• design of experiments (DoE)
• design space
• immunoglobulins
• nanofiltration
• virus retentive filtration

• G-CSF
• GM-CSF
• anti-GD2 monoclonal antibody
• cytokines
• dinutuximab
• dinutuximab beta
• immunotherapy
• naxitamab
• neuroblastoma
• sargramostim

• Humans
• Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use
• Granulocyte Colony-Stimulating Factor/therapeutic use
• Antibodies, Monoclonal/therapeutic use
• Neuroblastoma/drug therapy
• Adjuvants, Immunologic/therapeutic use
• Immunotherapy

• Partner Therapeutics, Inc.

• B7-H3
• Breast cancer
• Cancer immunotherapy
• Immune checkpoint
• Targeted immunotherapy
• Tumor microenvironment

• Humans
• Female
• Breast Neoplasms/drug therapy
• B7 Antigens/metabolism
• Immunotherapy
• Immunomodulation
• Tumor Microenvironment

• N20201006 Major project of Wuxi Science and Technology Bureau
• J202106 Wuxi Health Commission Precision Medicine Project
• F202034 Jiangsu Provincial Maternal and Child Health Research Project
• No. YY-124 Jiangsu Provincial Six Talent Peaks Project

• CD20
• FcγRIIIA
• NKG2D
• antibody therapy
• bispecific antibody
• lymphoma
• phage display

• Humans
• Antibodies, Bispecific/pharmacology
• Antibodies, Bispecific/metabolism
• NK Cell Lectin-Like Receptor Subfamily K/metabolism
• Killer Cells, Natural
• Neoplasms
• Lymphoma/metabolism
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal/metabolism
• Antigens, CD19

• CD55
• antibodies
• colon cancer
• complement-dependent cytotoxicity
• miR-132-3p

• Humans
• Complement Activation
• Membrane Cofactor Protein/genetics
• Membrane Cofactor Protein/metabolism
• CD59 Antigens/genetics
• CD59 Antigens/metabolism
• CD55 Antigens/genetics
• Complement System Proteins
• Colonic Neoplasms/genetics
• MicroRNAs/genetics
• Cell Line, Tumor

• amino-bis-phosphonates
• antibody-drug conjugate
• colorectal cancer
• epidermal growth factor receptor
• gammadelta T lymphocytes
• tumor associated fibroblasts

• Antibody-dependent cellular cytotoxicity (ADCC)
• Urokinase-type plasminogen activator receptor (uPAR)
• cancer therapeutics
• cross-reactive antibody
• single B-cell screening

• IL-2 mutein
• anti-CD20
• immunocytokine
• immunotherapy
• lymphoma

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.

• B7-H3
• Biomarker
• Cancer immune checkpoints
• Cancer immunotherapy
• Tumor microenvironment

• ADCC
• HER2-positive cancer
• PEGylated IFN-α1b
• Trastuzumab
• synergistic effect

• TNBC
• breast cancer
• drug discovery
• drug targets
• immunotherapeutics
• immunotherapy
• lag-3
• tigit
• tim-3
• translational drug development
• triple-negative breast cancer

• NK cells
• TLR agonists
• antibody-dependent cellular cytotoxicity
• cetuximab
• head and neck cancer
• immunosuppression
• immunotherapy

• Animals
• Antibody-Dependent Cell Cytotoxicity/immunology
• Cell Line, Tumor
• Cetuximab/pharmacology
• Cetuximab/therapeutic use
• Cytokines/metabolism
• Drug Therapy, Combination
• Female
• Head and Neck Neoplasms/therapy
• Humans
• Immunotherapy
• Killer Cells, Natural/immunology
• Leukocytes, Mononuclear/cytology
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/metabolism
• Lipopeptides/pharmacology
• Lipopeptides/therapeutic use
• Mice
• Mice, Nude
• Receptors, IgG/agonists
• Receptors, IgG/metabolism
• Toll-Like Receptor 2/agonists
• Toll-Like Receptor 2/metabolism
• Transplantation, Heterologous

• CCA2016213 Cancer Center Amsterdam

• antibody drugs
• biomaterials
• cancer immunotherapy
• cancer treatment
• delivery system

