Q&A: A ‘Trojan Horse’ to fight cancer

Smuggling in an army to help the immune system unwittingly destroy tumors

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Advaxis’ Dr. David Mauro and Dr. Robert Petit recently talked to DDNews about how their company’s technology is designed to deliver an army of genetically engineered bacteria to “trick” a patient’s immune system into thinking that cancer cells are Listeria-infected cells and should therefore be eliminated.
DDNews: Please tell our readers a bit about Advaxis’ beginnings and development over its brief history.
Robert Petit: Advaxis is a clinical-stage biotechnology company focused on developing cancer immunotherapies that use the body’s natural immune system to redirect the immune response to kill cancer. For decades, cancer researchers have been trying to stimulate the body’s immune system to identify and kill cancer cells, with the goal of creating “immunologic” treatments against cancers that are more effective and tolerable than traditional chemotherapy or radiation. Our clinical programs are evaluating the ability of Advaxis cancer immunotherapies to improve survival with reduced incidence and severity of side effects than typical chemotherapy and radiation regimens.
Advaxis technology was discovered at the University of Pennsylvania and is based on live attenuated bioengineered gram-positive bacteria that stimulate the patient’s own immune system to selectively target cancer cells for elimination, while reducing tumor defenses in the microenvironment. Advaxis’ technology—like a Trojan Horse—delivers an army of genetically engineered bacteria to “trick” the patient’s immune system into thinking that the cancer cells are Listeria-infected cells and should therefore be eliminated. Advaxis is developing the only cancer immunotherapies shown to actively suppress the key components in the tumor microenvironment, Tregs [regulatory T cells] and myeloid-derived suppressor cells (MDSCs), which protect the tumor from immunologic attack and contribute to tumor progression.
DDNews: How was the company’s Listeria-based immunotherapy technology developed?
Petit: The Advaxis platform technology uses live attenuated bioengineered Listeria monocytogenes (Lm) and is undergoing clinical research as a therapeutic agent. We start with a live attenuated strain of Listeria, then add multiple copies of a plasmid that encodes a fusion protein sequence, including a fragment of the LLO (listeriolysin O) molecule joined to the antigen of interest. This fusion protein is secreted by the Listeria inside the antigen presenting cells, and other cells, which has been shown to result in a stimulation of both the innate and adaptive arms of the immune system and the potential reduction in tumor defense mechanisms.
The Advaxis research platform is built on four elements of a cancer immunotherapy that may be clinically important.
  • First, Advaxis’s investigational immunotherapies are designed to preferentially infect antigen-presenting cells and escape into the cytoplasm to secrete antigens for the targeted tumor.
  • Second, the Lm-LLO immunotherapies are developed around a hypothesis of generating a strong, cytotoxic T-cell response to clear Listeria that is redirected to the tumor via the secreted tumor target antigens.
  • Thirdly, acute “perceived” listeriosis is hypothesized to stimulate a new acute immune response against tumor target antigens, in the immunologic context of responding to a potential infection. This new immune response develops before inhibitory checkpoints can hold it back.
  • Finally, Advaxis’ immunotherapies are being investigated for generating TAA-specific T cells that access the protected tumor microenvironment and override Treg and MDSCs within the tumor, which enables cytotoxic T cells to kill the tumor cells.
DDNews: What, if anything, may be the limitation(s) of the technology in terms of anti-cancer activity?
David Mauro: Thus far, in our clinical trials, we have seen activity against tumor targets from viruses or over-expressed “self” targets like HER2. We have seen the complete disappearance of bulky, metastatic refractory solid tumors in patients who were treated with Advaxis immunotherapy alone and have seen the ability to prevent recurrence and potentially eliminate micro-metastases from aggressive diseases like osteosarcoma. Of course, cancer is a formidable foe, and we are committed to finding combination therapies that can further enhance cancer treatment by combining Advaxis immunotherapies with other active treatments, like in our combination trials with Merck’s Keytruda, AstraZeneca/MedImmune’s MEDI4736 PD-L1 blocking antibody and with Incyte’s IDO1 inhibitor.
DDNews: What is the derivation of the term Lm-LLO?
