Recombinant Listeria Monocytogenes as a tumor therapeutic / George Raymond Gunn, III.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Gunn, George Raymond, III.

Contributor:

Paterson, Yvonne, 1941- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Allergy and Immunology.

Academic Dissertations as Topic.

Medical Subjects:

Allergy and Immunology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Immunology.

Immunology--Penn dissertations.

Physical Description:

xiii, 137 pages : illustrations ; 29 cm

Production:

2001.

Summary:

Naturally arising tumor antigens can be categorized into four groups, shared tumor antigens, tissue-specific tumor antigens, mutated self antigens and antigens of tumor-associated viruses. Recombinant Listeria monocytogenes (rLm) has been demonstrated in animal models to induce a potent anti-tumor immune response by targeting an artificial tumor antigen to the immune system. In order to examine the ability of rLm to induce immune responses to actual tumor antigens two systems were developed. The first utilized the E7 gene derived from the human papillomavirus (HPV) and expressed in the majority of human cervical cancers to investigate the ability of rLm strains to induce immunity to a naturally occurring virally derived tumor antigen. The second system targeted the tumor antigen, P815A, to examine if rLm strains expressing a shared tumor antigen could overcome potential tolerance to these "self" proteins. To test the ability of rLm to induce immunity to the E7 antigen two rLm strains were constructed. One, Lm-E7, expressed and secreted the E7 gene product from a single chromosomally integrated gene. The second, Lm-LLO-E7, expressed and secreted a fusion protein comprised of a non-hemolytic listeriolysin O joined at the C-terminus to E7 and encoded by an episomal expression system. In spite of the induction of measurable E7 specific CTL responses, Lm-E7 had little effect on the growth of the E7 expressing tumor line, TC-1. Lm-E7 failed to induce a sufficient CD4+ T help response, and the depletion of CD4+ cells actually improved the effectiveness of Lm-E7 treatment. In contrast, Lm-LLO-E7 induced complete regression of established TC-1 tumors that was dependent on CD8+, CD4+ cells and the cytokine IFN-gamma.

The second model system tested the capabilities of rLm to secrete the shared tumor antigen P815A and the influence that an rLm strain secreting this protein had on established tumors of the antigen positive P815 tumor line. The results demonstrate that hydrophobic domains within a recombinant antigen can block secretion of the antigen by the rLm strain. Also, a P815A secreting rLm strain induced only weak immunity to P815A, insufficient to control P815 tumor growth.

Notes:

Adviser: Yvonne Paterson.

Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2001.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3015316.

OCLC:

244971879