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      Taking up Cancer Immunotherapy Challenges: Bispecific Antibodies, the Path Forward?

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          Abstract

          As evidenced by the recent approvals of Removab (EU, Trion Pharma) in 2009 and of Blincyto (US, Amgen) in 2014, the high potential of bispecific antibodies in the field of immuno-oncology is eliciting a renewed interest from pharmaceutical companies. Supported by rapid advances in antibody engineering and the development of several technological platforms such as Triomab or bispecific T cell engagers (BiTEs), the “bispecifics” market has increased significantly over the past decade and may occupy a pivotal space in the future. Over 30 bispecific molecules are currently in different stages of clinical trials and more than 70 in preclinical phase. This review focuses on the clinical potential of bispecific antibodies as immune effector cell engagers in the onco-immunotherapy field. We summarize current strategies targeting various immune cells and their clinical interests. Furthermore, perspectives of bispecific antibodies in future clinical developments are addressed.

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          IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.

          V Shankaran, H. Ikeda, A. T. Bruce … (2001)
          Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice. However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response. Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals.
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            Distinct role of macrophages in different tumor microenvironments.

            Claire Lewis, Jeffrey W Pollard (2006)
            Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes.
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              Stromal gene expression predicts clinical outcome in breast cancer.

              Greg Finak, Nicholas Bertos, François Pépin … (2008)
              Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.
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                Author and article information

                Contributors
                Christian Klein: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Antibodies (Basel)
                Journal ID (iso-abbrev): Antibodies (Basel)
                Journal ID (publisher-id): antibodies
                Title: Antibodies
                Publisher: MDPI
                ISSN (Electronic): 2073-4468
                Publication date (Electronic): 26 December 2015
                Publication date Collection: March 2016
                Volume: 5
                Issue: 1
                Electronic Location Identifier: 1
                Affiliations
                [1 ]Inserm, U1068, CRCM, Marseille F-13009, France; joanie.del-bano@ 123456inserm.fr (J.D.B.); patrick.chames@ 123456inserm.fr (P.C.); daniel.baty@ 123456inserm.fr (D.B.)
                [2 ]Aix-Marseille University, Marseille F-13284, France
                [3 ]CNRS, UMR7258, CRCM, Marseille F-13009, France
                [4 ]Institut Paoli-Calmettes, Marseille F-13009, France
                Author notes
                [* ]Correspondence: brigitte.kerfelec@ 123456inserm.fr ; Tel.: +33-491-828-833; Fax: +33-491-828-840
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: antibodies-05-00001
                DOI: 10.3390/antib5010001
                PMC ID: 6698871
                PubMed ID: 31557983
                SO-VID: 5948c89d-260f-4f86-913b-a062a2f39bfd
                Copyright © © 2015 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 12 November 2015
                Date accepted : 18 December 2015
                Categories
                Subject: Review

                Keywords: bispecific antibody,cancer immunotherapy,nk cells,t-cells,immune effector cells,immuno-checkpoint
                Data availability:
                Keywords: bispecific antibody, cancer immunotherapy, nk cells, t-cells, immune effector cells, immuno-checkpoint

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