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New Advances in Leukaemia Immunotherapy by the Use of Chimeric Artificial Antigen Receptors

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New Advances in Leukaemia Immunotherapy by the Use of Chimeric Artificial Antigen Receptors Biagi et al. Italian Journal of Pediatrics 2011, 37:46 http://www.ijponline.net/content/37/1/46 ITALIAN JOURNAL OF PEDIATRICS REVIEW Open Access New advances in leukaemia immunotherapy by the use of Chimeric Artificial Antigen Receptors (CARs): state of the art and perspectives for the near future Ettore Biagi*, Virna Marin, Greta Maria Paola Giordano Attianese, Irene Pizzitola, Sarah Tettamanti, Elisabetta Cribioli and Andrea Biondi Abstract Leukaemia immunotherapy represents a fascinating and promising field of translational research, particularly as an integrative approach of bone marrow transplantation. Adoptive immunotherapy by the use of donor-derived expanded leukaemia-specific T cells has showed some kind of clinical response, but the major advance is nowadays represented by gene manipulation of donor immune cells, so that they acquire strict specificity towards the tumour target and potent lytic activity, followed by significant proliferation, increased survival and possibly anti- tumour memory state. This is achieved by gene insertion of Chimeric T-cell Antigen Receptors (CARs), which are artificial molecules containing antibody-derived fragments (to bind the specific target), joined with potent signalling T-Cell Receptor (TCR)-derived domains that activate the manipulated cells. This review will discuss the main application of this approach particularly focusing on the paediatric setting, raising advantages and disadvantages and discussing relevant perspectives of use in the nearest future. Keywords: Leukaemia immunotherapy, cell therapy, gene therapy, chimeric artificial receptors Introduction exhibit specific lysis towards tumour cells and cytokine Chimeric T-cell Antigen Receptors (CARs) are a fasci- secretion upon exposure to the respective target antigen. nating bio-technologic step in the field of immunother- The CAR-mediated effector function may produce sus- apy to orient the activity of immune cells towards tained tumour cell lysis more likely than humoral specific molecular targets expressed on the cell surface immune responses alone, based on the use of monoclo- of various tumours, including haematological malignan- nal antibodies. The perforin/granzyme killing mechan- cies. CARs are artificial T-cell receptors constituted by ism may be effective against cells that are relatively an antigen-recognizing extracellular domain derived resistant to antibody and complement, while cytokine from an antibody molecule linked to a T-cell triggering secretion recruits additional components of the immune domain [1-4]. CARs are generated by joining the heavy system, amplifying and prolonging the anti-tumour and light chain variable regions of a monoclonal anti- immune response. Moreover, effector T cells display body, expressed as a single-chain Fragment variable efficient tumour penetration and homing capabilities (scFv) molecule, to an intracellular signalling domain, [1-4]. usually the zeta-chain of the TCR/CD3 complex or the The CAR approach permits to overcome the major gamma-chain from the Fc-epsilon-RI receptor Figure 1. limitations associated with the use of a “classical” TCR T lymphocytes genetically engineered to express CARs transgenic molecule. In fact, target recognition by CAR is non-MHC restricted and independent of antigen pro- * Correspondence: [email protected] cessing, therefore allowing its use in patients with differ- Centro di Ricerca Fondazione “Matilde Tettamanti”, Clinica Pediatrica Azienda ent haplotypes and bypassing tumour escape due to Ospedaliera San Gerardo, Università Milano-Bicocca, via Pergolesi 33, Monza, MHC-molecules down-regulation. In addition, CARs 20900, Italy © 2011 Biagi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Biagi et al. Italian Journal of Pediatrics 2011, 37:46 Page 2 of 9 http://www.ijponline.net/content/37/1/46 Figure 1 the structure of a CAR. can be targeted toward molecules other than peptides, genetically modified cells was associated with tumour like carbohydrates and glycolipids, and there is no risk regression or necrosis in half of the subjects tested [6]. to trigger unpredictable and potentially harmful specifi- cities, as it may happen with transduced TCR, that How to build a Chimeric Artificial Receptor could form hybrids with the endogenous TCR [1-4]. The ectodomain represents the extracellular part of the Different CARs have been generated so far [2,3,5], artificial T-cell receptor. It is generally composed by a against a wide range of surface molecules expressed by signal peptide, an