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Dr. David Carbone (right) recently published a study that shows Vascular Endothelial Growth Factor plays a larger role in the progressionof cancerous tumors than was previously thought.

Tumor protector identified.- Study finds VEGF inhibits cancer-fighting dendritic cells

BY: DOUG CAMPBELL

11/15/1996 - Researchers at the Vanderbilt Cancer Center have discovered that a common growth factor plays a larger role in the progression of cancerous tumors than was previously thought.

In an article appearing inthe journal Nature Medicine, investigators show that vascular endothelial growth factor (VEGF) serves as a crucial accomplice in cancer cells' ability to escape the human body's natural impulse to defend itself.

"Cancer patients have a reduced ability to mount immune responses," said Dr. David P. Carbone, associate professor of Medicine and Cell Biology, the study's senior investigator. "Humans and animals with cancer have a reduced ability to mount immune responses. The question is why?

"What we discovered is that, not only is VEGF important in inducing blood vessels to grow into tumors to provide the tumor with nutrients, but it also causes dendritic cells not to work properly."

These dendritic cells play a vital role in the body's immune response to cancer and other invading entities such as bacteria, viruses, etc.

Immune responses require that the target be displayed properly to the T-cells, which do the dirty work of killing the invaders. Dendritic cells are a type of antigen-presenting cell (APC) which present these targets.

"These cells are designed to take tumor antigens and present them to T-cells so that the T-cells can learn how to recognize the tumor antigens and kill the tumor cells expressing that antigen," Carbone said.

The T-cells are, in effect, the soldiers that hunt down and kill the tumor. The APCs are the generals that tell the T-cells what targets to attack. In cancer patients the lines of communication are compromised and the message becomes garbled. Prior to this study it was unclear exactly what was going on. Is it that the soldiers didn't have bullets in their guns? Or is it that the generals didn't know what to tell the soldiers to do?

"What we found is that there is a problem with the generals," Carbone said. "The T-cells were normal in the breast cancer patients and in the animals we studied.

"We found a specific defect in the ability of the dendritic cells to present antigens to the T-cells. We were the first to show that there was a specific problem with these cells."

The next question addressed by Carbone and his colleagues was to determine how the tumor caused this dendritic cell defect, which essentially short circuits the body's ability to mount an immune response.

Dendritic cells are derived from stem cells in bone marrow, the same stem cells often transplanted in cancer patients to help recover from high-dose chemotherapy. In the study, Carbone and his colleagues found that tumor cells made factors which, when cultered with stem cells, made them unable to form functional dendritic cells. The normal formation of the cancer-fighting dendritic cells were essentially blocked by these tumor-derived factors.

"One of the major factors responsible for this block is VEGF," Carbone said. "It protects the tumor from having these antigens presented to the T-cells, and prevents the tumor from inducing an immune response to itself and thus allows the tumor to grow without being attacked by the T-cells.

"VEGF only affects growing dendritic cells. Once you have dendritic cells, they are not affected by VEGF; it only affects the ability of the stem cell to differentiate into dendritic cells."

According to the study, mature dendritic cells from cancer patients don't work, while those from healthy patients work properly. Adding VEGF to these mature dendritic cells has no impact.

"That means that blocking VEGF with antibodies wouldn't fix antigen presentation immediately because all the non-functioning dendritic cells would still be in the body and not affected," Carbone said.

"What it would do is allow a new crop of dendritic cells to come from the bone marrow that would be functional."

The use of a VEGF-blocking antibody is one way to possibly get the dendritic cells and T-cells communicating again to kick-start the body's immune system.

"There is an antibody being prepared for human use which blocks VEGF action in patients. It's possible that this antibody could not only prevent blood vessels from growing into tumors, which would limit their growth rate, but it could also potentially block the effect on stem cells, which will allow the body to reject the tumor by activating the dendritic and T-cells, which could then kill the tumor," Carbone said.

A clinical trial using this method is currently being planned.

Another way to perhaps circumvent VEGF's ability to inhibit immune response is to allow the stem cells to form dendritic cells outside the body.

"We plan to take out the stem cells from cancer patients and culture them outside the body into dendritic cells, then use these to immunize the patients to induce an immune response," Carbone said.

"Our lab findings suggest that this will be an effective method. Using this procedure, for the first time we've been able to take animals with palpable, pre-existing tumors and see a clinical response. If immunized with normal dendritic cells or dendritic cells from tumor-bearing animals that have been grown outside the body, we can dramatically prolong the survival of these animals."

Carbone and his colleagues are cautiously optimistic about the possible ramifications of this study.

"We think it is very promising. In these models (antibody or dendritic cells cultured outside the body) the treatment only halts the progression of the tumor. But it's possible that adding this approach to standard chemotherapy, radiation or surgery could lead to cures that wouldn't have otherwise occurred," Carbone said.

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