Rhabdomyosarcoma Lysis by T Cells Expressing a Human Autoantibody-Based Chimeric Receptor Targeting the Fetal Acetylcholine Receptor

Gattenlöhner, Stefan; Marx, Alexander; Markfort, Birgit; Pscherer, Sibylle; Landmeier, Silke; Juergens, Heribert; Müller-Hermelink, H. K.; Matthews, Ian; Beeson, David; Vincent, Angela; Rössig, Claudia

doi:10.1158/0008-5472.can-05-0542

Cited by 42 publications

(38 citation statements)

References 19 publications

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“…The expression of the tumor-specific antigens MAGE, GAGE, and BAGE were detected in RMS, and initial efforts showed that RMS cells are able to process MAGE-A proteins and present the resulting peptides to T cells [100]. Based on the high expression level of the fetal type acetycholine receptor (fAChR) by RMS tumors in contrast to the expression of the adult type by mature skeletal muscle, fAChR has been proposed as another candidate target antigen for immunotherapy [101]. As a strategy to bypass the intrinsic immune resistance of RMS cells, T lymphocytes were engineered to express a chimeric receptor consisting of the antigen-binding domain of a human antifAChR antibody combined with the cytoplasmic signaling domain of the human T cell receptor ζ chain.…”

Section: Rms and Tumor Immunitymentioning

confidence: 99%

Fusions Involving PAX and FOX Genes in the Molecular Pathogenesis of Alveolar Rhabdomyosarcoma: Recent Advances

Mercado¹,

Barr²

2007

CMM

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Rhabdomyosarcoma is the most frequent soft tissue sarcoma in the pediatric population. Two main histopathologic variants have been described, embryonal (ERMS) and alveolar (ARMS), which demonstrate clinical and genetic differences. In particular, most ARMS but not ERMS tumors are characterized by the presence of recurrent chromosomal translocations, which have been cytogenetically defined as t(2;13)(q35;q14) and t(1;13)(p36;q14). These translocations form PAX3-FKHR and PAX7-FKHR gene fusions, which encode chimeric transcription factors. These chimeric proteins are hypothesized to generate a novel transcriptional program in the target cell, thereby contributing to multiple aspects of ARMS tumorigenesis. This review highlights recent advances in numerous areas of biomedical investigation that are providing new insights into the biology, molecular pathology, and translational science of ARMS: the identification of downstream targets of PAX3-FKHR and collaborating events in the process of tumorigenesis and metastasis; generation of animal models based on the gene fusion and collaborating events; development of new assays for diagnosis, prognosis, and detection of minimal disseminated disease; and exploration of immune recognition of this tumor and the fusion protein. These findings highlight the continued importance of the fusion proteins in understanding the biology of this tumor and developing improved diagnostics for this tumor, and have led to the initiation of efforts to explore therapeutic strategies based on the increasing understanding of the biology of these fusion proteins.

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Section: Rms and Tumor Immunitymentioning

confidence: 99%

Fusions Involving PAX and FOX Genes in the Molecular Pathogenesis of Alveolar Rhabdomyosarcoma: Recent Advances

Mercado¹,

Barr²

2007

CMM

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“…Immune therapy may offer such an approach because RMS cells are potentially susceptible to cytolysis by redirected T cells, 14 antigen-independent cytokine-induced killer cells, 29 and activated natural killer cells, 30 although with disappointing low efficacy. Herein, we show that this may be due to, at least in part, inefficient effector cell activation as the result of lack of costimulation.…”

Section: Discussionmentioning

confidence: 99%

“…Written informed consent, according to the Declaration of Helsinki, was obtained from all patients or their legal guardians, depending on the patients' age. All cases were studied by RT-PCR for fAChR expression 14 and for PAX-FKHR fusion transcript status by the Molecular Biology Laboratory at Olga Hospital (Stuttgart). 24 …”

Section: Biopsy Specimensmentioning

confidence: 99%

“…To generate the cDNA for the fAChR-specific CAR, the DNA coding for scFv35 14 was amplified by PCR and flanked by RcaI (5 0 ) and BamHI (3 0 ) restriction sites (both italicized), respectively, using the following set of primer oligonucleotides: 5 0 -ATGAATTTTCAGGTGCAGATTTTC-AGCTTCCTGCTAATCAGTGCCTCAGTCATAATGTC-TAGAGTGATGACCCAGTCTCCATCCTCCC-3 0 (sense) and 5 0 -GGATCCGGAGAGACGGTGACCGTTGT-3 0 (antisense). The sense primer contains a mouse leader fragment (italicized) to ensure the export of the antibody fragment.…”

Section: Generation Of Chimeric Antigen Receptorsmentioning

confidence: 99%

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Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

Simon-Keller

Paschen

Hombach

et al. 2013

The American Journal of Pathology

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Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas inducible T-cell co-stimulator ligand (ICOS-L; alias B7H2) was expressed by a subset of RMSs and was inducible by tumor necrosis factor a in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag À/À mice with fetal acetylcholine receptorespecific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-celle based therapy. (Am J Pathol 2013, 182: 2121e2131; http://dx

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“…Recent studies have shown an expansion of receptors against other antigen targets on solid tumors, such as epidermal growth factor receptor vIII on glioblastoma [116], prostate stem cell antigen on prostate cancer [117], fetal acetylcholine receptor on rhabdomyosarcoma [118], and MUC1 on breast cancer cells [17]. In addition, novel, antigenic targets on hematological cancers have been addressed, such as CD38 on non-Hodgkin's lymphoma [119].…”

Section: Discussionmentioning

confidence: 99%

Genetic redirection of T cells for cancer therapy

Westwood

Kershaw

2010

Journal of Leukocyte Biology

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Adoptive immunotherapy can induce dramatic tumor regressions in patients with melanoma or viral-induced malignancies, but extending this approach to many common cancers has been hampered by a lack of naturally occurring tumor-specific T cells. In this review, we describe recent advances in the genetic modification of T cells using genes encoding cell-surface receptors specific for tumor-associated antigen. Using genetic modification, the many functional properties of T cells, including cytokine secretion and cytolytic capacity, are redirected from their endogenous specificity toward the elimination of tumor cells. Advances in gene design, vectors, and cell production are discussed, and details of the progress in clinical application of this approach are provided.

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Rhabdomyosarcoma Lysis by T Cells Expressing a Human Autoantibody-Based Chimeric Receptor Targeting the Fetal Acetylcholine Receptor

Cited by 42 publications

References 19 publications

Fusions Involving PAX and FOX Genes in the Molecular Pathogenesis of Alveolar Rhabdomyosarcoma: Recent Advances

Fusions Involving PAX and FOX Genes in the Molecular Pathogenesis of Alveolar Rhabdomyosarcoma: Recent Advances

Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

Genetic redirection of T cells for cancer therapy

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