How the German Dendritic Cell − Tumor Cell Fusion Vaccine Works
Before You Start
The National Cancer Institute’s Cancer.gov has an that is good background reading for this explanation. (Note: Links will open in new window)
Be aware that the fusion vaccine discussed here is somewhat different from the vaccines described at the CancerTrials site. I would also ignore the statement there that vaccines might not work well in advanced cancer, since it appears that this vaccine is working in advanced cancer, and also because vaccine research is very young – who knows what innovative new approaches, like this one, might do!
How the German Fused Dendritic – Tumor Cell Vaccine Works
The German vaccine is a very clever way of getting the immune system to recognize and respond to your tumor. To understand it you need to understand something about the immune system.
The immune system is an astoundingly complex and wonderful system – perhaps second only to the brain in complexity and mystery. It has many different pathways, mechanisms, and feedback loops that enable it to recognize and destroy highly evolved invaders like bacteria, viruses, and parasites… and sometimes tumor cells – without destroying the normal healthy cells which make up your body. I am not an immunologist but I have tried to understand enough about how this dendritic cell vaccine works to be able to give you an idea of how it works. But there’s also a lot I don’t understand. If you happen to be a scientist reading this and can answer any of my questions I solicit your comments!
Antigens and Normal Antigen Display
The immune system attacks things it recognizes as foreign. This recognition involves binding to very specific molecular sequences called “antigens”. Antigens are commonly proteins, or more specifically small parts of proteins.
The cells in your body process bits of the proteins inside them and display them on their surface (the cell membrane) bound to special presenting proteins called MHC or HLA. When a virus infects a cell, it takes over the cells protein manufacturing equipment to make viral proteins which are assembled into new viruses. One of the defenses of the body is that the infected cell presents these viral proteins on its surface where it can be recognized by cells of the immune system, including cells called cytotoxic T-Cells, which bind to cells displaying foreign antigens and send them a signal telling them to self-destruct. Tumor cells may also make abnormal proteins and can also be destroyed in this way. If the immune system can recognize and respond to an abnormal protein displayed on the tumor cell’s surface, that is.
Cytotoxic T-Cells each recognize exactly one specific antigen – if they recognize their specific antigen on the surface of a cell, they bind and send the self destruct signal. But it turns out that cytotoxic T-Cells need to be “activated” in a special way before they will kill infected or cancerous cells. Once cytotoxic T-cells are activated, they will not only kill cells displaying the antigen they recognize, but they will also multiply. Cytotoxic T-Cells are activated by encounters with special immune cells called Antigen Presenting Cells.
Antigen Presenting Cells (Including Dendritic Cells)
There is another class of immune cells called “Antigen Presenting Cells” (APCs) which “eat” possible foreign matter that they encounter in their environment. Dendritic cells are a type of antigen presenting cell. (Immune cells you may have heard of called macrophages, which are often portrayed as “scavenger cells”, also act as antigen presenting cells).
When an antigen presenting cell eats something, it processes it and displays possible antigens on its surface in a way that is similar to how all cells display samples of what is inside them. APCs also display special “co-stimulatory” proteins on their surface.
When a cytotoxic T-Cell encounters its antigen on an antigen-presenting cell, it binds to both that and the co-stimulatory protein. It then becomes activated and is ready to actually destroy cells it encounters which display its specific antigen. The activated cells are also stimulated to multiply.
Cytotoxic T-Cells normally reside in immune tissues like the lymph nodes. When APCs enter a lymph node, and an antigen is recognized, an army of specific killers is created which goes forth from the node to do battle with the enemy.
Another class of T-Cells called “Helper T-Cells” is required to generate a effective an cytotoxic T-Cell response. It is less clear to me exactly what role these cells play – but they are the immune cells which are destroyed by the AIDS virus. And when they are gone, the result, as we all know, is a total failure of the immune system. So they are critical. They also play an important part in the immune response generated by this vaccine – one which I am still trying to understand.
The Helper T Cell has a specific antigen and also binds to antigen presenting cells at the same time as the cytotoxic T-Cell.
Anyway, the helper T-Cell generates a variety of immune regulating proteins called “Cytokines” – different types of helper cells generate different profiles of cytokines which stimulate and regulate the immune response. One important cytokine generated by helper cells is Interleukin-2, which stimulates T-Cell growth, including growth of cytotoxic T-Cells, and which is also a major treatment for advanced renal cell cancer. But IL-2 is only one of many cytokines the helpers make. Helpers can actually generate different sets of cytokines which apparently help direct the immune response towards either a cellular response (what we want here) or an antibody dominant response.
