In vivo secretion of anti-CD3 × anti-tumor bispecific antibodies by gene-modified cells: over a decade of T-cell engagement
Authors: Marta Compte, Laura Sanz, Luis Álvarez-Vallina
Journal: Molecular Therapy (2015)

To the editor: The recently published paper by Iwahori et al.1Iwahori K Kakarla S Velasquez MP Yu F Yi Z Gerken C et al.Engager T cells: a new class of antigen-specific T cells that redirect bystander T cells.Mol Ther. 2015; 23: 171-178Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar describes the generation of T cells secreting a bispecific anti-CD3 × anti-EphA2 tandem single-chain variable fragment antibody, or BiTE (bispecific T-cell engager). The authors claim that gene-modified T cells secreting bispecific antibodies present a "new class of antigen-specific T cells" with the unique ability to redirect bystander T cells to tumor cells in an antigen-dependent manner. In 2003 our group reported for the first time a cancer immunotherapy strategy based on the secretion of a bispecific anti-CD3 × anti-carcinoembryonic antigen (CEA) diabody by gene-modified human cells that activate and redirect T cells to the tumor in vivo.2Blanco B Holliger P Vile RG Álvarez-Vallina L Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells.J Immunol. 2003; 171: 1070-1077Crossref PubMed Scopus (49) Google Scholar As a result of this proof-of-concept article, our group has been considerably productive in this field. Since then, we have published 12 scientific (original and review) articles3Sanz L Blanco B Álvarez-Vallina L Antibodies and gene therapy: teaching old "magic bullets" new tricks.Trends Immunol. 2004; 25: 85-91Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar,4Sanz L Qiao J Vile RG Álvarez-Vallina L Antibody engineering, virus retargeting and cellular immunotherapy: one ring to rule them all?.Curr Gene Ther. 2005; 5: 63-70Crossref PubMed Scopus (9) Google Scholar,5Sanz L Cuesta AM Compte M Álvarez-Vallina L Antibody engineering: facing new challenges in cancer therapy.Acta Pharmacol Sin. 2005; 26: 641-648Crossref PubMed Scopus (49) Google Scholar,6Compte M Blanco B Serrano F Cuesta AM Sanz L Bernad A et al.Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA × anti-CD3 diabodies from lentivirally transduced human lymphocytes.Cancer Gene Ther. 2007; 14: 380-388Crossref PubMed Scopus (57) Google Scholar,7Compte M Cuesta AM Sánchez-Martín D Alonso-Camino V Vicario JL Sanz L et al.Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.Stem Cells. 2009; 27: 753-760Crossref PubMed Scopus (74) Google Scholar,8Compte M Alonso-Camino V Santos-Valle P Cuesta AM Sánchez-Martín D López MR et al.Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system.Gene Ther. 2010; 17: 745-751Crossref PubMed Scopus (22) Google Scholar,9Álvarez-Vallina L Sanz L The therapeutic potential of engineered human neovessels for cell-based gene therapy.Expert Opin Biol Ther. 2011; 11: 67-76Crossref PubMed Scopus (5) Google Scholar,10Sanz L Compte M Guijarro-Muñoz I Álvarez-Vallina L Non-hematopoietic stem cells as factories for in vivo therapeutic protein production.Gene Ther. 2012; 19: 1-7Crossref PubMed Scopus (17) Google Scholar,11Sánchez-Martin D Sanz L Álvarez-Vallina L Engineering human cells for in vivo secretion of protein therapeutics.Curr Opin Biotechnol. 2011; 22: 924-930Crossref PubMed Scopus (12) Google Scholar,12Guijarro-Muñoz I Compte M Álvarez-Vallina L Sanz L Antibody gene therapy: getting closer to clinical application?.Curr Gene Ther. 2013; 13: 282-290Crossref PubMed Scopus (18) Google Scholar,13Compte M Álvarez-Cienfuegos A Nuñez-Prado N Sainz-Pastor N Blanco-Toribio A Pescador N et al.Functional comparison of single-chain and two-chain anti-CD3-based bispecific antibodies in gene immunotherapy applications.Oncoimmunology. 2014; 3: e28810Crossref PubMed Scopus (24) Google Scholar,14Saenz Del Burgo L Compte M Aceves M Hernández RM Sanz L Álvarez-Vallina L et al.Microencapsulation of therapeutic bispecific antibodies producing cells: immunotherapeutic organoids for cancer management.J Drug Target. 