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Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies

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Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies Published OnlineFirst March 17, 2016; DOI: 10.1158/1535-7163.MCT-15-0759 Small Molecule Therapeutics Molecular Cancer Therapeutics Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies Sebastien Cornet1,2,3,4, Doriane Mathe2,3,4, Kamel Chettab1,2,3,4, Anne Evesque2,3,4, Eva-Laure Matera2,3,4, Olivier Tredan 5, and Charles Dumontet1,2,3,4 Abstract Therapeutic mAbs exert antitumor activity through various filgrastim in murine xenograft models treated with mAbs. This þ mechanisms, including apoptotic signalization, complement- was observed with rituximab in CD20 models and with trastu- þ dependent cytotoxicity, and antibody-dependent cellular cyto- zumab in HER2 models. Stimulation with pegfilgrastim was toxicity (ADCC) or phagocytosis (ADCP). G-CSF and GM-CSF associated with significant enhancement of leukocyte content have been reported to increase the activity of antibodies in in spleen as well as mobilization of activated monocytes/ preclinical models and in clinical trials. To determine the poten- granulocytes from the spleen to the tumor bed. These results tial role of pegfilgrastim as an enhancer of anticancer antibodies, suggest that pegfilgrastim could constitute a potent adjuvant for we performed a comparative study of filgrastim and pegfilgrastim. immunotherapy with mAbs possessing ADCC/ADCP properties. We found that pegfilgrastim was significantly more potent than Mol Cancer Ther; 15(6); 1238–47. Ó2016 AACR. Introduction Most clinically used mAbs belong to the IgG subclass and their Fc domain interacts with IgG Fc receptors (Fcg receptors). The mAbs are increasingly used for the treatment of cancer patients. human IgG receptor family includes several members, most of Their mechanisms of action are complex as antibodies can either which are activating (CD64 or FcgRI, CD32a or FcgRIIa, CD16a or target the tumor cells themselves or the microenvironment, FcgRIIIa, CD16b or FcgRIIIb) and one which is inhibitory including tumor vasculature or the surrounding immune cells. (CD32b or FcgRIIb) with various affinities for the IgG subclasses. Among antibodies targeting tumor cells directly, various mechan- Several of the mAbs currently used in the clinic rely at least partly isms of action are likely to be involved including direct apoptotic on Fcgreceptor–mediated mechanisms and novel antibodies, signalization after recognition of the cognate antigen and extra- such as obinutuzumab, have been specifically engineered to cellular effector mechanisms such as complement-dependent possess enhanced ADCC properties (3). Fc receptor polymorph- cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity isms that affect affinity for IgG (FcgRIIa-131H/R and FcgRIIIa- (ADCC) or its closely related phenomenon antibody-dependent 158V/F) have been found to influence the clinical response to cellular phagocytosis (ADCP; ref. 1). Despite this diversity of rituximab (anti-CD20; ref. 4), cetuximab (anti-EGFR; ref. 5), or mechanisms of antitumor activity, treatment by mAbs has not trastuzumab (anti-HER2; ref. 5) therapy in lymphoma, colorectal, allowed to obtain cure in most of the approved indications, either and breast cancer patients, respectively, suggesting that Fcg recep- as a single agent or in combination with other agents. The case of tor–mediated effector functions play an important role in cancer follicular non-Hodgkin lymphoma (NHL) is exemplary as certain treatment. patients can benefit from single-agent therapy but resistance to The nature of the Fcg receptor–bearing cells involved in cyto- treatment will eventually develop. In addition, a significant pro- toxic activity is not completely elucidated. Classically, natural portion of responding patients will no longer benefit of retreat- killer (NK) cells have been considered as the main effector cells for ment with this mAb after relapse (2). ADCC (6). NK cells express the high-affinity receptor FcgRIIIa, and the association between Fc receptor alleles and clinical success of mAb therapy has been attributed to NK cells (7). However, 1 2 Hospices Civils de Lyon, Pierre Benite, France. Universite de Lyon, other cell populations can act as potential effector cells for mAb- Lyon, France. 3INSERM U1052, Centre de Recherche en Cancerologie de Lyon, Lyon, France. 4CNRS UMR 5286, Centre de Recherche mediated tumor regression, including myeloid effector cells such en Cancerologie de Lyon, Lyon, France. 5Departement d'Oncologie as monocytes/macrophages and neutrophils (8). ^ Medicale,Centre de Lutte Contre le Cancer Lyon et Rhone-Alpes, Lyon, Neutrophils are the most abundant circulating leukocyte sub- France. population in peripheral blood. In addition, this population can Note: Supplementary data for this article are available at Molecular Cancer be amplified and/or mobilized by the administration of granu- Therapeutics Online (http://mct.aacrjournals.org/). locyte (macrophage)-colony stimulating factors (G-CSF and GM- Corresponding Author: Charles Dumontet, Centre de Recherche en CSF; refs. 9–11). Neutrophils have been described as potent Cancerologie de Lyon, 8 avenue Rockefeller, Lyon 69008, France. Phone: cytotoxic effectors, able to produce many cytotoxic molecules 334-7877-7123; Fax: 334-7877-7088; E-mail: [email protected] (12) and exert direct tumoricidal activity (13). Their ability to doi: 10.1158/1535-7163.MCT-15-0759 directly recognize tumor cells is limited but is highly enhanced in Ó2016 American Association for Cancer Research. the presence of mAbs (14). 