NEW IMMUNOTHERAPEUTIC APPROACH FOR GLIOBLASTOMA

New Immunotherapy Approach to Be Tested in Glioblastoma

January 15, 2009 — A new immunotherapy approach to the treatment of glioblastoma has shown promise in animal studies and is due to be tested in patients later this year. The strategy involves injecting adenovirus vectors directly into the tumor-tissue cavity after resection, and the results from a mouse model suggest a potential for cure, says the lead researcher, Maria Castro, PhD, from the Cedars-Sinai Medical Center in Los Angeles, California.

The research was published online January 13 in PLoS Medicine.

Glioblastoma multiforme is a particularly aggressive cancer, and better treatments are badly needed, according to an editor's summary of the paper. One avenue that is being explored is immunotherapy, but past attempts to induce a clinically useful anti-tumor immune response in glioblastoma have been unsuccessful, it notes. In part, this is because the brain contains very few dendritic cells, which "kick start" effective immune responses by presenting foreign particles to other immune system cells. Another barrier is immune evasion, in which tumors find ways to avoid immune responses, such as by reducing the expression of proteins that would be recognized as foreign.

The new approach involves a 2-pronged strategy to overcome both of these problems. The researchers developed adenovirus vectors expressing 2 different proteins — Fms-like tyrosine kinase 3 ligand, which attracts dendritic cells into the tumor, and thymidine kinase, which kills tumor cells and causes them to release tumor-cell antigen. This antigen is the trigger for the immune response, Dr. Castro explained; it reacts with the dendritic cells and the complex drains into the lymphatic system, where it mounts a systemic anti-tumor immune response, leading to the release of cytotoxic T lymphocytes, which then kill the tumor.

"This is a very powerful approach," Dr. Castro said. These killer cells will destroy the tumor and, because they have memory, they will act on any new tumor cells that reappear.

Improved Survival

In a mouse model of glioma, this approach "shrank the tumors and greatly improved the survival of the mice," notes the editor's summary. Dr. Castro said that the untreated mice died within 1 month of tumor implantation, but 60% of the treated mice were still alive after 6 months. All the animals were sacrificed at the end of the study, but they would have continued to live indefinitely and they appeared to have been cured, Dr. Castro commented.

The editor's summary cautions that results from such mouse models do not always lead to effective treatments for human patients, but states: "Nevertheless, the findings from this study provide new insights into how an effective immune response against brain tumors may be brought about."

Dr. Castro told Medscape Oncology that, in addition to the mouse model of glioma described in the paper, her group has also shown that the technique is effective in 4 different rat models of glioma and in a mouse model of brain metastases from melanoma and lung cancers. Human trials are planned to start in mid-2009, with an early-phase study in patients with respectable recurrent glioma. The adenovirus vectors are stored in a frozen vial, and are injected directly into the tumor tissue after the resection. "This is very straightforward from a practical point of view, and it can be done anywhere in the world, providing you have neurosurgical skills," she added. The hope is that the immunotherapy will destroy any remaining tumor, and also prevent any further recurrences, Dr. Castro explained.

The discovery of the mechanisms involved in "overcoming immune ignorance to brain tumor antigens provides a new therapeutic approach in the fight against brain tumors," commented senior coauthor Pedro Lowenstein, MD, PhD, director of the Board of Governors Gene Therapeutics Research Institute at Cedars Sinai Medical Center. "Our conclusions relating to anti-glioma immune responses have also been extended to enhancing immune responses against a number of other metastatic brain cancers, such as melanoma," he said in a statement.