in Zapata et al. (1995). Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al, 2006; Holliger & Hudson, 2005; Le Gall et al, 2004; Reff & Heard, 2001 ; Reiter et al, 1996; and Young et al, 1995 further describe and enable the production of effective antibody fragments. In some embodiments, the antibody of the present invention is a single chain antibody. As used herein the term "single domain antibody" has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also "nanobody®". For a general description of (single) domain antibodies, reference is also made to the prior art cited above, as well as to EP 0 368 684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al, Trends Biotechnol, 2003, 21(l l):484-490; and WO06/030220, WO06/003388.

In some embodiments, the antibody is a humanized antibody. As used herein, "humanized" describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules. Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference. In some embodiments, the antibody is a fully human antibody. Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ- line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest. Following immunization of these mice (e.g., XenoMouse (Abgenix), HuMAb mice (Medarex/GenPharm)), monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans. In vitro methods also exist for producing human antibodies. These include phage display technology (U.S. Pat. Nos. 5,565,332 and 5,573,905) and in vitro stimulation of human B cells (U.S. Pat. Nos. 5,229,275 and 5,567,610). The contents of these patents are incorporated herein by reference.

In some embodiments, the antibody of the present invention is a single chain antibody. As used herein the term "single domain antibody" has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also "nanobody®". For a general description of (single) domain antibodies, reference is also made to the prior art cited above, as well as to EP 0 368 684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al, Trends Biotechnol, 2003, 21(11):484-490; and WO06/030220, WO06/003388.

In some embodiments, the antibody comprises human heavy chain constant regions sequences but will not induce antibody dependent cellular cytotoxicity (ADCC). Accordingly, in some embodiments, the antibody of the present invention does not comprise an Fc domain capable of substantially binding to a FcgRIIIA (CD 16) polypeptide. The terms "Fc domain" "Fc portion," and "Fc region" refer to a C-terminal fragment of an antibody heavy chain, e.g., from about amino acid (aa) 230 to about aa 450 of human gamma heavy chain or its counterpart sequence in other types of antibody heavy chains (e.g., α, δ, ε and μ for human antibodies), or a naturally occurring allotype thereof. Unless otherwise specified, the commonly accepted Kabat amino acid numbering for immunoglobulins is used throughout this disclosure (see Kabat et al. (1991 ) Sequences of Protein of Immunological Interest, 5th ed., United States Public Health Service, National Institute of Health, Bethesda, MD). In some embodiments, the antibody lacks an Fc domain (e.g. lacks a CH2 and/or CH3 domain) or comprises an Fc domain of IgG2 or IgG4 isotype. In some embodiments, the antibody consists of or comprises a Fab, Fab', Fab'-SH, F (ab') 2, Fv, a diabody, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments. In some embodiments, the antibody is not linked to a toxic moiety. In some embodiments, one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered C2q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos. 6,194,551 by ldusogie et al. An "inhibitor of expression" refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene. In a preferred embodiment of the invention, said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme. For example, anti-sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of the targeted mRNA (e.g. IGF1R or PD-1) by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of the protein (e.g. IGF1R or PD-1), and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence can be synthesized, e.g., by conventional phosphodiester techniques. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732). Small inhibitory RNAs (siRNAs) can also function as inhibitors of expression for use in the present invention. TIM-3 or PD-1 gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that TIM-3 or PD-1 gene expression is specifically inhibited (i.e. RNA interference or RNAi). Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing the targeted protein (e.g. IGF1R or PD-1). Typically, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siR A, shRNA or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known to the art. In some embodiments, the method of the present invention comprises coadministering the PD-1 inhbitor and the IGF1R inhibitor to the subjet. As used herein the term "co-administering" as used herein means a process whereby the combination of the IGF1R inhibitor and the PD-1 inhibitor, is administered to the same subject. The IGF1R inhibitor and the PD-1 inhibitor may be administered simultaneously, at essentially the same time, or sequentially. The IGF1R inhibitor and the PD-1 inhibitor need not be administered by means of the same vehicle. The IGF1R inhibitor and the PD-1 inhibitor may be administered one or more times and the number of administrations of each component of the combination may be the same or different. In addition, the IGF1R inhibitor and the PD-1 inhibitor need not be administered at the same site.

