Generation of Tumor-Specific Immunity Using HER2/NEU Positive Tumor Derived Chaperone-Rich Cell Lysate (CRCL)

Persistent Link:
http://hdl.handle.net/10150/193817
Title:
Generation of Tumor-Specific Immunity Using HER2/NEU Positive Tumor Derived Chaperone-Rich Cell Lysate (CRCL)
Author:
Li, Gang
Issue Date:
2007
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
HER2/neu is an oncogenic tumor-associated antigen over-expressed in several human tumors including breast and ovarian cancer. The selective expression of HER2/neu and its role in epithelial carcinogenesis makes HER2/neu an ideal target for immunotherapy. Tumor-derived chaperone-rich cell lysate (CRCL), containing numerous heat shock proteins, has successfully been used to generate tumor-specific immunity against a wide range of murine tumors and is a great candidate for an effective vaccine against HER2/neu positive tumors. In the first part of this study, the potency of human ovarian cancer-derived CRCL to activate dendritic cells (DCs) and to generate tumor-specific T cells in vitro has been investigated. Chaperone-rich cell lysate was generated from primary ovarian cancer tissues and SKOV3-A2, a HER2/neu, Wilm's tumor gene 1 (WT1) and HLA-A2 positive human ovarian tumor cell line. T cells from healthy donors and from ovarian cancer patients secreted higher amounts of interferon-γ following in vitro re-stimulation with ovarian cancer-derived CRCL compared to HER2/neu or WT1 peptide-pulsed DCs. We were also able to generate cytotoxic T lymphocyte activity against cancer-specific antigens such as HER2/neu and WT1 from all healthy donors, but from only one of the four ovarian cancer patients with bulky disease. In the second part of the study, the potency of tumor-derived CRCL to elicit the humoral immune response against a murine HER2/neu positive tumor (TUBO) has been examined. Vaccination of mice bearing a palpable tumor efficiently delayed the development of the tumor. In the vaccinated mice, CRCL vaccination induced significant anti-HER2/neu antibodies. Using B cell deficient mice and antibody transfer experiments, we have shown that the induction of anti-HER2/neu antibodies is both necessary and sufficient for the anti-tumor effect. Further, we have demonstrated that serum from TUB0 CRCL-vaccinated mice stimulated the internalization of the HER2/neu molecules, resulting in the down-regulation of their surface expression. Moreover, antibody-dependent cellular cytotoxicity has been observed against TUBO cells when presented with sera from vaccinated mice. These results indicate that CRCL may be a potent adjuvant for women suffering from HER2/neu positive ovarian or breast cancer and that this personalized vaccine may be a promising approach for active immunotherapy.
Type:
text; Electronic Dissertation
Keywords:
Cancer; HER2/neu; vaccine; heat shock protein; chaperone-rich cell lysate
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Microbiology & Immunology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Katsanis, Emmanuel

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleGeneration of Tumor-Specific Immunity Using HER2/NEU Positive Tumor Derived Chaperone-Rich Cell Lysate (CRCL)en_US
dc.creatorLi, Gangen_US
dc.contributor.authorLi, Gangen_US
dc.date.issued2007en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractHER2/neu is an oncogenic tumor-associated antigen over-expressed in several human tumors including breast and ovarian cancer. The selective expression of HER2/neu and its role in epithelial carcinogenesis makes HER2/neu an ideal target for immunotherapy. Tumor-derived chaperone-rich cell lysate (CRCL), containing numerous heat shock proteins, has successfully been used to generate tumor-specific immunity against a wide range of murine tumors and is a great candidate for an effective vaccine against HER2/neu positive tumors. In the first part of this study, the potency of human ovarian cancer-derived CRCL to activate dendritic cells (DCs) and to generate tumor-specific T cells in vitro has been investigated. Chaperone-rich cell lysate was generated from primary ovarian cancer tissues and SKOV3-A2, a HER2/neu, Wilm's tumor gene 1 (WT1) and HLA-A2 positive human ovarian tumor cell line. T cells from healthy donors and from ovarian cancer patients secreted higher amounts of interferon-γ following in vitro re-stimulation with ovarian cancer-derived CRCL compared to HER2/neu or WT1 peptide-pulsed DCs. We were also able to generate cytotoxic T lymphocyte activity against cancer-specific antigens such as HER2/neu and WT1 from all healthy donors, but from only one of the four ovarian cancer patients with bulky disease. In the second part of the study, the potency of tumor-derived CRCL to elicit the humoral immune response against a murine HER2/neu positive tumor (TUBO) has been examined. Vaccination of mice bearing a palpable tumor efficiently delayed the development of the tumor. In the vaccinated mice, CRCL vaccination induced significant anti-HER2/neu antibodies. Using B cell deficient mice and antibody transfer experiments, we have shown that the induction of anti-HER2/neu antibodies is both necessary and sufficient for the anti-tumor effect. Further, we have demonstrated that serum from TUB0 CRCL-vaccinated mice stimulated the internalization of the HER2/neu molecules, resulting in the down-regulation of their surface expression. Moreover, antibody-dependent cellular cytotoxicity has been observed against TUBO cells when presented with sera from vaccinated mice. These results indicate that CRCL may be a potent adjuvant for women suffering from HER2/neu positive ovarian or breast cancer and that this personalized vaccine may be a promising approach for active immunotherapy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCanceren_US
dc.subjectHER2/neuen_US
dc.subjectvaccineen_US
dc.subjectheat shock proteinen_US
dc.subjectchaperone-rich cell lysateen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMicrobiology & Immunologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairKatsanis, Emmanuelen_US
dc.contributor.committeememberAkporiaye, Emmanuel T.en_US
dc.contributor.committeememberSchluter, Samuel F.en_US
dc.contributor.committeememberCranmer, Lee D.en_US
dc.identifier.proquest2016en_US
dc.identifier.oclc659746612en_US
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