Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies

Biagi, Ettore; Marin, Virna; Attianese, Greta Maria Paola Giordano; Dander, Erica; D’Amico, Giovanna; Biondi, Andrea

doi:10.3324/haematol.10873

Cited by 30 publications

(19 citation statements)

References 59 publications

(81 reference statements)

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“…Thus, clinical protocols may have to be tailored to each individual or rely upon complicated engineering of the effector cells in order to enable them to recognize antigens commonly expressed on B-cell neoplasms. 20,21 As a potential target for adoptive immunotherapy, the CD1d molecule exhibits very attractive features: i) it is monomorphic, ii) it binds to the synthetic lipid antigen α-GalCer which is capable of stimulating most CD1d-restricted T cells and is clinically approved, and iii) it is expressed on several lympho-and myelo-proliferative disorders and not on most non-hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

Adoptive immunotherapy mediated by ex vivo expanded natural killer T cells against CD1d-expressing lymphoid neoplasms

Bagnara¹,

Ibatici²,

Corselli³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundCD1d is a monomorphic antigen presentation molecule expressed in several hematologic malignancies. Alpha-galactosylceramide (α-GalCer) is a glycolipid that can be presented to cytotoxic CD1d-restricted T cells. These reagents represent a potentially powerful tool for cell mediated immunotherapy. Design and MethodsWe set up an experimental model to evaluate the use of adoptively transferred cytotoxic CD1d-restricted T cells and α-GalCer in the treatment of mice engrafted with CD1d + lymphoid neoplastic cells. To this end the C1R cell line was transfected with CD1c or CD1d molecules. In addition, upon retroviral infection firefly luciferase was expressed on C1R transfected cell lines allowing the evaluation of tumor growth in xenografted immunodeficient NOD/SCID mice. ResultsThe C1R-CD1d cell line was highly susceptible to specific CD1d-restricted T cell cytotoxicity in the presence α-GalCer in vitro. After adoptive transfer of CD1d-restricted T cells and α-GalCer to mice engrafted with both C1R-CD1c and C1R-CD1d, a reduction in tumor growth was observed only in CD1d + masses. In addition, CD1d-restricted T-cell treatment plus α-GalCer eradicated small C1R-CD1d + nodules. Immunohistochemical analysis revealed that infiltrating NKT cells were mainly observed in CD1d nodules. ConclusionsOur results indicate that ex vivo expanded cytotoxic CD1d-restricted T cells and α-GalCer may represent a new immunotherapeutic tool for treatment of CD1d + hematologic malignancies.Key words: lymphoproliferative disorders, natural killer T cells, α-galactosylceramide, CD1d, CD1d-restricted T cells. Ibatici A, Corselli M, Sessarego N, Tenca C, De Santanna A, Mazzarello A, Daga A, Corvò R, De Rossi G, Frassoni F, Ciccone E, and Fais F CD1d-expressing lymphoid neoplasms. Haematologica 2009;94:967-974.doi:10.3324/haematol.2008 This is an open-access paper. Citation: Bagnara D, . Adoptive immunotherapy mediated by ex vivo expanded natual killer T cells against Adoptive immunotherapy mediated by ex vivo expanded natural killer T cells against CD1d-expressing lymphoid neoplasms

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Section: Discussionmentioning

confidence: 99%

Adoptive immunotherapy mediated by ex vivo expanded natural killer T cells against CD1d-expressing lymphoid neoplasms

Bagnara¹,

Ibatici²,

Corselli³

et al. 2009

Haematologica

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“…Adoptive transfer of T lymphocytes genetically modified to express CARs conveniently combines both antibodymediated specificity and T cell-effector functions. 17,32 Because the ideal tumor-associated antigen should be expressed by tumor cells but virtually absent in normal tissues, we took advantage of the selective higher expression of CD23 by CLL cells to target malignant cells while sparing normal B cells. We cloned a fully humanized CAR specific for the CD23 antigen, which is highly expressed by CLL cells, and showed that T lymphocytes carrying this receptor efficiently eliminated CD23 ϩ tumor cell lines and primary CLL cells while sparing normal B cells.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