As used herein, the term "therapeutically effective amount" as used herein refers to an amount or dose of the IGF1R inhibitor or dose of the PD-1 inhibitor that is sufficient to treat the SRC. The "therapeutically effective amount" is determined using procedures routinely employed by those of skill in the art such that an "improved therapeutic outcome" results. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.

In some embodiments, the PD-1 inhibitor and/or the IGF1R inhibitor is(are) administered to the subject in combination with a chemo therapeutic agent. The term "chemotherapeutic agent" refers to chemical compounds that are effective in inhibiting tumor growth. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estrarnustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimus tine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33: 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idanrbicin, marcellomycin, mitomycins, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomgrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defo famine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pento statin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogennanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylarnine; trichothecenes (especially T-2 toxin, verracurin A, roridinA and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobromtol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and phannaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are antihormonal agents that act to regulate or inhibit honnone action on tumors such as anti- estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.

According to the invention, the IGF1R inhibitor and the PD-1 inhibitor are administered to the subject in the form of a pharmaceutical composition. Typically, the IGF1R inhibitor and the PD-1 inhibitor may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms. Typically, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The IGFIR inhibitor and the PD-1 inhibitor can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. The preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES:

Figure 1: mRNA levels of IGF-1 (A) and IGF-2 (B)

Figure 2: mRNA levels of IGF1R (A) and IR (B)

Figure 3: mRNA levels of A and B insulin isoforms in cancer tissue (A) and ANCT (B)

Figure 4: mRNA levels of IGFBP-3 (A) and IGF2R (B)

Figure 5: mRNA levels of PD-L1 (A) and PD-L2 (B)

Figure 6: Proportion of Tregs infiltrates in PD-L1 + and PD-L1 - tumors EXAMPLE 1: METHODS

Patients: We retrieved the clinical datas of 67 patients that underwent a gastrectomy for gastric cancer in our institution between December 2005 and December 2014 (SRC: n = 32, GA : n = 35). Exclusion criteria were : personal or familial history of gastric cancer, Siewert 1 or 2 cardial cancer, unclear pathology report, isolated dysplasia or intra-epithelial tumour, and type 1 or 2 diabetes to avoid false positives, since diabetic patients hyperexpress IGFIR (24). 17 SRC and 12 GA were eligible for our study. Clinical data are shown on Table 1.

RT-qPCR:

Gastric cancer samples: Frozen cancer tissues obtained from the resection of primary gastric cancer were retrieved in 13 SRC and 12 GA. Adjacent non-cancerous tissues (ANCT) were available in 13 SRC and 9 GA. We performed 50 μιη sections, immediately put in liquid nitrogen, then stored at -80°C until RNA extraction. Before and after each sample, we performed a 10 μιη section, which was stained (hematoxylin/eosin) and reviewed by a pathologist to assess the presence of tumoral cells.

RNA Extraction: Total RNA was extracted using RNeasy mini kit (Qiagen, USA). Quality and concentration of RNA samples was assessed using NanoVue (GE Healthcare Life Sciences, USA). Integrity was assessed on a RNA chip (Affymetrix, USA) to determine RNA Integrity Number (RIN). As previously described (25), a RIN > 5 was considered suitable for qPCR analysis. Cancer tissues were suitable for qPCR in 11 SRC and 11 GA. ANCT were suitable for qPCR in 7 SRC and 8 GA.

Reverse transcription: Reverse transcription was performed using QuantiTect Reverse Transcription kit (Qiagen, USA) according to the manufacturer's instructions. cDNA was stored at -20°C until use.

qPCR: qPCR was performed to quantify the levels of IGFIR pathway's genes and PD-

L1/PD-L2 genes on cancer tissue and ANCT. Primers were obtained by a review of literature and verified using NCBI-BLAST (National Center for Biotechnology Information-Basic Local

Alignment Search Tool.

