KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity

Škoberne, Mojca; Yewdall, Alice W.; Bahjat, Keith S.; Godefroy, Emmanuelle; Lauer, Peter; Lemmens, Edward E.; Liu, Weiqun; Luckett, Will; Leong, Meredith L.; Dubensky, Thomas W.; Brockstedt, Dirk G.; Bhardwaj, Nina

doi:10.1172/jci31350

Cited by 35 publications

(23 citation statements)

References 52 publications

(98 reference statements)

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“…Lastly, mimotopes may be identified by screening of peptides with antibodies, enabling immunization with epitopes that are difficult to create artificially, which is particularly important for vaccination against cancer (125). A special case of vectors is represented by killed but metabolically active Listeria bacteria (10,107). These bacteria can still be taken up by dendritic cells, carrying with them foreign genes that express proteins in those professional antigen-processing cells.…”

Section: Miscellaneous Strategiesmentioning

confidence: 99%

Vaccines: the Fourth Century

Plotkin

2009

Clin Vaccine Immunol

216

151

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Vaccine development, which began with Edward Jenner's observations in the late 18th century, has entered its 4th century. From its beginnings, with the use of whole organisms that had been weakened or inactivated, to the modern-day use of genetic engineering, it has taken advantage of the tools discovered in other branches of microbiology. Numerous successful vaccines are in use, but the list of diseases for which vaccines do not exist is long. However, the multiplicity of strategies now available, discussed in this article, portends even more successful development of vaccines.

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Section: Miscellaneous Strategiesmentioning

confidence: 99%

Vaccines: the Fourth Century

Plotkin

2009

Clin Vaccine Immunol

216

151

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“…In the past decade, a large body of studies have demonstrated that a live-attenuated LM vector can induce both CD4 þ and CD8 þ T-cell responses without causing harmful toxicity when used in an animal model or clinical study (Shedlock et al, 2003;Souders et al, 2006;Skoberne et al, 2008;Seavey et al, 2009;Wallecha et al, 2009). It is widely understood that Listeria is rapidly taken-up by immune cells such as dendritic cells and macrophages upon entering the host.…”

Section: Discussionmentioning

confidence: 99%

“…As an intracellular parasite, LM has direct access to the cytoplasm of antigen-presenting cells such as macrophages and dendritic cells. The antigenpresenting cells infected by LM, which carries foreign antigen genes, present foreign antigens with both major histocompatibility complex (MHC) class I and MHC class II molecules efficiently, thus inducing both a CD8 þ and CD4 þ antigen-specific T-cell response (Shedlock et al, 2003;Souders et al, 2006;Skoberne et al, 2008). Another important feature of LM is the hemolytic activity of listeriolysin O, which has a critical role in allowing the bacterium to be effectively targeted by the cellular immune system (Gedde et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma

Chen

Yang

et al. 2011

Oncogene

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Live attenuated Listeria monocytogenes (LM) is a promising bacterial vector able to induce a T-cell response to tumor-associated antigens and demonstrates great potential for use in vaccine development. A novel recombinant LM-based vaccine (Lmdd (LM DdalDdat)-MPFG (multiple peptide fusing genes)) was developed with the ability to express and secrete hepatocellular carcinoma (HCC)-related tumor-associated antigens fragments due to the insertion of hepatitis B virus (HBV)-X protein (HBx)-derived epitopes HBx 52À60 and HBx 140À148 , the universal T-helper epitope, alpha-fetoprotein (AFP) epitope AFP 158À166 , and melanoma antigen gene (MAGE)-3 271À279 into the HBV core protein. Following immunization with the Lmdd-MPFG vaccine, macrophages exhibited uptake of the bacteria; the vaccine was then nearly cleared 3 days after the first administration. It disappeared even more quickly following subsequent vaccinations. However, recombinant Lmdd-MPFG allowed for the full development of an antitumor response towards the human leukocyte antigen (HLA)-A0201 epitopes of MPFG. Each epitope stimulated an augmented T-cell proliferation and enhanced the supernatant level of interferon (IFN)-c in vitro. In addition, IFN-c-producing CD8 þ T cells as well as in vivo cytolytic activity were significantly increased in HLA-A2 transgenic mice. Additionally, the Lmdd-MPFG developed a strong antitumor response, as indicated by the significant resistance of immunized mice to MPFG-positive Hepa1-6 cell challenge in both a prophylactic and therapeutic setting. Tumor regression was accompanied by an enhanced cytotoxic T lymphocyte response and a decrease of regulatory T cells in the tumor. Collectively, these results suggest that utilizing attenuated LM as a vaccine vector, able to carry the MPFG gene, presents a potentially feasible strategy for prevention of HCC.

