Regression of HPV-Positive Tumors Treated With a New Listeria monocytogenes Vaccine

Sewell, David L.; Douven, Dennis; Pan, Zhen-Kun; Rodriguez, Alex; Paterson, Yvonne

doi:10.1001/archotol.130.1.92

Cited by 53 publications

(47 citation statements)

References 33 publications

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“…Recombinant L. monocytogenes vaccines that express tumor antigens have been shown to lead to the generation of tumor-specific T-lymphocytes and tumor regression in mouse models (1)(2)(3)(4)(5). In the present study, we have determined that the fusion of the antigen to a PEST sequence is critical for the efficacy of these vaccines.…”

Section: Discussionmentioning

confidence: 89%

“…Once in the cytoplasm, bacterial proteins are effectively presented to cytotoxic T lymphocytes, thus initiating a cellular immune response against bacterial antigens. By engineering recombinant Listeria vaccines to secrete not only bacterial antigens but also tumor antigens, immune responses have been generated sufficient to cause the regression of established tumors in animal models (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

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Recombinant Listeria Vaccines Containing PEST Sequences Are Potent Immune Adjuvants for the Tumor-Associated Antigen Human Papillomavirus-16 E7

et al. 2004

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Previous work in our laboratory has established that the fusion of tumor-associated antigens to a truncated form of the Listeria monocytogenes virulence factor listeriolysin O (LLO) enhances the immunogenicity and antitumor efficacy of the tumor antigen when delivered by Listeria or by vaccinia. LLO contains a PEST sequence at the NH 2 terminus. These sequences, which are found in eukaryotic proteins with a short cellular half-life, target proteins for degradation in the ubiquitin-proteosome pathway. To investigate whether the enhanced immunogenicity conferred by LLO is due to the PEST sequence, we constructed new Listeria recombinants that expressed the HPV-16 E7 antigen fused to LLO, which either contained or had been deleted of this sequence. We then compared the antitumor efficacy of this set of vectors and found that Listeria expressing the fusion protein LLO-E7 or PEST-E7 were effective at regressing established macroscopic HPV-16 immortalized tumors in syngeneic mice. In contrast, Listeria recombinants expressing E7 alone or E7 fused to LLO from which the PEST sequence had been genetically removed could only slow tumor growth. Because CD8 ؉ T cell epitopes are generated in the ubiquitin-proteosome pathway, we also investigated the ability of the vaccines to induce E7-specific CD8 ؉ T cells in the spleen and to generate E7-specific tumor-infiltrating lymphocytes. A strong correlation was observed between CD8 ؉ T-cell induction and tumor homing and the antitumor efficacy of the Listeria-E7 vaccines. These findings suggest a strategy for the augmentation of tumor antigen-based immunotherapeutic strategies that may be broadly applicable.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Recombinant Listeria Vaccines Containing PEST Sequences Are Potent Immune Adjuvants for the Tumor-Associated Antigen Human Papillomavirus-16 E7

et al. 2004

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“…The adjuvant properties of LLO have been demonstrated not only in the context of L. monocytogenes (17) but also in various vaccine platforms, such as modified vaccinia virus Ankara (MVA) or plasmid DNA (pDNA), and as a protein carrier for anti-idiotypic immune therapy of non-Hodgkin's lymphoma (12,13,(17)(18)(19)(20), suggesting broad applicability in immunotherapeutic strategies. Although there are sufficient data supporting LLO as a potent immune activator, how it exerts these effects is unknown.…”

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confidence: 99%

Listeria monocytogenes-Derived Listeriolysin O Has Pathogen-Associated Molecular Pattern-Like Properties Independent of Its Hemolytic Ability