Real-time RT-PCRs were carried out using the Real-Time System with SYBR Green according to the manufacturer's instructions. Briefly, after cDNA denaturation (95°C, 5 minutes), amplification and quantification was carried out for 40 cycles (95°C, 15 seconds, followed by 20 seconds at hybridization temperature, and 15 seconds at 72°C), and a melting curved was performed (range from 60 to 99°C with a 0,5°C/sec increase). The content of each gene's transcripts was normalized to the content of the housekeeping gene Beta-Actin. The normalized quantity of the target gene was calculated as 2^"ΔΔα. AACt was obtained by subtracting Ct for the target gene from Ct for the Beta-Actin gene. The final result was expressed as 2^~ΔΔα. All PCR assays were carried out in triplicates for each sample, and the values were averaged.

Immuno-histochemistry:

TMA construction: Every sample used in our study were derived from formalin- fixed, paraffin-embedded tissue samples obtained from the the resection of primary gastric cancer. Hematoxylin-eosin stained sections from the tissue blocks were reviewed by a pathologist, who marked representative tumor areas for the construction of the TMA blocks. Each tumour was represented by 4 cancerous spots, 1 mm in diameter. Each TMA block also contained 1 ANCT spot per patient, serving as controls. Cancer tissues were available in 17 SRC and 12 GA. ANCT were available in 13 SRC and 12 GA.

Immunohistochemistry: 4 μιη sections were cut on TMA blocks and mounted on slides. The immunohistochemical labelling was performed at the laboratory of pathology of Lariboisiere hospital, using BenchMark ULTRA staining module (Ventana Medical Systems). The sections were incubated with primary antibodies for 28 min at 36°C. Primary antibodies were used at optimized dilutions previously determined on control tissues.

Interpretation of the IHC results: Sections were read by a pathologist blinded to the patient's data. For the evaluation of IGFIR, we used a semi-quantitative approach previously described (32) : The percentage of positive cells per core (0-100%) was multiplied by the dominant intensity pattern of staining, 1 being considered as negative or trace, 2 weak, 3 moderate, 4 strong, giving a modified H-score ranging from 0 to 400 . A score < 100 qualified the tumour as IGFIR negative (IGFIR -) whereas a score > 100 qualified the tumour as positive (IGFIR +). For the evaluation of PD-Ll, we used a qualitative approach as described by (33). FoxP3 positivity was defined as positive nuclear staining in more than 10 lymphocytes on 3 fields at a 200 magnification (33).

Statistical analysis: Relative RNA-expressions, and modified H-scores are expressed as means ± SD. Mann Whitney non parametric test was used to compare means. Percentage comparisons were carried out using a Fisher's exact test. Statistical analysis was performed using GraphPad Prism 5 software (GraphPad Software, San Diego, CA). A p < 0,05 was considered statistically significant.

EXAMPLE 2: IGFIR Pathway:

Figure 1 shows IGF-1 and IGF-2 relative expressions for SRC and GA groups. mRNA levels of IGF-1 and IGF-2 were significantly higher in SRC cancer tissue compared with GA cancer tissue (respectively p = 0,004; figure 5A and p = 0,007; figure IB). mRNA level of IGF-1 was also higher in cancer tissue than in ANCT for SRC group (p = 0,007; figure 1A). There was no difference in IGF-2 expression between cancer tissue and ANCT in SRC group (figure IB). mRNA levels of IGF1R and IR were higher in SRC cancer tissue compared with GA cancer tissue (respectively p = 0,018; figure 2A and p = 0,006; figure 2B). IHC data confirmed IGF1R overexpression in SRC cancer tissue compared with GA cancer tissue: Mean IGF1R H-Score was 171 ± 76 in SRC versus 102 ± 113 in GA (p = 0,017) and 14/17 SRC tumours were IGF1R + versus 4/12 GA (p = 0,029). Furthermore, we observed a linear correlation between genetic expression of IGF1R on qPCR, and proteic expression of IGF1R on IHC (r = 0,66; p < 0,001). IR-B isoform mRNA level was higher in SRC cancer tissue compared with GA cancer tissue (figure 3 A). In ANCT, IR-A isoform mRNA level was higher in SRC than in GA, without reaching statistical significance (p = 0,053; figure 3B). There was no difference between SRC and GA in IGFBP-3 expression, in cancer tissue as well as in ANCT (figure 4A), and IGF2R expression was lower in GA cancer tissue than in any other group of the study (figure 4B).

