Searching for the ideal cancer vaccine

Abstract

Dissatisfaction with traditional cancer treatments has spurred interest in new approaches to cancer, among them immunotherapies. Cancer immunotherapies, have been under investigation for the past thirty years, and like vaccines administered for infectious diseases, cancer vaccines use the immune system to fight diseases through presentation of antigens, in this case large molecules on the surfaces of cancer cells.

Dendreon’s Provenge® prostate cancer vaccine, currently is in Phase III human testing, is an example of autologous vaccines that employ cells from a patient’s own body. Provenge stimulates an immune response against cells possessing prostatic acid phosphatase, an antigen found in 95% of prostate cancers. Autologous vaccines, which have a high cost that results from creating unique vaccines for each patient, are not the only platform technology for cancer vaccine development

Another platform, live microbial cancer vaccines, exploits medical science’s 150-year experience using attenuated microbes as vaccines for infectious diseases. Live vaccines are unique in their ability to induce the most complete, robust immune system response, stimulating multiple immune mechanisms, in addition to producing cancer-fighting cytokines. Live vaccines exploit the fact that the method of presenting antigens to the body may be as important as the antigens themselves. This raises the possibility that benign, bioengineered, immunogenic microbes might serve as vehicles for both priming the immune system and presenting cancer antigens to specific immune system cells. Lovaxin B, a Listeria-based cancer vaccine under development at Advaxis, Inc. for treating breast cancer, is based on this premise.

Breast cancer strikes more than two hundred thousand American women per year, and kills forty thousand of them. The second most common deadly cancer in women, breast cancer is the fifth leading cause of death overall.

Lovaxin B is directed against HER2-neu, an antigen implicated in approximately 40% of all breast cancer cases. Patients with tumors that over-express HER2-neu have poor prognoses. Her/2-neu is also over-expressed in 30% of melanomas, 20% of pancreatic cancers, and 19% of gastric cancers. Lovaxin B is constructed by fusing a Listeria enzyme, listeriolysin, with molecular fragments of a version of HER2-neu.

Unique Antigen Presentation Vehicle

Listeria’s lifecycle makes it a unique antigen carrier for therapeutic vaccines. Like most pathogenic bacteria, Listeria stimulates innate, or general immunity, as well as adaptive immunity, through which the immune system targets specific signals or agents. The adaptive immune mechanism consists of two distinct arms called Class I and Class II type responses   Cancer cells are attacked by cellular immunity and Class I responses generate Killer T cells that attack cancer cells, while Class II responses generate Helper T cells that support Killer T cell function and are required to be effective.

The Listeria strain used in Lovaxin B has been attenuated to reduce infectivity and virulence, but nevertheless elicits a powerful immune response independent of the cancer antigens it may be carrying. These immune mechanisms are therefore primed to recognize the cancer antigens incorporated into Lovaxin B.

Cancer antigens carried and secreted by the Lovaxin B Listeria microbe exist not in their native form but as fusion proteins – chemical chimeras consisting of antigen and a non-hemolytic fragment of the protein listeriolysin O, which is a Listeria virulence factor with strong adjuvant properties. More than 90% of the Listeria that are engulfed by Antigen Processing Cells (APC), are digested, and killed in a way that stimulates the Class II pathway.  Through the action of LLO, between 5-7% of the time the bacteria create a pore in the immune cell’s digestive vacuole, allowing the Listeria to escape into the cytosol where it can divide and infect other cells, and stimulate the Class I pathway.  The LLO-antigen fusion protein is an antigen and adjuvant in one molecule and a very strong stimulator of immune events, and this specific, accelerated, high-dose antigen delivered directly to the MHC-1 class 1 pathway in turn generates an abundance of activated Killer T cells.

Potential Limitations

A possible drawback of Listeria-based vaccines is this microorganism’s potential to cause serious infections, especially in immunocompromised cancer patients, those with HIV/AIDS, or women in their third trimester of pregnancy, transplant patients receiving immunosuppressant drugs, or to cancer patients receiving certain types of chemotherapy. However, even in late stage metastatic cancer patients who had failed prior therapy no untoward listerial symptoms were observed.  Patients in early clinical studies were hospitalized as a precaution, but during Phase II testing and beyond will likely receive treatment on an outpatient basis.

Preliminary Results

Lovaxin B is being developed as a treatment for patients with existing cancers rather than as a preventive vaccine. Advaxis has produced several different development-stage vaccines for treating cervical, breast, prostate, lung, pancreatic, and skin cancers, as well as tumors of the head and neck. The Lovaxin platform is a powerful method for generating immune responses to tumor cells bearing wide-ranging antigens. Animal studies have demonstrated response rates in some transplanted tumors of close to 100%. Animals that are cured appear to be protected against a future cancer reoccurrence. .

It is impossible to say at this juncture how long protection will persist after administration of Lovaxin vaccines. Some vaccinations, like DPT, appear to work for life while others, like tetanus vaccine, are effective for just eight to ten years. The persistence of immunity from Listeria-based vaccines will probably depend on the patient’s immune response and the type of cancer.

Where It Began

Dr. Yvonne Paterson, a microbiologist at the University of Pennsylvania and a scientific founder of Advaxis, Inc., conceived and demonstrated proof of principle for Listeria vaccines that are now under development at Advaxis. The company retains exclusive licensing rights to future Listeria developments from Dr. Paterson’s laboratory as well. Through their close, ongoing relationship, U-Penn remains a major shareholder in Advaxis, and Dr. Paterson consults for the company under an exclusivity agreement.

“We are quite interested in continuing to work with Advaxis,” Dr. Paterson states. “Seeing one’s laboratory inventions enter the clinic is gratifying both personally and professionally, and the potential benefit for cancer patients is great. The academic-industrial partnership with Advaxis is a good conduit for bringing lab work to the bedside.”

As a breast cancer survivor of more than twenty-five years, Dr. Paterson has a special interest in cancer vaccines. Lovaxin B, the Listeria vaccine construct that carries the well-known breast tumor antigen HER2neu (the target of the blockbuster monoclonal antibody drug Herceptin), is one of her earliest cancer vaccines.

Recently, Dr. Paterson and Advaxis has been looking at another approach to breast cancer, targeting molecules that are expressed on the dedicated blood vessels supplying tumors with nutrients. The idea is to weaken or destroy the blood vessels, and thereby starve the tumor. Differentiating tumor blood vessels from those forming in other parts of the body will require a bit of artistry, but as Dr. Paterson notes other anti-angiogenesis treatments face the same challenge.

For this work, Dr. Paterson has received a 2008 BCRF-AACR Grant for Translational Breast Cancer Research. These awards are a joint effort of the Breast Cancer Research Foundation and the American Association for Cancer Research, which awards only three research grants of this type per year.