Genetically Modified Dendritic Cells Enhance Immune Response

BUFFALO, NY--Some researchers are beginning to think of cancer as a chronic inflammatory disease, and new research shows that patients with increased numbers of dendritic cells as part of their immune response to their tumor have a better prognosis.

"With a chronic inflammatory response to tumor, we see a profound increase in inflammatory cells, including lymphocytes and dendritic cells. Our goal is to put these dendritic cells, suitably modified, directly into the tumor to enhance the immune response," said Michael T. Lotze, MD, chief of Surgical Oncology, University of Pittsburgh Cancer Institute, at the first meeting of the Regional Cancer Center Consortium for Biological Therapy of Cancer, hosted by Roswell Park Cancer Institute.

One experiment involved the human papilloma virus (HPV)-induced murine C3 tumor line. Cells from the tumor were treated with dendritic cells pulsed with an HPV16 tumor antigen. Initial results showed a regression of the C3 tumor and induction of long-term immunity to that tumor. Subsequent challenges by the C3 tumor antigens were rebuffed.

"One difficulty with this line of research is the apoptosis of dendritic cells induced by the tumor cells themselves. We know that murine tumors can cause apoptotic death (programmed cell death) of both human and murine dendritic and T cells," Dr. Lotze said. "We have evidence that tumor cells can begin to destroy dendritic cells within 15 minutes of exposure [see figure]."

In another study, a male patient with melanoma that had metastasized to his liver, lung, and spleen received intravenous injections of interleukin-2 (IL-2) and had a complete response. After 2 years, another metastatic site was found on the patient’s tonsils that was no longer responsive to IL-2 therapy. The tumor was resected and treated with gamma knife irradiation.

He recurred in a submandibular lymph node, which shrank to less than 10% of its original size after four weekly injections of IL-12-transfected autologous fibroblasts. This site was resected, as called for in the protocol, and the patient was again clear of tumor for 2 years.

Brain Mets Are the Achilles’ Heel

"This patient did quite well on the therapy we selected. However, when he presented with a solitary metastatic brain lesion, this therapy was no longer a viable option, and he underwent gamma knife irradiation to this site. Brain metastases are the Achilles’ heel of biological therapy," Dr. Lotze said.

The next line of dendritic cell research involves modifying the dendritic cells and, in turn, protecting these cells from the tumor with IL-12 transfection. A study was performed in which dendritic cells expressing IL-12 were injected directly into murine tumors. After a single injection, two of five animals were tumor free. Subsequent research is attempting to determine how many additional injections are needed to boost this response rate.

Dr. Lotze said that clinical trials should begin this spring with genetically modified, IL-12-transfected dendritic cells.