Vaccines-2013 - OMICS Group

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Zelig Eshhar, J Vaccines Vaccin 2013, 4:5http://dx.doi.org/10.4172/2157-7560.S1.0163 rd International Conference onVaccines & VaccinationJuly 29-31, 2013 Embassy Suites Las Vegas, NV, USAThe T-body approach combining antibody specificity with T cell activity for adoptivevaccination of cancerZelig EshharThe Weizmann Institute of Science, IsraelThe “T-body” approach is based on engineered T cells expressing chimeric antibody receptor (CAR) that endows themwith antibody-type specificity to any pre-defined target antigen. We have designed the modular CAR construct so that themodified, redirected T cells will undergo activation and perform their effector or regulatory function upon encountering theirtarget. Accordingly, the CAR’s composition includes extracellular recognition domain made of a single chain variable fragment(scFv) of an antibody linked to intracellular domains of various stimulatory and co-stimulatory molecules that dictate thefunction of the transduced cells. For antitumor reactivity we constructed CARs made of scFv specific to human Her2/neu, CEAand CD24 (a cancer stem cell marker of certain adenocarcinomas such as pancreatic and colorectal ones).To optimize the antitumor effect in therapeutic settings we have treated either immunodeficient mice bearing human cancerxenografts or transgenic mice that spontaneously develop tumors expressing TAA. T-bodies effectively rejected primary as wellas disseminated tumors. Multiple systemic administrations of T-bodies were required for complete elimination of xenograftsand autologous murine tumors. Of note, single intratumoral injection was sufficient to eliminate breast, prostate cancer bonemetastases as well as colorectal and pancreatic cancers. Moreover, under certain conditions, we have established a time-windowwhich allows allogeneic T-bodies to serve as universal donors.Recently, our pioneering studies in murine models have been reproduced and applied in pilot trials to end-stage cancerpatients. Dramatic complete responses have been already reported in neuroglioma, chronic lymphocyte leukemia, and acutechild and adult B cell lymphoma patients. These trials have also reported on several treatment-related severe yet manageableside effects (mostly associated with acute ‘cytokine-storm’ and ‘tumor lysis’ syndrome, both outcomes of the vigorous antitumorresponses of the T-bodies that could eliminate a huge tumor mass within the first few weeks treatment. The dynamics of theT-body antitumor effect reflect both their built-in ability to specifically recognize the tumor, propagate and reject it and furtherdifferentiate into memory cells that keep the tumor on-check.BiographyZelig Eshhar has completed his Ph.D. at the Weizmann Institute and post doctoral studies from Harvard University Medical School. He spentsabbatical years of research at DNAX Institute of Molecular Biology and Stanford University and at the National Cancer Institute at the NIH. Heserved as the Chairman of the Department of Immunology at the Weizmann Institute and holds the position of Chairman of research in ImmunologyTel Aviv Sourasky Medical Center and guest Professor at the Faculty of Medicine of Tel Aviv University. He has published more the 210 researcharticles.zelig.eshhar@weizmann.ac.ilJ Vaccines Vaccin 2013ISSN: 2157-7560, JVV an open access journalVaccines-2013July 29-31, 2013Volume 4 Issue 5Page 56
Milan Raska et al., J Vaccines Vaccin 2013, 4:5http://dx.doi.org/10.4172/2157-7560.S1.0163 rd International Conference onVaccines & VaccinationJuly 29-31, 2013 Embassy Suites Las Vegas, NV, USANovel non-pyrogenic hydrophobized norAbuMDP and norAbuGMDP analogues forconstruction of proteoliposome vaccinesMilan Raska 1 and Jaroslav Turanek 21Palacky University, Czech Republic2Veterinary Research Institute, Czech RepublicNickel-chelating nanoliposomes represent a versatile platform for the construction of self-assembling proteoliposomevaccines. New non-pyrogenic hydrophobised norAbuMDP and norAbuGMDP analogues were incorporated intoproteoliposomes as adjuvants. Immunomodulatory activity was compared with Alum or MDP in experimental mice immunizedby intradermal route with recombinant Candida albicans Hsp90 or Borrelia burgdorferi OspC. Using ELISA determination ofantigen specific antibody isotypes we confirmed that for each of the tested norAbuMDP and norAbuGMDP derivates (MT01- MT08), substantially different Hsp90- and OspC-specific antibody titers of individual isotypes were detected. Although thestrongest antibody response was obtained after immunization with both antigens plus Alum, dominating isotype was consistentlyof IgG1 isotype. Experiments identified that some MDP analogues are optimal for the elicitation of Th1- and another ones forTh2-type of antigen-specific immune responses. For example immunization with rHsp90 with MDP analogues MT03, MT07and to a lesser extent MT06, MT05, and MT02 exhibited a high efficacy in elicitation of Hsp90-specific titers in IgG2a and IgG2bisotypes indicating Th1 polarization of the specific immune response. Furthermore MT-adjuvanted OspC proteoliposomessurpassed Alum with respect to OspC-specific titers in IgG2a, IgG2b isotypes when MT06 was used and IgG3, IgM isotypes whenMT05 was used. The Th1/Th2 polarization was consistent with IFN-γ and IL-4 production by antigen-stimulated splenocytesin ELISPOT. Furthermore MT exhibited better adjuvanticity than MDP and proved themselves as nonpyrogenic. This conceptrepresents a new promising platform for construction of recombinant vaccines. Supported by grants GAČR P304/10/1951,CZ.1.07/2.3.00/20.0164, Czech Republic.BiographyMilan Raska has completed his Ph.D. at the age of 35 years from Palacky University, Olomouc, Czech Republic and postdoctoral fellowship fromUniversity of Alabama at Birmingham, USA. He is Associate Professor of immunology at Faculty of Medicine and Dentistry, Palacky University,Olomouc, Czech Republic. He has published more than 37 papers in reputed journals.raskamil@uab.eduJ Vaccines Vaccin 2013ISSN: 2157-7560, JVV an open access journalVaccines-2013July 29-31, 2013Volume 4 Issue 5Page 57
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