Our increased understanding of tumour biology gained over the last few years has led to the development of targeted molecular therapies, e.g., vascular endothelial growth factor A (VEGF-A) antagonists, poly[ADP-ribose] polymerase 1 (PARP1) inhibitors in hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutants), increasing survival and improving the quality of life. However, the majority of ovarian cancer (OC) patients still do not have access to targeted molecular therapies that would be capable of controlling their disease, especially resistant or relapsed. Chimeric antigen receptors (CARs) are recombinant receptor constructs located on T lymphocytes or other immune cells that change its specificity and functions. Therefore, in a search for a successful solid tumour therapy using CARs the specific cell surface antigens identification is crucial. Numerous in vitro and in vivo studies, as well as studies on humans, prove that targeting overexpressed molecules, such as mucin 16 (MUC16), annexin 2 (ANXA2), receptor tyrosine-protein kinase erbB-2 (HER2/neu) causes high tumour cells toxicity and decreased tumour burden. CARs are well tolerated, side effects are minimal and they inhibit disease progression. However, as OC is heterogenic in its nature with high mutation diversity and overexpression of different receptors, there is a need to consider an individual approach to treat this type of cancer. In this publication, we would like to present the history and status of therapies involving the CAR T cells in treatment of OC tumours, suggest potential T cell-intrinsic determinants of response and resistance as well as present extrinsic factors impacting the success of this approach.

• chemoresistance
• chimeric antigen receptors
• ovarian cancer
• relapse

• Avelumab
• Eribulin
• Urothelial carcinoma

• OX40
• colorectal cancer
• immune escape
• microenvironment

• Anti-CD20
• IL-2
• IL-2 mutein
• immunotherapy
• lymphoma

Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) titers exhibited by vaccine-induced neutralizing antibodies, which correlate fairly well with vaccine-conferred protection. Contrarily, non-neutralizing antibodies and their therapeutic potential are less well defined, yet, recent advances in anti-influenza antibody research indicate that non-neutralizing Fc-effector activities, especially antibody-dependent cellular cytotoxicity (ADCC), also serve as a critical mechanism in antibody-mediated anti-influenza host response. Monoclonal antibodies (mAbs) with Fc-effector activities have the potential for prophylactic and therapeutic treatment of influenza infection. Inducing mAbs mediated Fc-effector functions could be a complementary or alternative approach to the existing neutralizing antibody-based prevention and therapy. This review mainly discusses recent advances in Fc-effector functions, especially ADCC and their potential role in influenza countermeasures. Considering the complexity of anti-influenza approaches, future vaccines may need a cocktail of immunogens in order to elicit antibodies with broad-spectrum protection via multiple protective mechanisms.

• Fc effector activities
• antibody-dependent cellular cytotoxicity (ADCC)
• influenza
• non-neutralizing monoclonal antibody

• Adaptive Immunity
• Animals
• Antibodies, Neutralizing/chemistry
• Antibodies, Neutralizing/immunology
• Antibodies, Viral/chemistry
• Antibodies, Viral/immunology
• Antibody-Dependent Cell Cytotoxicity
• Hemagglutinin Glycoproteins, Influenza Virus/chemistry
• Hemagglutinin Glycoproteins, Influenza Virus/immunology
• Host-Pathogen Interactions/immunology
• Humans
• Immunity, Innate
• Influenza A virus/immunology
• Influenza Vaccines/immunology
• Influenza, Human/immunology
• Influenza, Human/prevention & control
• Influenza, Human/virology
• Structure-Activity Relationship

• R01AI141889 NIGMS NIH HHS

• ADCC
• ADCP
• Antibody
• CDC
• Complement
• Fc receptor
• Macrophages
• NK cells

• CAR-adaptor
• Chimeric antigen receptor (CAR)
• adaptor molecule
• adoptive T cell therapy
• antibody
• immunological synapse
• universal CAR-T cells

• Antibody-dependent cellular cytotoxicity
• cancer
• natural killer cell (NK cell)
• therapeutic monoclonal antibody (mAb)

• Animals
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/therapeutic use
• Antibody-Dependent Cell Cytotoxicity/immunology
• Humans
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/pathology
• Receptors, Fc/immunology
• Receptors, IgG/immunology

• Antibody-dependent cell cytotoxicity
• Natural Killer cell
• microfluidics
• organotypic model
• solid tumor