Petit: Lm derivation is Listeria monocytogenes, which is a gram-positive bacterium that is a potent immune stimulator and serves as the base for Advaxis’ cancer immunotherapies. LLO derivation is listeriolysin O, a protein key to Lm’s ability to escape into the cytoplasm. Advaxis’ cancer immunotherapies use a fragment of the LLO molecule and fuse it with the tumor antigen of interest. This fusion protein has been shown to stimulate the innate and adaptive immune system against the targeted tumor antigen.
DDNews: The Advaxis website lists 20 immunotherapies currently under development. What is the current status of the entities progressing through the Advaxis pipeline?
Petit: Advaxis has validated the versatility of its platform technology by demonstrating preliminary clinical safety and efficacy with two different immunotherapies—ADXS-HPV in women with recurrent cervical cancer and with ADXS-HER2 in pet dogs with bone cancer (osteosarcoma). Advaxis is progressing both of these product candidates to the next stage of clinical development with the goal of regulatory approval and commercialization. As of now, ADXS-HPV is being evaluated in a Phase 2 clinical trial in invasive cervical cancer, a Phase 1/2 in head and neck cancer, Phase 1/2 in anal cancer and a Phase 1/2 study in combination with MEDI4736 for cervical cancer and head and neck cancer. We are also seeking to initiate a Phase 3 trial of ADXS-HPV in high-risk, locally advanced cervical cancer and a Phase 2/3 study with RTOG [Radiation Therapy Oncology Group] Foundation in anal cancer.
In addition, early-stage clinical trials with ADXS-PSA for prostate cancer and ADXS-HER2 for patients with HER2/Neu expressing cancers have begun. The remaining 16 immunotherapies are currently in preclinical development.
Advaxis has three commercial partnerships with major biopharmaceutical companies for the development and commercialization of Advaxis immunotherapies. Biocon and Global BioPharma have exclusive licensing agreements for the development and commercialization of ADXS-HPV for the treatment of cervical cancer in India and Asia, respectively. Aratana Therapeutics has an exclusive license for the development and commercialization of ADXS-HER2 for canine osteosarcoma, as well as three other Lm-LLO immunotherapy product candidates for three other cancers in canines and felines.
Advaxis has established several strategic collaborations with recognized cancer centers of excellence, such as the University of Pennsylvania, Georgia Regents University Cancer Center, University of California San Francisco, Brown University and Mount Sinai’s Icahn School of Medicine.
DDNews: How will the Lm-LLO platform work with checkpoint inhibitors provided by partners such as Merck, MedImmune and Incyte (and perhaps others)?
Mauro: Based on preclinical investigations, an Lm-LLO immunotherapy, like ADXS-PSA, generates TAA-specific T cells and neutralizes Tregs and MDSCs in the tumor microenvironment. Meanwhile, the PD-1 antibody, such as Merck’s Keytruda, blocks the inhibitory effects of PD-1 ligand binding, which results in a significantly larger number of tumor antigen-specific T cells to fight against the cancer. Overall, the data suggests that the combination of ADXS-PSA with Keytruda may lead to an enhanced antitumor response.
An HPV infection stimulates the expression of PD-L1. Advaxis’ Lm-LLO immunotherapy ADXS-HPV generates TAA-specific T cells and neutralizes Tregs and MDSCs in the tumor microenvironment, and MedImmune’s MEDI4736 blocks the inhibitory effects of PD-L1, which results in a significantly larger number of tumor antigen-specific T cells to be generated that can infiltrate into and fight against the cancer.
Lm-LLO immunotherapy treatment provides the drive to activate tumor-antigen specific cytotoxic T cells while IDO1 inhibition can eliminate known mediators of tumor protection that inhibit anticancer immunity in the tumor microenvironment, making it easier for immune cells to kill the tumor cells.

Dr. David Mauro joined Advaxis as chief medical officer in October 2014. Previously, he served as executive director and section head of Oncology Clinical Development at Merck & Co., where he was involved in the strategic oversight and tactical implementation of the clinical development and translational science for multiple programs within the oncology portfolio, including Keytruda (pembrolizumab). Prior to Merck, Dr. Mauro was director at Bristol-Myers Squibb, where his responsibilities included Erbitux medical strategy and oncology early development.
Dr. Robert Petit is chief scientific officer at Advaxis, having joined from Bristol-Myers Squibb, where he was the U.S. medical strategy lead for the Ipilimumab program, director of medical strategy for new oncology products and director of global clinical research. Prior to joining Bristol-Myers Squibb, Petit served as vice president of clinical development at MGI Pharma and also at Aesgen Inc. His scientific focus has been to develop immunologic-based therapies with a particular emphasis on immunologic oncology treatment.

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