EXAMPLE 3: PD-1 IMMUNE CHECKPOINT:

Figure 5 shows mRNA levels of PD-Ll and PD-L2 in SRC and GA groups. mRNA levels of PD-Ll and PD-L2 were detected in both cancer tissue and ANCT, in SRC as well as in GA. There were no statistical differences in mRNA levels of PD-Ll and PD-L2 in cancer tissue between SRC and GA. In ANCT, PD-L2 was slightly more expressed in SRC than in GA (p = 0,03; figure 5B). IHC confirmed these data: PD-Ll was expressed in 15/29 (51,7%) tumours of our study, without differences between SRC (9/17 PD-Ll +) and GA (6/12 PD-Ll +). 10/29 patients had FoxP3 + tumour, without any differences between SRC (4/17 FoxP3+) and GA (6/12 FoxP3 +). Our study showed that local expression of PD-Ll was associated with FoxP3 + lymphocytes (Tregs) infiltration: On 94 spots available for PD-Ll and FoxP3 qualitative interpretation, 24/43 (56%) of PD-L1+ spots displayed Tregs infiltrates while only 9/51 (18%) of PD-Ll - spots had Tregs infiltrates (p = 0,0002; figure 6).

Table 1: Clinicopathological data of the patients included in the study

Age 54 ± 16 ans 74 ± 8 ans 0,0009

Carcinose peritoneale 8/17 1/12 0,043

Envahissement ganglionnaire 16/17 3/12 0,0002

Resection R0 9/17 9/12 0,273

Aspect de linite (endoscopique ou per- operatoire) 9/17 1/12 0,019

Chimio pre-operatoire 5/17 0/12 0,059

Engainements peri-nerveux 16/17 8/12 0,130

Emboles vasculaires 12/17 6/12 0,438

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Claims

CLAIMS:

A method of treating signet ring cell gastric carcinoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one PD-1 inhibitor or at least one IGFIR inhibitor.

The method of claim 1 wherein the PD-1 inhibitor is selected from the group consisting of PD-1 antibodies, PD-L1 antibodies and PD-L2 antibodies.

The method of claim 1 wherein the PD-1 inhibitor is an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region of an immuglobulin.

The method of claim 1 wherein the IGFIR inhibitor is selected from the group consisting of imidazopyrazine IGFIR inhibitors, quinazoline IGFIR inhibitors, pyrido-pyrimidine IGFIR inhibitors, pyrimido-pyrimidine IGFIR inhibitors, pyrrolo- pyrimidine IGF inhibitors, pyrazolo-pyrimidine IGFIR inhibitors, phenylamino- pyrimidine IGFIR inhibitors, oxindole IGFIR inhibitors, indolocarbazole IGFIR inhibitors, phthalazine IGFIR inhibitors, isoflavone IGFIR inhibitors, quinalone IGFIR inhibitors, and tyrphostin IGFIR inhibitors, and all pharmaceutically acceptable salts and solvates of such IGFIR inhibitors, imidazopyrazine IGFIR inhibitors, pyrimidine-based IGF-1R inhibitors, cyclolignans, cyclolignans, pyrrolopyrimidines, pyrrolotriazine, pyrrolo[2,3-d], heteroaryl-aryl ureas, and the like.

The method of claim 1 wherein the IGFIR inhibitor is an anti-IGFIR antibody.

The method of claim 1 wherein the PD-1 inhibitor and the IGFIR inhibitor are coadministered to the subject.

The method of claim 1 or 6 wherein a chemotherapeutic agent is also administered to the subjet.