It is ideal for the target antigen of a cytotoxic therapeutic antibody against cancer to be cancer-specific, but such antigens are rare. Thus an alternative strategy for target selection is necessary. Desmoglein 3 (DSG3) is highly expressed in lung squamous cell carcinoma, while it is well-known that anti-DSG3 antibodies cause pemphigus vulgaris, an autoimmune disease. We evaluated DSG3 as a novel target by selecting an epitope that exerts efficacy against cancer with no pathogenic effects in normal tissues. Pathogenic anti-DSG3 antibodies induce skin blisters by inhibiting the cell–cell interaction in a Ca²⁺-dependent manner. We screened anti-DSG3 antibodies that bind DGS3 independent of Ca²⁺ and have high antibody-dependent cell cytotoxicity (ADCC) activity against DSG3-expressing cells. These selected antibodies did not inhibit cell–cell interaction and showed ADCC activity against squamous cell carcinoma cell lines. Furthermore, one of the DSG3 antibodies showed anti-tumour activity in tumour mouse models but did not induce adverse effects such as blister formation in the skin. Thus it was possible to generate an antibody against DSG3 by using an appropriate epitope that retained efficacy with no pathogenicity. This approach of epitope selection may expand the variety of druggable target molecules.

Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations.

We examined if olaparib, when combined with IgG₁ antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab.

NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15Rα further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2; and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma.

These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.

The online version of this article (10.1186/s40425-018-0445-4) contains supplementary material, which is available to authorized users.

• ADCC
• BRCA
• PARP inhibitors
• Prostate carcinoma
• TRAIL

• ADCC
• Biotherapeutic products
• Primary natural killer cells
• Validation assay

Natural killer (NK) cells play a pivotal role in monoclonal antibody-mediated immunotherapy through the antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. NK-92MI is an interleukin-2 (IL-2)-independent cell line, which was derived from NK-92 cells with superior cytotoxicity toward a wide range of tumor cells in vitro and in vivo. Nonetheless, the Fc-receptor (CD16) that usually mediates ADCC is absent in NK-92 and NK-92MI cells. To apply NK-92MI cell-based immunotherapy to cancer treatment, we designed and generated two chimeric receptors in NK-92MI cells that can bind the Fc portion of human immunoglobulins. The construct includes the low-affinity Fc receptor CD16 (158F) or the high-affinity Fc receptor CD64, with the addition of the CD8a extracellular domain, CD28 transmembrane domains, two costimulatory domains (CD28 and 4-1BB), and the signaling domain from CD3ζ. The resulting chimeric receptors, termed CD16-BB-ζ and CD64-BB-ζ, were used to generate modified NK-92MI cells expressing the chimeric receptor, which were named NK-92MI^hCD16 and NK-92MI^hCD64 cells, respectively. We found that NK-92MI^hCD16 and NK-92MI^hCD64 cells significantly improved cytotoxicity against CD20-positive non-Hodgkin's lymphoma cells in the presence of rituximab. These results suggest that the chimeric receptor-expressing NK-92MI cells may enhance the clinical responses to currently available anticancer monoclonal antibodies.

• NK-92MI
• chimeric CD16/CD64-BB-ζ receptor
• therapeutic antibody

Therapeutic strategies aiming at mobilizing immune effector cells to kill tumor cells independent of tumor mutational load and MHC expression status are expected to benefit cancer patients. Recently, we engineered various peptide-Fc fusion proteins for directing Fcg receptor-bearing immune cells toward tumor cells. Here, we investigated the immunostimulatory and anti-tumor effects of one of the engineered Fc fusion proteins (WN-Fc). In contrast to the Fc control, soluble WN-Fc-1 fusion protein activated innate immune cells (e.g. monocytes, macrophages, dendritic cells, NK cells), resulting in cytokine production and surface display of the lytic granule marker CD107a on NK cells. An engineered Fc-fusion variant carrying two peptide sequences (WN-Fc-2) also activated immune cells and bound to various cancer cell types with high affinity, including the murine 4T1 breast carcinoma cells. When injected into 4T1 tumor-bearing BALB/c mice, both peptide-Fc fusions accumulated in tumor tissues as compared to other organs such as the lungs. Moreover, treatment of 4T1 tumor-bearing BALB/c mice by means of two intravenous injections of the WN-Fc fusion proteins inhibited tumor growth with WN-Fc-2 being more effective than WN-Fc-1. Treatment resulted in tumor infiltration by T cells and NK cells. These new engineered WN-Fc fusion proteins may be a promising alternative to existing immunotherapies for cancer.