antigen recognition region and a many solid tumours and haematological malignancies. spacer sequence. The signal peptide directs the nascent The efficacy of this strategy has been recently proved by protein into the endoplasmic reticulum. This is essential a phase I clinical trial in patients with neuroblastoma. In if the receptor needs to be glycosylated and anchored in this study, the authors generated a CAR directed to the the cell membrane leading to the CAR expression. The diasialoganglioside G(D2a), a tumour-associated antigen antigen recognition domain is usually a scFv, obtained expressed by human neuroblastoma cells. They demon- by the fusion of the variable regions of the heavy (VH) strated that Epstein-Barr virus (EBV)-specific cytotoxic and light (VL) chains of Immunoglobulins (Igs), joined T lymphocytes (CTLs) engineered to express the G(D2a) together with a short linker. The latter is usually a ser- specific-CAR survive longer than T cells activated by the ine-glycine rich motif, whose flexibility assures a high CD3-specific antibody OKT3 expressing the same CAR, mobility capacity to the molecule Figure 1. This chi- but lacking virus specificity. Moreover, infusion of these meric domain retains the specificity of the original Ig, Biagi et al. Italian Journal of Pediatrics 2011, 37:46 Page 3 of 9 http://www.ijponline.net/content/37/1/46 despite removal of the constant regions and the intro- annealing possibilities. The overlapping oligonucleotides duction of a linker peptide. The traditional method to are then joined together exploiting a basic PCR reaction obtain the scFv was based on the use of mouse hybri- in order to generate the putative template. A second doma producing the specific antibody necessary to have reaction of PCR is then needed to amplify the new syn- the variable fragments of the VL and VH chains [7]. A thetic template using flanking primers Figure 2. new approach, more suitable in this contest, is repre- sented by the technology of synthetic DNA. To generate Clinical application in haematology the scFv binding domain by a “synthetic DNA “ Haematological malignancies represent optimal targets approach, guidelines published by Rydzanicz et al. can for the exploitation of CARs, because of the bright be adopted [8]. As a DNA template for the VH and VL expression of specific antigens on the surface of tumour fragment it is possible to use a humanized antibody cells. Previous studies from our group demonstrated published sequence. Once the final scFv sequence con- that B-lineage acute lymphoblastic leukaemia can be taining the leader sequence and the flexible linker is efficiently targeted by a CAR directed against the CD19 found and projected, it is possible to proceed with the antigen [9,10]. We have shown that, after transduction synthetic DNA generation. The Rydzanicz et al. method with anti-CD19 CARs, cytokine induced killer (CIK) is based on dividing the putative sequence into different cells, a peculiar population of effector cells, acquire overlapping oligonucleotides. To generate specific and potent anti-leukemic activity in terms of cytotoxicity, functional overlapping oligonucleotides, they created a proliferation and release of immunostimulatory cyto- free online software “Assembly PCR oligo maker” http:// kines upon specific antigen recognition. In line with www.ncbi.nlm.nih.gov/pmc/articles/PMC1160141/. This these observations, an European consortium http://www. software calculates the overlapping oligonucleotides fol- childhope.eu/contents.php have been developed, funded lowing the putative sequence with specific values of T in the contest of a STREP (6th framework) to target melting (Tm), thus avoiding non-specific and random high-risk B-ALL in molecular relapse after Figure 2 the Synthetic DNA Technology applied to the anti-CD23.CAR. Biagi et al. Italian Journal of Pediatrics 2011, 37:46 Page 4 of 9 http://www.ijponline.net/content/37/1/46 transplantation using donor-derived anti-CD19. CAR- exception of acute promyelocytic leukaemia, the curative expressing EBV-CTLs. The preclinical in vivo data, tar- potential of Mylotarg as a single agent is still limited geting primary patient-derived high-risk B-ALL [11], [16]. Immunotherapy with T cells using unmanipulated demonstrated the efficacy of such an approach and donor lymphocyte infusion (DLI) for the treatment of paved the way, for the first time in the field of paediatric leukaemia recurrence in Haematological Stem Cells leukaemia, for the design of a phase I clinical trial. In Transplantation (HSCT) recipients has shown some this trial paediatric patients, who received allogeneic positive results in AML, but the use of DLI carries a sig- transplantation, will be infused with donor-derived anti- nificant risk
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