Wednesday, June 3, 2009

Searching for the Ideal Cancer Vaccine

IN THE LAB: Lab Analysis

Cancer Vaccines Continue to Show Tremendous Promise


Traditional cancer treatments - surgery, radiation, and chemotherapy - entail serious, treatment-limiting side effects. The search for novel cancer treatments that operate outside of traditional cytotoxic mechanisms has focused on various role players, for example the cytokines, monoclonal antibodies, and even DNA.

All these approaches affect individual components of immune function, but none by themselves can direct a simultaneous, integrated response of the entire immune system that is robust enough to keep cancer at bay for very long.

Newer, targeted therapies like Herceptin and Avastin are beginning to turn the tide in cancer therapy by shutting down cancer-specific pathways, while sparing healthy biological mechanisms. Within a decade, results from the human genome project and follow-on "omics" sciences will identify even more such pathways, while identifying patient populations most likely to respond and least susceptible to serious side effects.

Immunotherapies - Cancer Vaccines

Researchers have been seeking immunotherapies for cancer for at least 30 years. Cancer vaccines are one type of targeted therapy, and even though development stages continue, vaccines promise a new level of safety and efficacy for cancer patients. Like vaccines administered for infectious diseases, cancer vaccines prime the body system to fight disease from within, through specialized immune system mechanisms.

Two recently approved products, Merck's Gardasil and Glaxo SmithKline's Cerverix, immunize women against strains of human papilloma virus most strongly associated with development of cervical cancer. These vaccines are not strictly cancer treatments, but more traditional infectious disease vaccines. However, they bridge the concepts of immune surveillance and cancer therapy.

Dendreon's Provenge prostate cancer vaccine, and Genitope's MyVax Personalized Immunotherapy, both in Phase III human testing, are examples of classical cancer vaccines. Provenge stimulates a patient's immune response against cells possessing prostatic acid phosphatase, an antigen found in 95 percent of prostate cancers; MyVax is based on autologous technology, which uses antigens from a patient's own tumor. These and other cancer vaccines, many of them unsuccessful, have significantly increased understanding of how vaccines might treat cancer.

All vaccines work through similar principles. The vaccine presents immune system cells with antigens - molecular constructs that are similar or identical to molecules on the surface of "non-self" invaders such as viruses and bacteria. Once the immune system recognizes these antigens, it primes itself to seek out and destroy bacteria when encountered later on.

When the immune system was evolving along with the human species, people didn't live long enough to experience the cancer rates we're seeing today. Manipulating the immune system to deal with cancer is an idea that was born just after the turn of the 1900s. Live vaccines are an important step in this evolution, and Listeria is the most promising of the live vaccines.

Early attempts at cancer vaccines focused on autologous products created from the patient's own cancer cells, bioengineered to target immune recognition. While this research has taught scientists much about cancer and immunity, they have not caught on as a platform technology for cancer vaccine development due to regulatory uncertainties and the high cost of creating unique vaccine products for each patient.

By contrast, live cancer vaccines exploit the 150-year experience in live vaccines for infectious diseases. Specifically, they are based on the idea that the manner in which antigens are presented to the immune system may be as important as the antigens themselves. Thus, a common antigen expressed in cancer, not unique to a specific patient, might produce an effective cancer vaccine if optimally presented to the immune system. This led to the possibility that harmless, bioengineered microbes to which the body already generates a strong immune response might serve as a vehicle for both priming the immune system in a general way, and presenting cancer antigens to specific immune system cells. This is the basis of Lovaxin C, a Listeria-based cancer vaccine under development at Advaxis, Inc.

Among the therapeutic immunotherapies, live vaccines alone are capable of inducing the most complete, robust immune system response. Vaccines stimulate Class 1, Class 2, humora and cellular immunity mechanisms, in addition to production of cancer-fighting cytokines.

All vaccines introduce some non-virulent element of a disease, in the hope of inducing immune responses when the disease-causing agent is encountered. In the case of infectious disease vaccines, the goal is to prevent infection. Cancer vaccines seek to cure by harnessing similar immune mechanisms. Lovaxin C is directed against HPV-16 E7, an antigen implicated in cancers of the cervix, head, and neck, and perhaps of the lung as well. This E7 antigen is conferred to cancer cells by the human papilloma virus.

Unique Antigen Presentation Vehicle

Listeria's lifecycle makes it a unique, if not ideal, antigen carrier for therapeutic vaccines. Listeria behaves as most pathogenic bacteria do; stimulates innate (non-specific, or general) immunity. Listeria also stimulates adaptive immunity, a process by which the immune system targets specific signals or agents. The adaptive immune mechanism consists of two distinct arms; humoral immunity, which involves antibodies, and cellular immunity, which is based on white blood cells known as T-lymphocytes. Although cellular immunity is what attacks and kills cancer cells, it may be assisted by the humoral immune system. Through the humoral system, antibodies find a target and make it more accessible to the cellular immune system.

Listeria employs several mechanisms within the adaptive immune system, one of which is infection of dendritic cells and macrophages - specialized immune system cells that direct the adaptive immune response. Macrophages ingest invaders and process them into smaller antigens and antigen fragments, which are subsequently used to stimulate broader immunologic functions.

The Listeria strain used in Lovaxin C has been attenuated to reduce infectivity and virulence. Despite its weakened state, this bacterium still elicits a powerful immune response by itself. The same immune mechanisms employed to fight wild type Listeria are therefore recruited and primed to recognize the unique cancer antigens incorporated into Lovaxin C.