• Fc-fusion proteins
• NK cells
• immunostimulation
• immunotherapy
• innate effector cells

Natural killer (NK) cells are known to play a role in mediating innate immunity, in enhancing adaptive immune responses, and have been implicated in mediating anti-tumor responses via antibody-dependent cell-mediated cytotoxicity (ADCC) by reactivity of CD16 with the Fc region of human IgG1 antibodies. The NK-92 cell line, derived from a lymphoma patient, has previously been well characterized and adoptive transfer of irradiated NK-92 cells has demonstrated safety and shown preliminary evidence of clinical benefit in cancer patients. The NK-92 cell line, devoid of CD16, has now been engineered to express the high affinity (ha) CD16 V158 FcγRIIIa receptor, as well as engineered to express IL-2; IL-2 has been shown to replenish the granular stock of NK cells, leading to enhanced perforin- and granzyme-mediated lysis of tumor cells. The studies reported here show high levels of granzyme in haNK cells, and demonstrate the effects of irradiation of haNK cells on multiple phenotypic markers, viability, IL-2 production, and lysis of a spectrum of human tumor cells. Studies also compare endogenous irradiated haNK lysis of tumor cells with that of irradiated haNK-mediated ADCC using cetuximab, trastuzumab and pertuzumab monoclonal antibodies. These studies thus provide the rationale for the potential use of irradiated haNK cells in adoptive transfer studies for a range of human tumor types. Moreover, since only approximately 10% of humans are homozygous for the high affinity V CD16 allele, these studies also provide the rationale for the use of irradiated haNK cells in combination with IgG1 anti-tumor monoclonal antibodies.

• ADCC
• NK lysis
• cetuximab
• high affinity CD16
• immunotherapy

• Cancer
• Immunology
• Immunotherapy
• Macrophage

• Humans
• Macrophages/immunology
• Neoplasms/immunology
• Prognosis
• Tumor Microenvironment/immunology

• Breakthrough Cancer Research

Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e., trastuzumab, pertuzumab) to chemotherapy significantly improves relapse-free and overall survival in patients with early-stage and advanced disease. Nonetheless, considerable proportions of patients develop resistance to treatment, highlighting the need for additional and co-adjuvant therapeutic strategies. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models. Antibody-dependent NK cell activation results in the release of cytotoxic granules as well as the secretion of pro-inflammatory cytokines (i.e., IFNγ and TNFα) and chemokines. Hence, NK cell tumor suppressive functions include direct cytolytic killing of tumor cells as well as the regulation of subsequent antitumor adaptive immunity. Albeit tumors with gene expression signatures associated to the presence of cytotoxic lymphocyte infiltrates benefit from trastuzumab-based treatment, NK cell-related biomarkers of response/resistance to HER2-specific therapeutic antibodies in breast cancer patients remain elusive. Several variables, including (i) the configuration of the patient NK cell repertoire; (ii) tumor molecular features (i.e., estrogen receptor expression); (iii) concomitant therapeutic regimens (i.e., chemotherapeutic agents, tyrosine kinase inhibitors); and (iv) evasion mechanisms developed by progressive breast tumors, have been shown to quantitatively and qualitatively influence antibody-triggered NK cell responses. In this review, we discuss possible interventions for restoring/enhancing the therapeutic activity of HER2 therapeutic antibodies by harnessing NK cell antitumor potential through combinatorial approaches, including immune checkpoint blocking/stimulatory antibodies, cytokines and toll-like receptor agonists.

• antibody-dependent cell-mediated cytotoxicity
• breast cancer
• human epidermal growth factor receptor 2
• immunotherapy
• natural killer cells
• pertuzumab
• trastuzumab

Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients.

• B16-F10
• CT26
• CTLA-4
• EMT-6
• IL-21
• MC38
• PD-1
• interleukin 21
• mouse tumor models

• Chronic inflammation
• EMT
• MMPs
• Natural killer cells
• Tumor metastasis

The aim of cancer therapy is to eradicate cancer without affecting healthy tissues. Current options available for treating colorectal cancer (CRC), including surgery, chemotherapy or radiotherapy, usually elicit multiple adverse effects and frequently fail to completely remove the tumor cells. Thus, there is a constant need for seeking cancer cell-specific therapeutics to improve the course of cancer therapy and reduce the risk of relapse. In this review we elaborate on the mechanisms underlying the immunotherapy with dendritic cells (DCs) and cytokine-induced killer (CIK) cells, and summarize their effectiveness and tolerability available clinical studies. Finally, we discuss the up-to-date combinatorial adoptive anti-cancer immunotherapy with CIK cells co-cultured with DCs that recently showed encouraging efficacy and usefulness in treating malignant disease, including CRC.

