Targeting Conic Hedgehog-GLI Signaling for the Treatment of Mantle Cell Lymphoma
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Transcript of Targeting Conic Hedgehog-GLI Signaling for the Treatment of Mantle Cell Lymphoma
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effector cells (CD27−CD28−CD45RA+) that were absent in theTAA responses. Taken together, these results suggest that TAA-responsive T cells are induced in breast cancer patients, butthose Tcells are phenotypically and functionally different fromCMV-responsive Tcells. Immunotherapies directed against TAAsmay need to alter these T cell signatures in order to beeffective.
doi:10.1016/j.clim.2007.03.488
Sa.102 Dendritic Cell-based Therapy for Mantle CellLymphomaCorey Munger, Graduate Student, Nebraska Medical Center,Genetics, Cell Biology, and Anatomy, Omaha, NE, GanapatiHegde, Postdoctoral Fellow, Nebraska Medical Center,Genetics, Cell Biology, and Anatomy, Omaha, NE, Julie Vose,Professor, Internal Medicine, Omaha, NE, Shantaram Joshi,Professor, Nebraska Medical Center, Genetics Cell Biology,and Anatomy, Omaha, NE, Dennis Weisenburger, Professor,Pathology and Microbiology, Omaha, NE
Mantle cell lymphoma (MCL) is an incurable B cellmalignancy due to the development of therapy-resistantcells. The ability of dendritic cells (DC) to stimulate tumor-specific cytotoxic T lymphocytes (CTL) makes DC-basedtherapy a promising strategy to treat therapy-resistant MCL.Therefore, we investigated the efficacy of DC-based immu-notherapy to treat resistant MCL. Specifically, DCs loadedwith MCL lysate, DCs fused with MCL cells, and DCselectroporated with MCL RNA were used to generatetumor-specific CTLs against the MCL cell line, Granta 519.CTL-mediated cytotoxicities at a 50:1 effector-to-targetratio using each method of DC priming are as follows: 58.4±12.7% (MCL lysate-pulsed), 54.0±8.3% (MCL RNA-transfec-tion), and 59.3±8.4% (DC-MCL hybrid). Cytotoxicity towardthe irrelevant HLA-matched cell line MDA-231 was 28.7±3.6%. To assess the in vivo cytotoxic abilities of CTLsstimulated by DC-MCL hybrids, NOD/SCID mice transplantedintravenously with 1×106 Granta 519 cells were treated withfour weekly injections of 3×106 HLA-matched CTLs. Histo-logical analysis revealed that 66% of the control mice at weekfive displayed significant tumor growth in the liver andkidneys versus only 16% in the treatment group. In addition toreducing the number of tumor nodules, the average size ofthe nodules was decreased in treated mice versus theuntreated control mice. These studies demonstrate eachmethod of DC priming stimulated tumor-specific CTLs in vitroand administration of DC-MCL hybrid-stimulated CTLs inhib-ited tumor formation in vivo. This study was supported bythe Lymphoma Research Foundation, New York, NY.
doi:10.1016/j.clim.2007.03.489
Sa.103 Targetting Sonic Hedgehog-GLI Signaling forthe Treatment of Mantle Cell LymphomaGanapati Hegde, Postdoctoral Research Associate,Department of Genetics, Cell Biology and Anatomy, Omaha,
NE, Corey Munger, Graduate Student, Department ofGenetics, Cell Biology and Anatomy, Omaha, NE, KatyEmanuel, Summer Student, Department of Genetics, CellBiology and Anatomy, Omaha, NE, Dennis Weisenburger,Professor, Pathology and Microbiology, Omaha, NE, AvadhutJoshi, Graduate student, Department of Genetics, CellBiology and Anatomy, Omaha, NE, Julie Vose, Professor,Internal Medicine, Oncology/Hematology, Omaha, NE,Shantaram Joshi, Professor, Department of Genetics, CellBiology and Anatomy, Omaha, NE
Mantle cell lymphoma (MCL) has one of the worst clinicaloutcomes among the B cell lymphomas with a mediansurvival of only 3–4 years. Particularly, the blastoid varianthas a poorer prognosis compared to classical MCL. Therefore,a better understanding of the underlying mechanisms thatregulate MCL proliferation and survival is clearly needed.Since, sonic hedgehog (Shh)-GLI signaling has been shown tobe important in the proliferation/survival of several cancers,and no such information is available in any B cell malig-nancies including MCL, this study was undertaken. Ourresults demonstrate that the molecules associated with Shhsignaling (PTCH, SMO, GLI) are considerably expressed inclassical, blastoid and patients’ primary MCL. Overexpres-sion of PTCH and GLI1, the Shh-GLI signaling target genes, inblastoid versus classical MCL suggests constitutive expressionof these genes in blastoid variant. Classical, but not theblastoid MCL cells responded (pb0.01) to perturbation of Shhsignaling in the presence of exogenous Shh/cyclopamine.Furthermore, down-regulation of GLI transcription factorsusing anti-sense oligonucleotides resulted in significantly(pb0.001) decreased proliferation of both blastoid andclassical MCL, and significantly (pb0.001) increased theirsusceptibility to chemotherapy. In addition, down-regulationof GLI by anti-sense ODN decreased Cyclin D1 (CCND1) andBCL2 transcript levels, which suggests that these keymolecules might be regulated by GLI in MCL. Thus, theseresults suggest a significant role for Shh-GLI signaling in theproliferation of MCL, and targeting GLI as therapeuticapproach to treat MCL effectively is very promising (thisstudy was supported by the Lymphoma Research Foundation,New York).
doi:10.1016/j.clim.2007.03.490
Sa.104 The Role of Thrombospondin-1 in DrivingRegulatory T Cell Generation FollowingExtracorporeal PhotopheresisAmy Krutsick, Senior Scientist, Therakos, Inc. RandCD,Exton, PA, Peter O’Brien, Principal Scientist, Therakos, Inc.RandCD, Exton, PA, Ryan Gailey, Research Associate I,Therakos, Inc. RandCD, Exton, PA, Kim Campbell, PrincipalResearch Scientist, Therakos, Inc. RandCD, Exton, PA, FrankStrobl, Director of Scientific Affairs, Therakos, Inc. RandCD,Exton, PA
Extracorporeal photopheresis (ECP) is an immune celltherapy approved for the palliative treatment of cuta-neous T cell lymphoma and has demonstrated activity inimmune-mediated inflammatory diseases. During ECP,
S109Abstracts