2015; 23: 170-179Crossref PubMed Scopus (22) Google Scholar in which we have validated this bispecific antibody–based gene therapy strategy using different formats of bispecific antibodies (diabody and BiTE), various types of cell carriers (human T-cell lines and primary T cells, human mesenchymal and hematopoietic stem cells, and human endothelial cells), several gene transfer systems (plasmids and lentiviral vectors), and several mouse cancer models.3Sanz L Blanco B Álvarez-Vallina L Antibodies and gene therapy: teaching old "magic bullets" new tricks.Trends Immunol. 2004; 25: 85-91Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar,4Sanz L Qiao J Vile RG Álvarez-Vallina L Antibody engineering, virus retargeting and cellular immunotherapy: one ring to rule them all?.Curr Gene Ther. 2005; 5: 63-70Crossref PubMed Scopus (9) Google Scholar,5Sanz L Cuesta AM Compte M Álvarez-Vallina L Antibody engineering: facing new challenges in cancer therapy.Acta Pharmacol Sin. 2005; 26: 641-648Crossref PubMed Scopus (49) Google Scholar,6Compte M Blanco B Serrano F Cuesta AM Sanz L Bernad A et al.Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA × anti-CD3 diabodies from lentivirally transduced human lymphocytes.Cancer Gene Ther. 2007; 14: 380-388Crossref PubMed Scopus (57) Google Scholar,7Compte M Cuesta AM Sánchez-Martín D Alonso-Camino V Vicario JL Sanz L et al.Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.Stem Cells. 2009; 27: 753-760Crossref PubMed Scopus (74) Google Scholar,8Compte M Alonso-Camino V Santos-Valle P Cuesta AM Sánchez-Martín D López MR et al.Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system.Gene Ther. 2010; 17: 745-751Crossref PubMed Scopus (22) Google Scholar,9Álvarez-Vallina L Sanz L The therapeutic potential of engineered human neovessels for cell-based gene therapy.Expert Opin Biol Ther. 2011; 11: 67-76Crossref PubMed Scopus (5) Google Scholar,10Sanz L Compte M Guijarro-Muñoz I Álvarez-Vallina L Non-hematopoietic stem cells as factories for in vivo therapeutic protein production.Gene Ther. 2012; 19: 1-7Crossref PubMed Scopus (17) Google Scholar,11Sánchez-Martin D Sanz L Álvarez-Vallina L Engineering human cells for in vivo secretion of protein therapeutics.Curr Opin Biotechnol. 2011; 22: 924-930Crossref PubMed Scopus (12) Google Scholar,12Guijarro-Muñoz I Compte M Álvarez-Vallina L Sanz L Antibody gene therapy: getting closer to clinical application?.Curr Gene Ther. 2013; 13: 282-290Crossref PubMed Scopus (18) Google Scholar,13Compte M Álvarez-Cienfuegos A Nuñez-Prado N Sainz-Pastor N Blanco-Toribio A Pescador N et al.Functional comparison of single-chain and two-chain anti-CD3-based bispecific antibodies in gene immunotherapy applications.Oncoimmunology. 2014; 3: e28810Crossref PubMed Scopus (24) Google Scholar,14Saenz Del Burgo L Compte M Aceves M Hernández RM Sanz L Álvarez-Vallina L et al.Microencapsulation of therapeutic bispecific antibodies producing cells: immunotherapeutic organoids for cancer management.J Drug Target. 2015; 23: 170-179Crossref PubMed Scopus (22) Google Scholar In 2007 we reported in Cancer Gene Therapy the usefulness of lentiviral vectors for the sustained expression of a bispecific anti-CD3 × anti-CEA diabody in human primary peripheral blood T lymphocytes.7Compte M Cuesta AM Sánchez-Martín D Alonso-Camino V Vicario JL Sanz L et al.Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.Stem Cells. 2009; 27: 753-760Crossref PubMed Scopus (74) Google Scholar In this paper we specifically stated that the recruitment of both gene-modified and nonmodified T cells, present at the tumor site, would amplify the effector response. Moreover, gene-modified human stem cells embedded in synthetic extracellular matrix scaffold and implanted in a location distant from the primary tumor, were able to secrete the anti-CD3 × anti-CEA diabody, which significantly reduced the tumor growth and resulted in effective and persistent systemic levels of therapeutic antibody for more than 40 days.7Compte M Cuesta AM Sánchez-Martín D Alonso-Camino V Vicario JL Sanz L et al.Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.Stem Cells. 2009; 27: 753-760Crossref PubMed Scopus (74) Google Scholar We moved a step forward, and in 2010 we explored the therapeutic potential of engineered neovessels after gene-modifying endothelial cells for the secretion of the above-mentioned bispecific diabody.8Compte M Alonso-Camino V Santos-Valle P Cuesta AM Sánchez-Martín D López MR et al.Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system.Gene Ther. 2010; 17: 745-751Crossref PubMed Scopus (22) Google Scholar Systemic antibody release was detected in plasma for 1 month and exerted a therapeutic effect in mice bearing distant CEA-positive tumors after inoculation of human T cells. Given the wide availability of free Internet-based search engines, we regret the omission of the above-mentioned pioneering works, all of them indexed in PubMed,2Blanco B Holliger P Vile RG Álvarez-Vallina L Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells.J Immunol. 2003; 171: 1070-1077Crossref PubMed Scopus (49) Google Scholar,3Sanz L Blanco B Álvarez-Vallina L Antibodies and gene therapy: teaching old "magic bullets" new tricks.Trends Immunol. 2004; 25: 85-91Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar,4Sanz L Qiao J Vile RG Álvarez-Vallina L Antibody engineering, virus retargeting and cellular immunotherapy: one ring to rule them all?.Curr Gene Ther. 2005; 5: 63-70Crossref PubMed Scopus (9) Google Scholar,5Sanz L Cuesta AM Compte M Álvarez-Vallina L Antibody engineering: facing new challenges in cancer therapy.Acta Pharmacol Sin. 2005; 26: 641-648Crossref PubMed Scopus (49) Google Scholar,6Compte M Blanco B Serrano F Cuesta AM Sanz L Bernad A et al.Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA × anti-CD3 diabodies from lentivirally transduced human lymphocytes.Cancer Gene Ther. 2007; 14: 380-388Crossref PubMed Scopus (57) Google Scholar,7Compte M Cuesta AM Sánchez-Martín D Alonso-Camino V Vicario JL Sanz L et al.Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.Stem Cells. 2009; 27: 753-760Crossref PubMed Scopus (74) Google Scholar,8Compte M Alonso-Camino V Santos-Valle P Cuesta AM Sánchez-Martín D López MR et al.Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system.Gene Ther. 2010; 17: 745-751Crossref PubMed Scopus (22) Google Scholar,9Álvarez-Vallina L Sanz L The therapeutic potential of engineered human neovessels for cell-based gene therapy.Expert Opin Biol Ther. 2011; 11: 67-76Crossref PubMed Scopus (5) Google Scholar,10Sanz L Compte M Guijarro-Muñoz I Álvarez-Vallina L Non-hematopoietic stem cells as factories for in vivo therapeutic protein production.Gene Ther. 2012; 19: 1-7Crossref PubMed Scopus (17) Google Scholar,11Sánchez-Martin D Sanz L Álvarez-Vallina L Engineering human cells for in vivo secretion of protein therapeutics.Curr Opin Biotechnol. 2011; 22: 924-930Crossref PubMed Scopus (12) Google Scholar,12Guijarro-Muñoz I Compte M Álvarez-Vallina L Sanz L Antibody gene therapy: getting closer to clinical application?.Curr Gene Ther. 2013; 13: 282-290Crossref PubMed Scopus (18) Google Scholar,13Compte M Álvarez-Cienfuegos A Nuñez-Prado N Sainz-Pastor N Blanco-Toribio A Pescador N et al.Functional comparison of single-chain and two-chain anti-CD3-based bispecific antibodies in gene immunotherapy applications.Oncoimmunology. 2014; 3: e28810Crossref PubMed Scopus (24) Google Scholar,14Saenz Del Burgo L Compte M Aceves M Hernández RM Sanz L Álvarez-Vallina L et al.Microencapsulation of therapeutic bispecific antibodies producing cells: immunotherapeutic organoids for cancer management.J Drug Target. 2015; 23: 170-179Crossref PubMed Scopus (22) Google Scholar showing the potential of in vivo secreted anti-CD3 × anti-(tumor-associated antigen) bispecific antibodies for cancer immunotherapy.