• colorectal cancer
• colorectal cancer treatment
• cytokine-induced killer cells
• dendritic cells
• immunotherapy

• ADCC
• Antibodies
• Antigen expression
• Flow cytometry
• HER2/neu
• NK cells

• Antibody-Dependent Cell Cytotoxicity/drug effects
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Breast Neoplasms/drug therapy
• Breast Neoplasms/immunology
• Breast Neoplasms/pathology
• Cell Degranulation/drug effects
• Cell Separation
• Female
• Flow Cytometry
• Gene Amplification
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/immunology
• MCF-7 Cells
• Receptor, ErbB-2/genetics
• Receptor, ErbB-2/metabolism
• Receptors, Fc/metabolism
• Tamoxifen/therapeutic use

• Aurora Cancer Care Research Award

• Fc receptors
• TLR
• antibody
• cancer
• cytokine
• inflammation

NK cells detect tumors through activating surface receptors, which bind self-antigens that are frequently expressed upon malignant transformation. To increase the recognition of tumor cells, the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80 and DNAM-1 (i.e. B7-H6, AICL and PVR, respectively) were fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2), which is displayed by various solid tumors. The resulting immunoligands, designated B7-H6:HER2-scFv, AICL:HER2-scFv, and PVR:HER2-scFv, respectively, bound HER2 and the addressed NK cell receptor. However, whereas B7-H6:HER2-scFv and AICL:HER2-scFv triggered NK cells to kill HER2-positive breast cancer cells at nanomolar concentrations, PVR:HER2-scFv was not efficacious. Moreover, NK cell cytotoxicity was enhanced synergistically when B7-H6:HER2-scFv or AICL:HER2-scFv were applied in combination with another HER2-specific immunoligand engaging the stimulatory receptor NKG2D. In contrast, no improvements were achieved by combining B7-H6:HER2-scFv with AICL:HER2-scFv. Additionally, B7-H6:HER2-scFv and AICL:HER2-scFv enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies trastuzumab and cetuximab synergistically, with B7-H6:HER2-scFv exhibiting a higher efficacy. In summary, antibody-derived proteins engaging NKp30 or NKp80 may represent attractive biologics to further enhance anti-tumor NK cell responses and may provide an innovative approach to sensitize tumor cells for antibody-based immunotherapy.

• ADCC
• B7-H6
• NK cells
• NKp30
• NKp80

AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers (mCRCs) addicted to epidermal growth factor receptor (EGFR) signalling.

METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science to identify eligible papers until March 21^st, 2016 using these following terms: ‘‘colorectal cancer’’, “predictive biomarkers’’, “anti-EGFR therapy”, “KRAS”, “NRAS’’, “PIK3CA”, “TP53”, “PTEN”, ‘‘EGFR”, “MET”, “HER2”, “epiregulin”, “amphiregulin”, “prognostic biomarkers”, “BRAF”, “miRNA” and “antibody-dependent cell-mediated cytotoxicity (ADCC) activity”. Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion.

RESULTS: The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mCRCs. Nevertheless, it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30%. Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers. So far the identification of predictive biomarkers have generated interesting, though preliminary and, at times, conflicting data on the importance of tumour mRNA levels of EGFR ligands, of activating mutations in other genes such as NRAS and PIK3CA. The prognostic value of selected microRNAs level and ADCC activity is under investigation, while the prognostic impact of BRAF status remains controversial.

CONCLUSION: This review focuses on the personalized treatment of mCRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy.

• Metastatic colorectal cancer
• Anti-epidermal growth factor receptor therapy
• KRAS
• Biomarkers
• Antibody-dependent cell-mediated cytotoxicity

• Antibody-Dependent Cell Cytotoxicity
• Biomarkers, Tumor/genetics
• Class I Phosphatidylinositol 3-Kinases
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• ErbB Receptors/antagonists & inhibitors
• Genes, p53
• Humans
• Mutation
• Neoplasm Metastasis
• Phosphatidylinositol 3-Kinases/genetics
• Prognosis
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins p21(ras)/genetics

• albumin nanoparticles
• antibodies
• immunotherapy
• neutrophils
• tumor