Advaxis logo. Image: AdvaxisIn the U.S. about 12,500 women are diagnosed with cervical cancer a year. Out of these women, about 4,500 progress into invasive cervical cancer or the end stage of the disease. This leaves about 8,000 women a year in the U.S. that are cured through existing standard of care treatment: surgery or chemotherapy/radiation. However, chemotherapy/radiation have terrible side effects in some cases and can greatly affect the body’s immune response to future illness.

Worldwide there are about 527,000 new diagnoses of cervical cancer annually. And outside the U.S., cervical cancer is considered an epidemic.

Current vaccines prevent infection by two (out of 15) oncogenic high-risk HPV (human papilloma virus) strains—the sexually transmitted infection that causes cervical cancer—but have no effect on the millions that are already infected.

The problem with any cancer is that the body sees the cancer as part of itself, and is no longer attacking it as cancer or a foreign invader. For example, a woman with invasive cervical cancer—tumors don’t reduce after treatment—gets a cut on her hand that becomes infected. Would her immune system be able to fight off the infection?

For many, the answer might seem like a no, as one’s immune response would be impaired while undergoing extensive treatment for cancer like chemotherapy/radiation. But really her immune system is capable of an immune response to that bacterial infection.

How? The answer is simple: a disruptive immunotherapy approach that tricks the immune system into thinking that cancer is a bacterial infection.

This is done by using genetically altered bacteria that can be infused into dendritic cells of the immune system, which are sentinels in our bodies that are looking for, what Daniel O’Connor, CEO, Advaxis, Princeton, N.J., calls foreign invaders. Once the bacteria enter the dendritic cells, they cause the body’s immune system to no longer look at the cancer itself as something that is protected, but instead looks at it as something that should be destroyed.

There are currently a few forms of immunotherapy approved by the FDA. A current well-known form is called a check point inhibitor. Check point inhibitors are much like traveling down a major highway that has multiple toll booths, those toll booths would represent where immune response stops. As you travel down this highway, or the drug travels in a person’s system, the immune response will stop at certain check points to ward off disease. Bristol-Myers Squibb, New York, N.Y., has developed a disruptive immunotherapy check point inhibitor call Yervoy, or CTLA4, for the particular check point it inhibits. Overall there are a total of five distinct check points that could be inhibited.

Dendreon, Seattle, Wash., has also developed an immunotherapy for cancer. Their immunotherapy works where they remove a patient’s dendritic cells from his or her body to manipulate those cells in a CGMP environment and then re-introduce those cells back into a patient.

However, Advaxis has developed a technology that goes well beyond check point inhibitors or other immunotherapies on the market. By incorporating the technology of existing immunotherapies, Advaxis’ ADXS-HPV immunotherapy overcomes immunosuppression at the site of the tumor.

Developed at the Univ. of Pennsylvania by a scientist who is also a breast cancer survivor, Advaxis has taken the immunotherapy technology and added to its effectiveness. The technology takes a gram-positive bacteria and genetically alters it in two predominate ways. One: it’s administered intravenously into a patient and has no pathology associated with it that ungenetically inhibited bacteria normally would exhibit. And two: The genetically altered bacteria gains access to the dendritic cells in a patient, where it will secrete a fusion protein—a piece of the bacterium—that is fused to an antigen of interest.

Since administered intravenously, the genetically altered bacteria gain access to dendritic cells inside the body, differing Advaxis’ immunotherapy from Dendreon’s . And once it gets inside those dendritic cells, the normal bacteria, if not genetically altered, would start to multiply inside the dendritic cell. “Because we genetically alter our bacteria, it doesn’t do that,” says O’Connor. “Instead, what it does is gets inside the dendritic cell and starts to secrete a piece of the bacteria which is highly immunogenic, meaning it has the ability to create a very strong immune response.” What the company has done with the genetic engineering is fused the highly immunogenic portion of the bacteria, which is secreted inside the dendritic cell by the bacteria itself, to a specific cancer antigen; their most developed product candidate is for HPV.

Advaxis’ product also overcomes immunosuppression at the site of the tumor. By harnessing an immune response, the body no longer looks at the tumor as something that needs protection, through the suppression of killer T-cells. However, the body views the immunotherapy as a bacterial infection, allowing those killer T-cells that have been made to the bacteria, as well at the antigen, to overcome that suppression of the tumor to go and do its job, attack.

“There are four elements to effective immunotherapy,” says O’Connor. “The first three are what current marketed products do: gain access to the dendritic cell, causing a profound immune response and then overcoming check point inhibitor. The fourth element, which is what Advaxis does, is the ability to overcome immunosuppression at the site of the tumor. We are not aware of any others in the market or in development other than our own.”

Overall, the company has completed two clinical trials with the immunotherapy platform. The first, conducted with product candidate ADXS-HPV, was a study conducted in India with 110 women who had advanced cervical cancer. The women were pre-treated with chemotherapy/radiation and surgery, or both, and their disease progressed, or their tumors continued. In that patient population Advaxis saw with one dose of their immunotherapy, that six women had a complete response (tumors were 100% eliminated), six women had a partial response (tumors were significantly reduced) and 35 showed cases of disease stabilization, an encouraging proof of survival.

The second study was conducted at the Univ. of Pennsylvania by a vet (Dr. Mason) who specializes in canine cancers, especially canine bone cancer (osteosarcoma). Over two years ago, Dr. Mason asked Advaxis to use product candidate ADXS-cHER2, a product candidate made to treat breast cancer, in a study that enrolled 13 dogs with highly aggressive canine osteosarcoma. Although made to treat breast cancer, the immunotherapy could also work to heal canine osteosarcoma as both cancers express the same cancer antigen, HER2. The dogs were randomized to receive three doses of ADXS-cHER2 three weeks apart. The Phase 1 data in canine osteosarcoma shows encouraging survival in companion dogs treated with ADXS-cHER2 versus those untreated. The dogs that received the immunotherapy are living significantly longer. “This study also shows that our immunotherapy is not just a single product candidate,” says O’Connor.

The future of the technology lies in first gaining approval of the immunotherapy platform directed toward the cancer antigen HPV.  In the U.S. Advaxis hopes to demonstrate its ability in a registration setting to increase survival in women with advanced cervical cancer. From there, the company hopes to expand the use of ADXS-HPV to HPV-associated head and neck cancer. The company has already gained an orphan indication for the FDA with respect to HPV-associated head and neck cancer.

Outside of the U.S., where cervical cancer is considered an epidemic, Advaxis hopes to license its candidate to market-dominant companies and places in the world where there is a high prevalence of HPV-associated disease. Advaxis has already licensed exclusively to Biocon, one of the world’s top biopharmaceutical companies, to develop and commercialize ADXS-HPV in India and other key approaching markets.

In 2014 Advaxis will also begin Phase I trials in breast and prostate cancer.