Limits...
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

A schematic representation of the plasmid pActA-E7. The recombinant plasmid was used to transform the Lm strain XFL-7 to create Lm-ActA-E7. The vector includes a promoter (pHly) and signal sequence (ss) from the hly gene, the actA gene, the human papillomavirus 16 E7 gene, and the transcription factor prfA. XFL-7 is a prfA-deleted strain of Lm. Thus, only bacteria that retain the plasmid will replicate in vivo. Adopted and modified from [49].
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3307007&req=5

fig3: A schematic representation of the plasmid pActA-E7. The recombinant plasmid was used to transform the Lm strain XFL-7 to create Lm-ActA-E7. The vector includes a promoter (pHly) and signal sequence (ss) from the hly gene, the actA gene, the human papillomavirus 16 E7 gene, and the transcription factor prfA. XFL-7 is a prfA-deleted strain of Lm. Thus, only bacteria that retain the plasmid will replicate in vivo. Adopted and modified from [49].

Mentions: Preclinical studies using a genetically engineered attenuated strain of Lm expressing HPV-16 E7 demonstrated therapeutic activity against E7-expressing tumors in animal models [7]. Two Lm-LLO-based immunotherapy vectors, one of which expresses the antigen HPV-16 E7 alone and one which expresses E7 fused to a truncated form of LLO, showed regression of the E7-expressing tumor, TC-1, established in syngeneic C57BL/6 mice [7]. A lung epithelial cell line (TC-1) immortalized with HPV-16 E6 and E7 and transformed with the c-ras oncogene was used in these studies. Paterson et al. have recently utilized a new recombinant strain of L that uses a multicopy episomal expression system (Lm-ActA-E7) to secrete the HPV protein E7 fused to the Lm protein ActA as shown in Figure 3.


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

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

A schematic representation of the plasmid pActA-E7. The recombinant plasmid was used to transform the Lm strain XFL-7 to create Lm-ActA-E7. The vector includes a promoter (pHly) and signal sequence (ss) from the hly gene, the actA gene, the human papillomavirus 16 E7 gene, and the transcription factor prfA. XFL-7 is a prfA-deleted strain of Lm. Thus, only bacteria that retain the plasmid will replicate in vivo. Adopted and modified from [49].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: A schematic representation of the plasmid pActA-E7. The recombinant plasmid was used to transform the Lm strain XFL-7 to create Lm-ActA-E7. The vector includes a promoter (pHly) and signal sequence (ss) from the hly gene, the actA gene, the human papillomavirus 16 E7 gene, and the transcription factor prfA. XFL-7 is a prfA-deleted strain of Lm. Thus, only bacteria that retain the plasmid will replicate in vivo. Adopted and modified from [49].
Mentions: Preclinical studies using a genetically engineered attenuated strain of Lm expressing HPV-16 E7 demonstrated therapeutic activity against E7-expressing tumors in animal models [7]. Two Lm-LLO-based immunotherapy vectors, one of which expresses the antigen HPV-16 E7 alone and one which expresses E7 fused to a truncated form of LLO, showed regression of the E7-expressing tumor, TC-1, established in syngeneic C57BL/6 mice [7]. A lung epithelial cell line (TC-1) immortalized with HPV-16 E6 and E7 and transformed with the c-ras oncogene was used in these studies. Paterson et al. have recently utilized a new recombinant strain of L that uses a multicopy episomal expression system (Lm-ActA-E7) to secrete the HPV protein E7 fused to the Lm protein ActA as shown in Figure 3.

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