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“…Thus, production/secretion, MHC processing, and presentation of vector immunogens in APC via the intravenous or intraperitoneal route would be expected to be more efficient for eliciting potent B-cell and T-cell responses. Such systemic vaccination with Listeria vectors may also readily provide access to dendritic cells for eliciting robust immune responses (28). It is noteworthy that subcutaneous injection delivering r-Listeria ⌬actA prfA* does not elicit humoral and cellular immune responses as efficiently as intravenous or intraperitoneal vaccinations.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Vaccination with the Recombinant Listeria monocytogenes ΔactA prfA*Mutant Elicits Robust Systemic and Pulmonary Cellular Responses and Secretory Mucosal IgA

Qiu

Lin

Chen

et al. 2011

Clin. Vaccine Immunol.

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We previously showed that recombinant (r) Listeria monocytogenes carrying ⌬actA and a selected prfA* mutation (r-Listeria ⌬actA prfA*) secreted >100-fold more immunogen in broth culture than wild-type r-Listeria or r-Listeria ⌬actA and elicited much greater cellular and humoral immune responses than r-Listeria ⌬actA after intravenous vaccination of mice. Here, we conducted comparative studies evaluating vaccine-elicited immune responses in systemic and mucosal sites after intranasal, intravenous, intraperitoneal, or subcutaneous immunization of mice with r-Listeria ⌬actA prfA* vaccine candidates. Intranasal vaccination of mice with r-Listeria ⌬actA prfA* vaccine candidates elicited a robust gamma interferon-positive (IFN-␥ ؉ ) cellular response in systemic sites, although intravenous or intraperitoneal immunization was more efficient. Surprisingly, intranasal vaccination elicited an appreciable pulmonary IFN-␥ ؉ cellular response that was nonstatistically higher than the magnitude induced by the intravenous route but was significantly greater than that elicited by subcutaneous immunization. Furthermore, although intranasal r-Listeria ⌬actA prfA* delivery induced poor systemic IgG responses, intranasal vaccination elicited appreciable secretory immunogen-specific IgA titers that were similar to or higher in mucosal fluid than those induced by subcutaneous and intravenous immunizations. Thus, intranasal vaccination with r-Listeria ⌬actA prfA* appears to be a useful approach for eliciting robust systemic and pulmonary cellular responses and measurable secretory mucosal IgA titers.Listeria monocytogenes is an intracellular bacterium with the unique ability to live in the cytoplasm and escape to the cytosol of antigen-presenting cells (APC). Listeria therefore can serve as a useful bacterial vaccine vector to deliver immunogens and to elicit strong CD8 ϩ T-cell immune responses (5,7,23,26,31). Since the deletion of the actA gene in L. monocytogenes results in remarkable attenuation without affecting immune potency, Listeria lacking actA have been explored as vaccine candidates for delivering immunogens against cancers (3,4,24). We recently showed that recombinant (r) Listeria ⌬actA vectors carrying a selected prfA(G155S) mutation (Listeria ⌬actA prfA*) secreted Ͼ100-fold-higher levels of vaccine immunogens in broth culture than wild-type r-Listeria or r-Listeria ⌬actA and consistently elicited much greater cellular and humoral immune responses than r-Listeria ⌬actA vectors after intravenous (i.v.) vaccination of mice (32).

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KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity

Abstract: Together, our data demonstrate that KBMA L. monocytogenes may be a powerful platform that can both deliver recombinant antigen to DCs for presentation and provide a potent DC-maturation stimulus, making it a potential cancer vaccine candidate.

Cited by 35 publications

References 52 publications

Vaccines: the Fourth Century

Vaccines: the Fourth Century

Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma

Intranasal Vaccination with the Recombinant Listeria monocytogenes ΔactA prfA*Mutant Elicits Robust Systemic and Pulmonary Cellular Responses and Secretory Mucosal IgA

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