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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

Effect of ampicillin treatment on therapy of TC1 by ADXS11-001. C57BL/6 mice were injected with 1 × 105 TC1 tumor cells. Seven days later, the mice were treated with 0.1 × LD50 of ADXS11-001. Beginning 3, 5, or 7 days after ADXS11-001 treatment, some of the mice received daily injections of 10 mg of Ampicillin, delivered for three consecutive days; the mice were then maintained on drinking water supplemented with Ampicillin at a concentration of 0.5 mg/mL. The data is adopted from [17].
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fig6: Effect of ampicillin treatment on therapy of TC1 by ADXS11-001. C57BL/6 mice were injected with 1 × 105 TC1 tumor cells. Seven days later, the mice were treated with 0.1 × LD50 of ADXS11-001. Beginning 3, 5, or 7 days after ADXS11-001 treatment, some of the mice received daily injections of 10 mg of Ampicillin, delivered for three consecutive days; the mice were then maintained on drinking water supplemented with Ampicillin at a concentration of 0.5 mg/mL. The data is adopted from [17].

Mentions: It should be noted that although Lm-LLO-based immunotherapy required a live attenuated bacteria as a carrier of the fusion antigen, the bacteria may be killed shortly after administration by antibiotic treatment and the immunotherapy will continue to demonstrate antitumor activity [20]. Experiments in mice by Bajénoff et al. showed that Lm-specific and Lm-nonspecific memory CD8+ T cells could be observed within 6 hours of infection and with Lm burden [41]. The Lm-specific and Lm-nonspecific memory CD8+ T cells were localized in red pulp of the spleen which formed clusters around Lm-infected cells. Memory CD8+ T cells produced inflammatory cytokines such as IFN-γ and CCL3 nearby infected myeloid cells which are known to be crucial for Lm killing. Corbin and Harty [42] reported that Lm-infected mice treated with antibiotics at 24 hours postinfection showed a robust increase in antigen-specific CD4+ and CD8+ T cells similar to the response in controls that did not receive the antibiotics. Furthermore, antibiotic treatment did not alter secondary antigen-specific T-cell expansion or protection with or without the antibiotics [42]. These experiments demonstrate that development of early CD4+ and CD8+ T cells show functional memory, independent of prolonged infection or antigen display on day 28. Figure 6 shows that administration of antibiotics on day 3 posttreatment with ADXS11-001 has no effect on efficacy as more than 90% tumor regression occurred in mice.


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

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

Effect of ampicillin treatment on therapy of TC1 by ADXS11-001. C57BL/6 mice were injected with 1 × 105 TC1 tumor cells. Seven days later, the mice were treated with 0.1 × LD50 of ADXS11-001. Beginning 3, 5, or 7 days after ADXS11-001 treatment, some of the mice received daily injections of 10 mg of Ampicillin, delivered for three consecutive days; the mice were then maintained on drinking water supplemented with Ampicillin at a concentration of 0.5 mg/mL. The data is adopted from [17].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Effect of ampicillin treatment on therapy of TC1 by ADXS11-001. C57BL/6 mice were injected with 1 × 105 TC1 tumor cells. Seven days later, the mice were treated with 0.1 × LD50 of ADXS11-001. Beginning 3, 5, or 7 days after ADXS11-001 treatment, some of the mice received daily injections of 10 mg of Ampicillin, delivered for three consecutive days; the mice were then maintained on drinking water supplemented with Ampicillin at a concentration of 0.5 mg/mL. The data is adopted from [17].
Mentions: It should be noted that although Lm-LLO-based immunotherapy required a live attenuated bacteria as a carrier of the fusion antigen, the bacteria may be killed shortly after administration by antibiotic treatment and the immunotherapy will continue to demonstrate antitumor activity [20]. Experiments in mice by Bajénoff et al. showed that Lm-specific and Lm-nonspecific memory CD8+ T cells could be observed within 6 hours of infection and with Lm burden [41]. The Lm-specific and Lm-nonspecific memory CD8+ T cells were localized in red pulp of the spleen which formed clusters around Lm-infected cells. Memory CD8+ T cells produced inflammatory cytokines such as IFN-γ and CCL3 nearby infected myeloid cells which are known to be crucial for Lm killing. Corbin and Harty [42] reported that Lm-infected mice treated with antibiotics at 24 hours postinfection showed a robust increase in antigen-specific CD4+ and CD8+ T cells similar to the response in controls that did not receive the antibiotics. Furthermore, antibiotic treatment did not alter secondary antigen-specific T-cell expansion or protection with or without the antibiotics [42]. These experiments demonstrate that development of early CD4+ and CD8+ T cells show functional memory, independent of prolonged infection or antigen display on day 28. Figure 6 shows that administration of antibiotics on day 3 posttreatment with ADXS11-001 has no effect on efficacy as more than 90% tumor regression occurred in mice.

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