Attianese

Marin

Hoyos

et al. 2011

Blood

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Chronic lymphocytic leukemia (CLL) is IntroductionChronic lymphocytic leukemia (CLL), the most common form of leukemia in adults in Western countries, 1 remains an incurable disease despite the development of new therapeutic regimens. 2,3 Allogeneic hematopoietic stem cell transplantation can be curative, but its application is limited to young adults, who represent a small percentage of patients with CLL. 2,4 Antibodies directed against different surface antigens are currently used in patients with CLL. 3 Although anti-CD52 (Campath-1) antibodies rapidly reduce the leukemic burden in the peripheral blood, they have limited biodistribution to secondary lymphoid organs, where CLL cells tend to accumulate. 5 In the case of anti-CD20 antibodies, the low levels of the antigen on leukemic B cells limit their use as a single agent in this disease. In addition, antibodies do not lead to long-term control of the disease because they do not establish an active memory immune response. 6 CLL is also susceptible to cell-mediated immune control, as indicated by the graft-versusleukemia effect associated with allogeneic hematopoietic stem cell transplantation, 7 and by the immune responses elicited in patients receiving leukemia-tumor vaccines. 8,9 Adoptive transfer of T lymphocytes genetically modified to express a chimeric antigen receptor (CAR) can combine the beneficial effects of both antibody-and T-cell-mediated immune responses. CARs are chimeric molecules that contain an extracellular binding moiety derived from an mAb (single-chain variable fragment [scFv]) coupled to an intracellular signaling moiety (usually the chain of the T-cell receptor complex). 6,10,11 When expressed by T lymphocytes, CARs can trigger T-cell activation and perforin/granzyme-B release 12 upon binding with the antigen expressed by tumor cells in a non-MHC-restricted manner, thus avoiding an important mechanism of tumor immune escape represented by the down-regulation of MHC molecules by tumor cells. 6 Adoptive transfer of CAR-transduced T lymphocytes may offer several advantages compared with the passive administration of antibodies, because T cells have enhanced tissue biodistribution and may establish a long-lasting antitumor immune response. 6 CARs targeting either CD19 or CD20 antigens have been developed to treat human B-cell-derived malignancies, [13][14][15] and clinical trials using these chimeric molecules are currently ongoing in several institutions. However, a potential major disadvantage of this strategy is that both CD19 and CD20 are expressed not only by leukemic cells, but also by normal B lymphocytes, and therefore the sustained elimination of these cells by CAR-modified T cells could result in a severe impairment of the humoral immunity, exacerbating the characteristic immunodeficiency present in patients with CLL. 16 Because of the importance of preserving the normal B cell compartment, the generation of CARs targeting antigens with a more restricted expression in tumor cells may have clinical relevance. 17 CD23 antigen repre...

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“…T cells can be genetically modified to redirect specificity through the introduction of full-length ab T cell receptors, which recognize antigen in the context of major histocompatibility complex (MHC) or through the introduction of chimeric antigen receptors (CARs) to recognize cell surface antigen independent of MHC (Rossig and Brenner, 2003;Biagi et al, 2007). Approaches to introduce CARs are viral (transduction with retrovirus=lentivirus) (Zanzonico et al, 2006;Lu et al, 2007) or nonviral using DNA plasmids (Fewell et al, 2005;Schmieder et al, 2007;Schertzer and Lynch, 2008) or mRNA (Smits et al, 2004;Van Tendeloo et al, 2007;Wiehe et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

piggyBac Transposon/Transposase System to Generate CD19-Specific T Cells for the Treatment of B-Lineage Malignancies

et al. 2010

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Nonviral integrating vectors can be used for expression of therapeutic genes. piggyBac (PB), a transposon= transposase system, has been used to efficiently generate induced pluripotent stems cells from somatic cells, without genetic alteration. In this paper, we apply PB transposition to express a chimeric antigen receptor (CAR) in primary human T cells. We demonstrate that T cells electroporated to introduce the PB transposon and transposase stably express CD19-specific CAR and when cultured on CD19 þ artificial antigen-presenting cells, numerically expand in a CAR-dependent manner, display a phenotype associated with both memory and effector T cell populations, and exhibit CD19-dependent killing of tumor targets. Integration of the PB transposon expressing CAR was not associated with genotoxicity, based on chromosome analysis. PB transposition for generating human T cells with redirected specificity to a desired target such as CD19 is a new genetic approach with therapeutic implications.

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Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies

Cited by 30 publications

References 59 publications

Adoptive immunotherapy mediated by ex vivo expanded natural killer T cells against CD1d-expressing lymphoid neoplasms

Adoptive immunotherapy mediated by ex vivo expanded natural killer T cells against CD1d-expressing lymphoid neoplasms

In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

piggyBac Transposon/Transposase System to Generate CD19-Specific T Cells for the Treatment of B-Lineage Malignancies

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