As I say I have many questions about why the helper cells are really necessary and how they “decide” which way to direct the immune response. There is a lot I don’t understand in this area! What I do understand is that the stimulaton provided by the helper cells is required for an effective immune response.
The vaccine is made by fusing tumor cells from the patient with dendritic cells isolated from unrelated donors in the lab with a technique that has been used for many years to join cells to create such cellular hybrids (Note that cells from an unrelated donor are said to be “allogenic”, while cells from the patient are said to be “autologous”). When the cells are fused they share one cell membrane. Once the cells are fused, the tumor antigens are now inside this hybrid cell which still functions as an antigen presenting cell. It is as if the dendritic cell ‘ate’ a tumor cell. Now it will present proteins from this tumor cell on its surface. Notice that we don’t have to know exactly what these antigens are in order to create an effective vaccine. Actually there may be many different important antigens. Different cancer cells from the same tumor may have different antigens. Without knowing what any of them are, they are now presented on the surface of these hybrid dendritic cells – ready to stimulate an immune response against your tumor! Pretty neat, eh?
The fused cells are then subjected to radiation (I am not sure of the purpose of this step, but I suspect the radiation renders the cells incapable of dividing, but does not kill them. This is presumably a safety measure.) and finally are injected into the patient near lymph nodes in the groin. Once in the patient these hybrid antigen presenting cells can stimulate an tumor specific immune response in the lymph nodes which send forth an army of tumor killers as I’ve already described.
Why Unrelated Donors?
A very interesting, and to me puzzling aspect, of this therapy is that the they used allogeneic rather than autologous dendritic cells. This turns out to be a mechanism for getting a response similar to that normally generated by helper T-Cells, but without requiring antigen specific helper cells. Why this is desirable is not at all clear to me, but it works like this: The unrelated donors are specifically selected to have an incompatible “tissue type” to the patient. These dendritic cells then are seen by the patient’s immune system as foreign in their own right and attract T-Cells which respond to the foreign antigen. They then generate stimulatory cytokines in a way that is similar to how the helper T-Cells generate them when they see their antigen on the presenting cells. So helper t-cell like stimulation is generated without needed specific helper T-cells.
It turns out that “tissue type” is determined by the type of HLA/MHC protein you produce. These are the same antigen presenting molecules that dendritic and normal cells use to present antigen on their surfaces! It turns out there are different variants of these proteins which are inherited. These are actually the same proteins which determine if an organ or marrow transplant from an unrelated donor will be rejected. It is virtually guaranteed that you have T-Cells which will respond to cells displaying foreign HLA on their surfaces, so this method should predictably produce the desired helper cell like response. The authors hint that this is more dependable than depending on a specific T-helper response, as would be required if the patients own dendritic cells were used, but it’s far from clear to me why. My understanding is that these hybrids will present tumor antigen on native MHC molecules using MHC from the tumor cells (!) as well as displaying the foreign MHC from the foreign dendritic cell.
Some of the things that puzzle me about this include:
- Why doesn’t the patient’s immune system actually destroy the foreign hybrid cells themselves? After all they are recognizable as foreign!
- What exactly is the advantage of using foreign dendritic cells rather than native ones in the first place?
The researchers vaccinated the patients multiple times. One hint as to the answer to my first question is that they deliberately used different HLA types for each vaccine. This was apparently out of a concern that the patient’s immune system would recognize and destroy subseqent administrations of vaccines containing the same foreign HLA markers as previous shots. It may then be that this type of immune response develops slowly enough that the tumor immune response can take place before the immune system reacts with full force to the foreign HLA antigen, but that if the patient is re-challenged with a foreign HLA antigen the immune system “remembers” the previous encounter and responds rapidly, destroying the vaccine before it can serve its intended function.
The B-Cell Vaccine
B-Cells are normally thought of as antibody producing cells, but apparently at least some B-Cells can also act as antigen presenting cells. And that was the premise behind the use of B-Cells in this vaccine. Dendritic cells specialize in antigen presentation and are thought to be more effective than B cells. which might account for superiority of the dendritic cell vaccine over the B- Cell vaccine (if indeed it really is superior).
The other “rub” with the B-Cell vaccine was that some of the patients were treated with a vaccine made of renal cancer cells from other patients. That there were responses to this suggests that different patients may share similar tumor antigens. That the response to vaccines made from other patient’s tumors actually looked better than with vaccines made from the patients own tumor is surprising and to me unexplained. With the small number of patients treated it’s possible the seemingly better results were just due to chance.
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: 2000, Last Updated: December 30, 2002