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Lm-LLO-Based Immunotherapies and HPV-Associated Disease.

Wallecha A, French C, Petit R, Singh R, Amin A, Rothman J - J Oncol (2012)

Bottom Line: ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7.In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome.This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.

View Article: PubMed Central - PubMed

Affiliation: Advaxis, Inc., 305 College Road East, Princeton, NJ 08540, USA.

ABSTRACT
HPV infection is a direct cause of neoplasia and malignancy. Cellular immunologic activity against cells expressing HPV E6 and E7 is sufficient to eliminate the presence of dysplastic or neoplastic tissue driven by HPV infection. Live attenuated Listeria monocytogenes- (Lm-) based immunotherapy (ADXS11-001) has been developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7. In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome. ADXS11-001 is currently being evaluated in Phase 2 clinical trials for cervical intraepithelial neoplasia, cervical cancer, and HPV-positive head and neck cancer. The use of a live attenuated bacterium is a more complex and complete method of cancer immunotherapy, as over millennia Lm has evolved to infect humans and humans have evolved to prevent and reject this infection over millennia. This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.

No MeSH data available.


Related in: MedlinePlus

Schematic presentation of LLO-Ag (HPV) fusion protein processing and presentation in antigen-presenting cell (APC) by Listeria monocytogenes. Advaxis in collaboration with Paterson et al. has developed human papilloma virus (HPV) and listeriolysin (LLO) fusion proteins in Lm for immunotherapy [17, 22–24]. Upon injection in vivo, these Lm are sequestered and engulfed by antigen-presenting cells (APCs) such as dendritic cells [23, 24, 31]. The bacteria are engulfed by vacuoles where most of the Listeria are killed [18, 32]. The bacterium while processing the tumor-associated antigen (HPV) and listeriolysin O (LLO) stimulates both arms of the adaptive immune system [20, 34]. Part of the antigen from the vacuole is processed via the MHC class II molecules which generate CD4+ T cells. Five to ten percent of these Lm escape into the cytosol with the assistance of the LLO where Listeria can undergo replication. The cytosolic HPV-LLO fusion protein behaves as endogenous antigens. The HPV-LLO fusion protein undergoes ubiquitination, and it is processed via the proteasome [20]. The resulting peptides are presented via the MHC class I molecules to generate CD8+ T cells [34]. These cells generate strong cell-mediated immune responses. Lm also evokes a strong innate immune response which leads to generation of numerous mediators such as nitric oxide which is involved in killing of the bacteria in the vacuoles and cytokines (such as TNF-β, IL-1, IL-18, IL-12, and IFNγ) which impart several types of bystander effects [20, 33, 35–37].
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Related In: Results  -  Collection


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fig1: Schematic presentation of LLO-Ag (HPV) fusion protein processing and presentation in antigen-presenting cell (APC) by Listeria monocytogenes. Advaxis in collaboration with Paterson et al. has developed human papilloma virus (HPV) and listeriolysin (LLO) fusion proteins in Lm for immunotherapy [17, 22–24]. Upon injection in vivo, these Lm are sequestered and engulfed by antigen-presenting cells (APCs) such as dendritic cells [23, 24, 31]. The bacteria are engulfed by vacuoles where most of the Listeria are killed [18, 32]. The bacterium while processing the tumor-associated antigen (HPV) and listeriolysin O (LLO) stimulates both arms of the adaptive immune system [20, 34]. Part of the antigen from the vacuole is processed via the MHC class II molecules which generate CD4+ T cells. Five to ten percent of these Lm escape into the cytosol with the assistance of the LLO where Listeria can undergo replication. The cytosolic HPV-LLO fusion protein behaves as endogenous antigens. The HPV-LLO fusion protein undergoes ubiquitination, and it is processed via the proteasome [20]. The resulting peptides are presented via the MHC class I molecules to generate CD8+ T cells [34]. These cells generate strong cell-mediated immune responses. Lm also evokes a strong innate immune response which leads to generation of numerous mediators such as nitric oxide which is involved in killing of the bacteria in the vacuoles and cytokines (such as TNF-β, IL-1, IL-18, IL-12, and IFNγ) which impart several types of bystander effects [20, 33, 35–37].

Mentions: As shown in Figure 1, attenuated Lm carrying the HPV antigen fused to LLO can be phagocytized by antigen-presenting cells, macrophages, and other cells [20, 30]. The attenuated bacterial cells are taken up into the endosome where they evoke a conserved pathogenic assault [31] and redirect the tumor antigen [23]. The PEST-like sequence of LLO is important as it has been shown to increase antitumor efficacy of Lm-based vectors expressing the fusion protein LLO-PEST-E7 in HPV-16 immortalized tumors [8]. This process stimulates cell-mediated immune response generating CD4+ cells and CD8+ T cells [20]. The fusion of antigens to LLO facilitates the secretion of the antigen [32] and increases antigen presentation [8] with a profound influence on CD8+ T-cell activation [20, 33].


