Antigen-Carrying Bacteria Prime Immune System Against Melanoma

Newswise — Therapeutic cancer vaccines, while still mostly in early development, are one of the more promising developments in medicine today. A study published in the October 1, 2008 edition of the journal Cancer Research reports some of the most promising results to date on a therapeutic cancer vaccine. Originally targeted to a deadly form of melanoma, the vaccine is broadly effective against a range of common cancers.

Researchers, including Dr. Paulo Maciag of North Brunswick, New Jersey-based vaccine biotechnology firm Advaxis, and scientists from the University of Pennsylvania School of Medicine in Philadelphia and the Hillman Cancer Center in Pittsburgh, describe powerful immune-mediated anti-tumor responses in laboratory mice implanted with melanoma tumor cells. Investigators used an experimental vaccine discovered at the University of Pennsylvania and under development at Advaxis, which is constructed by fusing an antigen found on the surface of melanoma cells with a protein from the common environmental bacterium, Listeria monocytogenes.

Researchers bioengineered a Listeria strain to express a recombinant molecule consisting of a fragment of the high molecular weight melanoma-associated antigen (HMW-MAA) fused to a fragment of listeriolysin O (LLO), a virulence factor Listeria uses to infect cells of the host.

HMW-MAA is overexpressed in other cancers beside melanoma, including; basal cell carcinoma, nervous system tumors (astrocytomas, gliomas, neuroblastomas), childhood leukemias, and breast cancers. HMW-MAA is apparently involved in the adhesion, spreading, and migration of cells and therefore implicated in tumor metastasis.

In theory, an immune system primed against the antigen could destroy cancer cells carrying the antigen. HMW-MAA is also expressed in activated pericytes, which are important for inducing and supporting blood vessels to grow within tumors and support cancer growth.

When ingested by antigen-presenting cells, Listeria secretes the LLO-antigen fusion protein, which after a series of events is recognized by the immune system which activates killer T-cells and a population of the specific immune cells that destroy cancer cells bearing the same antigen.

Investigators tested the vaccine in mice that were transplanted with a melanoma cell line. Animals were vaccinated three, ten, and seventeen days after implantation. Control groups received a sham vaccination or were unvaccinated. Tumors developed and grew rapidly in untreated mice, but significant anti-tumor immunity was noted in animals that had been vaccinated. Fifty-six days after immunization, five of eight mice in which tumors were implanted prior to treatment were tumor-free. Moreover, when tumor cells were implanted a 2nd time in the tumor free responders new tumors did not grow.

Interestingly, both CD4+ and CD8+ T immune system cells were required for the vaccine to have an effect. The vaccine did not shrink tumors in mice whose CD4+ or CD8+ cells had been depleted by antibody treatment. In one experiment, CD8+ cells harvested from healthy vaccinated mice significantly reduced the ability of melanoma to take hold in a group of unvaccinated mice. This proved that immunity arose from the immune system, and could be transferred to vaccine-naïve animals.

Surprisingly, the vaccine also significantly impaired the growth of non-targeted cancer cell lines derived from kidney and breast cancers, which do not express HMW-MAA.

What could be responsible for this cross-immunity?

Dr. Maciag and his team hypothesized that the vaccine might be targeting pericytes, which are important for angiogenesis in a wide range of tumors. For example in the breast tumor experiments, immunization caused CD8+ T-cell infiltration into the tumor, and a significant decrease in tumor vascular growth as a result of the decrease in the number of pericytes in the tumor blood vessels.

Listeria is an ideal organism for antigen presentation. On its own, the bacterium "primes" the immune system by inducing a strong cell-mediated immune response. It achieves this by preferentially infecting antigen-presenting cells that activate the immune system and present specific antigens for the immune system to attack. Since Listeria is a bacterium, it also stimulates innate immunity, which involves non-specific activation of the entire immune system to support the "adaptive" immune response. Listeria also stimulates a cytokine cascade. Interestingly, Listeria that deliver LLO-antigen fusions can reduce the source of immune inhibition (called regulatory T cells) that are believed to prevent some immunotherapies from resulting in a therapeutic effect. Together, these immune-stimulating mechanisms provide a directed, powerful cellular immune response capable of killing cancer cells.

This study is the first time HMW-MAA has been used as an anti-angiogenic target for treating cancer. Anti-angiogenesis is a mechanism proposed decades ago for fighting cancer by starving tumors of their blood supply. The blockbuster drug Avastin is an anti-angiogenesis agent. One benefit of targeting this HMW-MAA is that attacking it does not appear to impair wound-healing, which is dependent on angiogenesis, as the research team demonstrated in the Cancer Research paper.

According to Advaxis VP of Clinical Development John Rothman, Ph.D., his company has filed a patent on a process to develop the HMW-MAA-Listeria vaccine by adding more than one fusion protein to a single Listeria vaccine.. "A two-antigen vaccine would enable us to target a different antigen on tumor cells as well as angiogenesis mechanisms common to many tumors simultaneously, with a single vaccine," he said. For example, the combination of HMW-MAA and prostate-specific antigen (PSA) could be used to attack prostate cancer, or an HMW-MAA-HER-2/neu vaccine might be effective against breast cancer.

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