Wallecha

Wood

Pan

et al. 2013

Clin Vaccine Immunol

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There is a constant need for improved adjuvants to augment the induction of immune responses against tumor-associated antigens (TAA) during immunotherapy. Previous studies have established that listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, exhibits multifaceted effects to boost the stimulation of immune responses to a variety of antigens. However, the direct ability of LLO as an adjuvant and whether it acts as a pathogen-associated molecular pattern (PAMP) have not been demonstrated. In this paper, we show that a detoxified, nonhemolytic form of LLO (dtLLO) is an effective adjuvant in tumor immunotherapy and may activate innate and cellular immune responses by acting as a PAMP. Our investigation of the adjuvant activity demonstrates that dtLLO, either fused to or administered as a mixture with a human papillomavirus type 16 (HPV-16) E7 recombinant protein, can augment antitumor immune responses and facilitate tumor eradication. Further mechanistic studies using bone marrow-derived dendritic cells suggest that dtLLO acts as a PAMP by stimulating production of proinflammatory cytokines and inducing maturation of antigen-presenting cells (APC). We propose that dtLLO is an effective adjuvant for tumor immunotherapy, and likely for other therapeutic settings.T he Gram-positive facultative intracellular pathogen Listeria monocytogenes expresses a highly conserved pore-forming toxin known as listeriolysin O (LLO). LLO is a member of a large family of cholesterol-dependent cytolysins (CDCs) found in several bacterial pathogens (1). In L. monocytogenes, LLO is the primary virulence factor and is essential for its pathogenesis (2). During intracellular infection, the pore-forming activity of LLO allows L. monocytogenes to escape from phagocytic or endocytic vacuoles into the host cell cytosol, where the bacteria are able to multiply proficiently (3, 4). CDCs have no known protein receptors, although cholesterol is a prerequisite for membrane pore formation. However, LLO and other CDCs are potent signaling molecules that trigger a variety of cellular responses. Stimulation of cells with LLO results in a multifaceted response involving production of cytokines (5), influx of calcium signaling (6), epigenetic modifications (7), alteration of immunosuppression (8, 9), and induction of apoptosis in T lymphocytes and dendritic cells (10). It has been suggested that the mechanism of signaling by LLO and other bacterial cytolysins is through their ability to act as pathogen-associated molecular patterns (PAMPs) and to interact with pathogen recognition receptors (PRRs) such as Toll-like receptor 4 (TLR4) (11).In accordance with the PAMP hypothesis, LLO has been reported to improve antigen presentation in the context of major histocompatibility complex (MHC) class I molecules and to enhance T cell-mediated immune responses when genetically fused to (12)(13)(14), mixed with (15), or conjugated to (16) antigens. The adjuvant properties of LLO have been demonstrated not only in the conte...

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“…We thus engineered a recombinant strain of Listeria monocytogenes to express and secrete HPV-16 E7 as a fusion protein with ActA. Studies assessing the ability of this vaccine strain of Listeria revealed complete regression of established, E7-expressing TC-1 tumors in C57BL/6 mice while inducing E7-specific cytotoxic T-lymphocyte activity [30].…”

Section: Listeria Monocytogenes As a Vector For Human Tumor Antigensmentioning

confidence: 99%

Cancer immunotherapy using Listeria monocytogenes and listerial virulence factors

et al. 2008

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Our laboratory is interested in how immunogenicity may be modulated in vivo in order to better design more effective immunotherapeutics against cancer. Our main approach is to use a facultative intracellular bacterium, Listeria monocytogenes, which has the unusual ability to live and grow in the cytoplasm of the cell and is thus an excellent vector for targeting passenger antigens to the major histocompatibility complex (MHC) class I pathway of antigen processing with the generation of authentic CTL epitopes. We have used this approach to target tumor antigens expressed on breast, melanoma and cervical cancer. We are also exploring the role of Listerial virulence factors in potentiating adaptive immune responses by activating innate immunity. Specifically, we are using these proteins as adjuvants for B cell lymphomas.

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Regression of HPV-Positive Tumors Treated With a New Listeria monocytogenes Vaccine

Cited by 53 publications

References 33 publications

Recombinant Listeria Vaccines Containing PEST Sequences Are Potent Immune Adjuvants for the Tumor-Associated Antigen Human Papillomavirus-16 E7

Recombinant Listeria Vaccines Containing PEST Sequences Are Potent Immune Adjuvants for the Tumor-Associated Antigen Human Papillomavirus-16 E7

Listeria monocytogenes-Derived Listeriolysin O Has Pathogen-Associated Molecular Pattern-Like Properties Independent of Its Hemolytic Ability

Cancer immunotherapy using Listeria monocytogenes and listerial virulence factors

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