Pretreatment with a dendritic cell vaccine appears to make glioblastoma multiforme tumors more sensitive to chemotherapy, according to an article published online and in the August print issue of Oncogene.

This finding builds on several studies recently published by the same research team. In 2003, the American researchers reported that a protein fragment previously found in melanomas also was detected in glioblastoma multiforme GBM. The immune system recognizes the peptide, tyrosinase-related protein (TRP)-2, as an antigen, making it a significant target for immunotherapy.

“Our findings suggest that TRP-2 could be a powerful molecule linking chemotherapy and immunotherapy,” said Keith L. Black, MD one of the paper’s authors, director of the Maxine Dunitz Neurosurgical Institute and director of the medical center’s Division of Neurosurgery and Comprehensive Brain Tumor Program.

“Based on our results, it appears that we can improve chemotherapy sensitivity by targeting TRP-2 and possibly other drug-resistant related tumor antigens. This may be a significant step in the fight against brain tumors and other malignant cancers because even as we have been able to develop very powerful and targeted chemicals, tumors have often been able to outmaneuver them,” said Black.

In 2004, the researchers documented that the combination of immunotherapy and chemotherapy significantly slowed tumor progression and extended survival of patients suffering from these malignancies. The two therapies together were able to accomplish results that neither could achieve by itself. The average length of survival was extended to about 26 months compared with 18 months for patients who received vaccine alone and 16 months for those undergoing chemotherapy alone.

Taking into account recent articles identifying TRP-2 as a contributing factor in the ability of tumor cells to mutate and resist a variety of therapeutic drugs, the research team now offers an explanation for the relative effectiveness of this two-wave, vaccine-chemotherapy assault. The first attack comes from the dendritic cell vaccine that is specially formulated to search and destroy tumor cells that contain TRP-2. It clearly launches cytotoxic T lymphocytes, which diminish or deplete the number of TRP-2-containing tumor cells. Other tumor cells survive, however, and continue to proliferate. But because they lack TRP-2 and therefore the ability to develop drug resistance, they are vulnerable in the follow-up assault of chemicals targeting their DNA.

John S. Yu, MD, senior author of the paper and co-director of the Comprehensive Brain Tumor Program, said lab results confirmed a strong immune response to TRP-2 in patients’ blood cells after vaccination, and cells removed from tumors after vaccination had significantly lower TRP-2 expression than did those removed earlier. Furthermore, the post-vaccine tumor cells were much more sensitive to anti-tumor drugs carboplatin and temozolomide.

“It is important to note also that four patients in our study that demonstrated a response to TRP-2, after tumor recurrence, responded to chemotherapy with what oncologists call complete responses, which means the tumors were no longer visible on magnetic resonance imaging,” he added. “This was a small initial study and it will be very interesting to see if similar results will be repeated in larger numbers.”