Lm-LLO-Based Immunotherapies and HPV-Associated Disease.

Wallecha A, French C, Petit R, Singh R, Amin A, Rothman J - J Oncol (2012)

Schematic presentation of LLO-Ag (HPV) fusion protein processing and presentation in antigen-presenting cell (APC) by Listeria monocytogenes. Advaxis in collaboration with Paterson et al. has developed human papilloma virus (HPV) and listeriolysin (LLO) fusion proteins in Lm for immunotherapy [17, 22–24]. Upon injection in vivo, these Lm are sequestered and engulfed by antigen-presenting cells (APCs) such as dendritic cells [23, 24, 31]. The bacteria are engulfed by vacuoles where most of the Listeria are killed [18, 32]. The bacterium while processing the tumor-associated antigen (HPV) and listeriolysin O (LLO) stimulates both arms of the adaptive immune system [20, 34]. Part of the antigen from the vacuole is processed via the MHC class II molecules which generate CD4+ T cells. Five to ten percent of these Lm escape into the cytosol with the assistance of the LLO where Listeria can undergo replication. The cytosolic HPV-LLO fusion protein behaves as endogenous antigens. The HPV-LLO fusion protein undergoes ubiquitination, and it is processed via the proteasome [20]. The resulting peptides are presented via the MHC class I molecules to generate CD8+ T cells [34]. These cells generate strong cell-mediated immune responses. Lm also evokes a strong innate immune response which leads to generation of numerous mediators such as nitric oxide which is involved in killing of the bacteria in the vacuoles and cytokines (such as TNF-β, IL-1, IL-18, IL-12, and IFNγ) which impart several types of bystander effects [20, 33, 35–37].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3307007&req=5

fig1: Schematic presentation of LLO-Ag (HPV) fusion protein processing and presentation in antigen-presenting cell (APC) by Listeria monocytogenes. Advaxis in collaboration with Paterson et al. has developed human papilloma virus (HPV) and listeriolysin (LLO) fusion proteins in Lm for immunotherapy [17, 22–24]. Upon injection in vivo, these Lm are sequestered and engulfed by antigen-presenting cells (APCs) such as dendritic cells [23, 24, 31]. The bacteria are engulfed by vacuoles where most of the Listeria are killed [18, 32]. The bacterium while processing the tumor-associated antigen (HPV) and listeriolysin O (LLO) stimulates both arms of the adaptive immune system [20, 34]. Part of the antigen from the vacuole is processed via the MHC class II molecules which generate CD4+ T cells. Five to ten percent of these Lm escape into the cytosol with the assistance of the LLO where Listeria can undergo replication. The cytosolic HPV-LLO fusion protein behaves as endogenous antigens. The HPV-LLO fusion protein undergoes ubiquitination, and it is processed via the proteasome [20]. The resulting peptides are presented via the MHC class I molecules to generate CD8+ T cells [34]. These cells generate strong cell-mediated immune responses. Lm also evokes a strong innate immune response which leads to generation of numerous mediators such as nitric oxide which is involved in killing of the bacteria in the vacuoles and cytokines (such as TNF-β, IL-1, IL-18, IL-12, and IFNγ) which impart several types of bystander effects [20, 33, 35–37].
Mentions: As shown in Figure 1, attenuated Lm carrying the HPV antigen fused to LLO can be phagocytized by antigen-presenting cells, macrophages, and other cells [20, 30]. The attenuated bacterial cells are taken up into the endosome where they evoke a conserved pathogenic assault [31] and redirect the tumor antigen [23]. The PEST-like sequence of LLO is important as it has been shown to increase antitumor efficacy of Lm-based vectors expressing the fusion protein LLO-PEST-E7 in HPV-16 immortalized tumors [8]. This process stimulates cell-mediated immune response generating CD4+ cells and CD8+ T cells [20]. The fusion of antigens to LLO facilitates the secretion of the antigen [32] and increases antigen presentation [8] with a profound influence on CD8+ T-cell activation [20, 33].

Bottom Line: ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7.In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome.This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.

View Article: PubMed Central - PubMed

Affiliation: Advaxis, Inc., 305 College Road East, Princeton, NJ 08540, USA.

ABSTRACT
HPV infection is a direct cause of neoplasia and malignancy. Cellular immunologic activity against cells expressing HPV E6 and E7 is sufficient to eliminate the presence of dysplastic or neoplastic tissue driven by HPV infection. Live attenuated Listeria monocytogenes- (Lm-) based immunotherapy (ADXS11-001) has been developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7. In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome. ADXS11-001 is currently being evaluated in Phase 2 clinical trials for cervical intraepithelial neoplasia, cervical cancer, and HPV-positive head and neck cancer. The use of a live attenuated bacterium is a more complex and complete method of cancer immunotherapy, as over millennia Lm has evolved to infect humans and humans have evolved to prevent and reject this infection over millennia. This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.

No MeSH data available.


Related in: MedlinePlus