Specifically, we were interested in stimulating the Class 1 pathway, which we achieve through engineering the antigen. Cancer antigens carried and secreted by the Lovaxin C Listeria microbe exist not as native antigens but as fusion proteins - chemical chimeras of antigen and a fragment of an enzyme that directs the antigen into the class 1 pathway. The enzyme, listeriolysin O (LLO), is a hemolytic Listeria enzyme, and useful for this purpose. More than 90 percent of the time that Listeria is engulfed by antigen processing cells, the bacterium is digested and killed, but 5 to 7 percent of the time LLO it secretes creates a pore in the immune cell's digestive vacuole, allowing the Listeria to escape into the cytosol where it can devide andinfect other cells. During this process, LLO is routed for rapid enzymatic destruction within the cell, along with the antigens, which generates antigen fragments that direct a specific immune repose. With Lovaxin C, the fusion protein uses LLO to route antigens to that part of the antigen processing cells that most stimulates an immune response. The result is highly specific, accelerated, high-dose antigen delivery directly to the MHC-1 class 1 pathway, which in turn generates an abundance of activated T cells.

In our clinical experience, intravenously administered Listeria induces a trivial infection that is rapidly cleared with no consequence to the subject, but which because of the fusion protein antigen is primed to generate relevant immune system cells. Patients in early clinical studies have been hospitalized as a precaution, and administered antibiotics to prevent the possibility of a serious infection. We expect that Phase II clinical trials and beyond will operate on an out-patient basis, and potentially without the necessity to administer antibiotics.

Potential Limitations

A possible drawback to Listeria-based vaccines is this microorganism's potential to cause serious infections, especially in immunocompromised cancer patients. Pathogen-based vaccines cannot be administered to immunocompromised individuals, for example, patients with AIDS, women in their third trimester of pregnancy, or transplant patients receiving immunosuppressant drugs, or, unfortunately, to cancer patients who are receiving certain types of chemotherapy. Since Listeria accumulates in the liver and spleen before clearing, individuals with serious liver disease may require a much lower dose.

Intrinsic methodologic limitations with respect to antigen type may limit the types of antigens used in the Listeria vaccine model. Listeria's genome and nucleus limit the size of antigens that can be formulated into Lovaxin-type vaccines. In these situations, it may be possible to break the antigen down into active fragments. Finally, certain antigens are incompatible with Listeria due to their amino acid content or high lipophilicity.

In animal models, we administer an antibiotic that wipes out the Listeria infection within 24 hours of vaccine administration, and still obtain a powerful anti-cancer response through the immune system's anamnestic or memory response. Through this mechanism, dormant, low-population T-cells with a "memory" for a particular antigen clone themselves and expand when confronted with that antigen, even years later. We have found a powerful memory response is still initiated when the Listeria infection is killed within 24 hours of vaccine administration.

Evidence suggests that cancer vaccines may assist in overcoming the inevitable mutations cancer cells undergo to elude the effect of treatment. Vaccines carrying multiple antigen epitopes, or specific antigen regions for which no evolutionary mechanism has been identified, might allow a patient's immune system to combat recurrent malignancies. Similarly, this multi-phase approach can be applied, through successive immunizations, as a type of booster strategy for keeping cancer at bay.

Preliminary Results

Although Lovaxin C might be used as a cancer preventive in at-risk individuals, the primary thrust of this vaccine's development is treating existing cancers. Advaxis has elaborated the Listeria-antigen idea in nine development-stage vaccines for treating cervical, breast, ovarian, prostate, lung, pancreatic, and skin cancers, as well as tumors of the head and neck and HIV. Lovaxin C is currently in Phase I/II testing for cancers of the cervix, head and neck. The Lovaxin platform represents a powerful method for generating immune responses to tumor cells bearing wide-ranging cancer antigens. For example, Lovaxin B, for treating melanoma and breast cancer, targets Her/2-neu, an antigen expressed in 40 percent of breast cancers, 30 percent of melanomas, 20 percent of pancreatic cancers, and 19 percent of gastric cancers. In animal studies we have observed response rates in transplanted tumors of close to 100 percent. Animals that are not outright cured show static or non-growing tumors; and once cured, they appear to be resistant to future cancer growth.

Although the initial clinical trial is in its earliest stages, research thus far suggests that Lovaxin C can be safely administered to late stage cancer patients. We have yet to determine the vaccine's effectiveness. However, the finding that this bacteria-based live vaccine can be administred safely to very sick cancer patients is an encouraging first step.

It is impossible to say at this juncture how long protection will persist after administration of Lovaxin C. Some vaccinations, like DPT, appear to work for the life of the patient while others, for example tetanus vaccine, are effective for eight to 10 years. The persistence of immunity from Listeria-based vaccines will probably depend on the patient's immune response and the type of cancer.

"Patients in early clinical studies have been hospitalized as a precaution, and administered antibiotics to prevent the possibility of a serious infection. We expect that Phase II clinical trials and beyond will operate on an out-patient basis, and potentially without the necessity to administer antibiotics."

Lovaxin C is administered intravenously. Patients in early clinical studies have been hospitalized as a precaution, and administered antibiotics to prevent the possibility of a serious infection. We expect that Phase II clinical trials and beyond will operate on an out-patient basis, and potentially without the necessity to administer antibiotics.


The search for the ideal cancer therapeutic has become a major goal of medical research in the new century. While targeted therapies that focus on mechanisms unique to cancer have begun to turn the tide, much work needs to be done. Cancer vaccines have shown tremendous promise in this regard. With two notable approvals and several more products in development, there is every reason to expect that these agents will, either alone or in combination with traditional surgery, chemotherapy, and radiotherapy, bring us closer to the day when most cancers, even advanced malignancies, are either manageable or curable. �

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