1238 Mol Cancer Ther; 15(6) June 2016 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 17, 2016; DOI: 10.1158/1535-7163.MCT-15-0759 Pegfilgrastim and Anticancer Antibodies Fcg receptors expressed on neutrophils are FcgRIIa, FcgRIIIb, cinoma epithelial cell line A549 (ATCC: CCL-185), and the breast and FcaRI. FcgRIIIb is the most abundant Fcg receptor on neu- cancer cell line MDA-MB361 (ATCC: HB-27), were purchased trophils, but evidence suggests that it is not involved in efficient directly from the ATCC. These cells were authenticated by ATCC tumor cell cytotoxicity (15). Antibody-dependent killing of tumor by generating human short tandem repeat profiles by simulta- cells by neutrophils in the absence of G-CSF is described to be neously amplifying multiple STR loci and amelogenin (for gender nonexistent or weak (16, 17) and is likely mediated through determination) using the Promega PowerPlex Systems. These cells FcgRIIa (18). Therefore, specific targeting of FcgRI has been were cultured in the laboratory for less than 6 months in culture proposed, as this may overcome potential inhibitory signals medium consisting of RPMI1640 (Life Technologies), 10% FCS through FcgRIIb when IgG mAbs are employed (19). (Integro), 100 U/mL of penicillin, and 100 mg/mL of strepto- To improve antibody-dependent cytotoxicity of leukocytes, mycin (Life Technologies). NFS-60 cells, kindly provided by coadministration of mAbs and different cytokines has been per- Dr.J.Ihle(St.JudeChildren'sResearchHospital,Memphis,TN) formed, in particular, with GM-CSF and G-CSF. Cartron and were maintained in RPMI1640 with 10% of FCS, 1% L-gluta- colleagues (20) performed a phase II clinical study combining mine (2 mmol/L), 1% b-mercaptoethanol (Sigma Aldrich), and GM-CSF and rituximab in patients with relapsed follicular lym- 20 U/mL of IL3 (Sigma-Aldrich). All cells were cultured at 37C phoma. This study reported an improvement in the expected in a 5% CO2 atmosphere. complete response rate with the combination compared with During the course of our experiments, cell culture was system- monotherapy (39% vs. 6%, respectively; ref. 21). The authors atically performed in compliance with good laboratory practice explain this result by the recruitment and activation of granulocytes and the specific culture conditions for each cell line used. Cell line and monocytes, leading to an increased antitumor potential, morphology was checked and the expressions of cell surface involving both ADCC and ADCP (22). While increasing the dose markers CD20 and HER2 were assessed by flow cytometry on of GM-CSF appears to decrease the ADCC exerted by peripheral RL, A549, and MDA-MB361 cell lines, respectively. Using MycoA- mononuclear cells (23), G-CSF or IFNg-primed neutrophils have lert Kit (Lonza) all cell lines used in this study tested mycoplasma- an increased potential for mAb-mediated cytotoxic activity through negative. upregulated expression of FcgRI both in vitro and in vivo (24). Van der Kolk and colleagues showed in a phase I/II clinical trial that, Cell assays when G-CSF was combined with rituximab in CLL, the median NFS-60, a murine myeloid leukemia cell line which prolif- time to progression observed for the combination was 24 months, erates in response to G-CSF, was used for cell-cycle experiments and only 13 months for rituximab as a single agent although the (26, 27). Cells were starved for 18 hours (no IL3 nor G-CSF) to – overall response rate was comparable in both groups (25). block NFS-60 cells in G0 G1 phase, then various concentrations Recombinant G-CSF (filgrastim) used to treat patients has a of filgrastim or pegfilgrastim (from 5 pmol/L to 1 nmol/L) were short half-life of in the blood stream (3–4 hours). Pegfilgrastim, a added to the cells for 18 hours. Cell-cycle distribution was filgrastim analogue carrying a 20 kDa polyethylene glycol (PEG) estimated by flow cytometry using propidium iodide as molecule on its N-terminus has a half-life of 15 to 80 hours in described previously (28). blood. Pegylation increases the molecular weight of filgrastim above the threshold for renal clearance. Consequently, the drug is Neutrophil preparation believed to be mostly cleared by neutrophils. Neutrophil-medi- Blood samples from healthy donors were provided by the Lyon ated clearance takes longer than renal clearance, thereby increas- Blood Bank. Neutrophils were obtained by performing a density ing the half-life of the drug. We show that filgrastim and pegfil- gradient centrifugation (Pancol, Pan-Biotech) followed by a dex- grastim display similar effects on normal human polymorpho- tran separation (3% Dextran, Sigma Aldrich). Remaining red nuclear cells in vitro.
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