Wednesday, December 1, 2010

A scientists explanation of the breast cancer vaccine research

Dear Uschi,

Unfortunately, there is not really a simple way to explain what we do in a very concise way that is both accurate and can be easily understood by non-scientists. However, I shall do my best.

If T lymphocytes are the fighting generals of the immune system, dendritic cells act as the reconnaissance scouts. DCs like to take up station at sites of anatomical barriers, i.e. where the "inside" meets the "outside", (the skin, mucous membranes, alimentary canal). Here they wait for two things, signs of infection and/or inflammatory tissue damage. The surface of DCs are studded with specialized receptors, which act as sensors for infection or inflammation. When they contact such signals, a specialized maturation/activation/migration program is initiated. DCs collect a "snapshot" of the proteins present in the environment of the activation signals (such as protiens from an infectious agent), gain acces to draining lymphatic vessels, and travel to the lymph nodes. The lymph nodes are populated by many T lymphocytes. The DCs seek out T cells and "present" the proteins acquired at the peripheral sites. The T cells then become activated by the DCs and then go out on a "search and destroy" mission to eliminate anything that resembles the proteins presented by the DC (such as a bacterium infecting the body). Now here are the reasons why we think our approach is giving us superior results. Please note in many cases, we were not the first to try some of these things (though in certain instances we were), but mostly it is the fact that we assembled a number of innovatons into an integrated strategy.

1) All vaccines used (like a standard tetanus shot) rely on the material provided by the immunization to be picked up by DCs for presentation to T cells. However, we believe that the sort of immune response needed to eliminate tumors is so intense, and of a particular type that the best way to achieve it is to actually culture large numbers of the DCs outside the body and then administer them already "loaded" with the vaccine proteins.

2) We activate the DCs in a special way that mimicks infection. We use a special preparation of a compound that makes up the cell wall of bactieria called lipopolysaccharide (LPS). One of the sensors on the surface of DCs specifically recognizes LPS leading to their activation. We think that by "fooling" the DCs into believing they are under attack by a microbe, the response they generate will be particularly strong. We are the first to use LPS to activated DCs in a clinical trial. We believe that other methods to activate the DCs do not allow for maximal function.

3) We think that soluble products produced by the DCs supply special signals to T cells that allow them to be particularly effective against cancer. Brian showed that one of these soluble products, called Interleukin-12 (IL-12) endowed the T cells with the capacity to recognize and kill tumors in the test tube. T cells that were sensitized by DCs incapable of producing IL-12 could not recognize or kill tumor cells. Most other investigators trying to produce anti-cancer vaccines under-appreciate the need for IL-12. By combining LPS with another cytokine called interferon gamma (IFN-g), the DCs can produce large quantities of IL-12. Most other methods of producing DCs for vaccination will not induce them to produce IL-12.

4) We inject the DC vaccines directly into the lymph nodes. Most others inject the DCs at distal locations with the expectation that the DCs will migrate to the nodes on their own. In fact, only a very small proportion of cultured DCs actually make thier way to lymph nodes after injection. So people who do not inject directly into the nodes are cheating themselves of the best possible immune response.

5) We harvest the vaccine DCs at a time point where they are making maximal amounts of IL-12. The DCs follow a very precise program after activation and only make IL-12 for a very short window of time. Supplying the DCs too early or too late will squander the benefit of IL-12. Most other investigators give no thought to the kinetics of cytokine production and only supply DCs long after they stop making such products.

6) We specifically target cancer proteins that are associated with the tumor's ability to cause disease. HER-2/neu is a poor prognostic indicator. HER-2/neu over-producing tumors are more likely to recur after surgical resection, are more likely to be invasive and metastatic, and can be resistant to some front-line chemotherapy agents. We target such proteins so that if we are lucky, all of the tumor is killed. If we are slightly less than lucky, we can cull the tumor of the most dangerous cells leaving behind a residuum of disease that is less aggressive, more indolent, and more amenable to other therapies.

7) We target early disease. Most vaccines of the past have targeted later stage disease. This is because experimental therapies are usually supplied only when the conventional therapies have failed (hence the patient is further along in course of disease). This causes a number of problems. Late stage patients are sicker, often have little time to live, have large volumes of tumor needing to be destroyed, pre-treatment with radiation and chemo can negatively impact the bone marrow (and hence immune system), and advanced tumor are known to play tricks to turn off the immune response. For all of these reasons, we want to make vaccine therapy the first line of defense rather than the last line of defense. We hope to get to a point where vaccine therapy is used first, followed by surgery, and then, if necessary, radiation and or chemo (concentrating on techniques that do the least damage to immunity). It is also important to note that with advances in screening, we are likely in the future to catch tumors earlier and earlier. So our new therapies should be targeted here rather than late-stage disease. This does not mean that vaccines could not have benefit in later disease. But we should optimize them on early disease first before trying them out on later disease.

8) There are two types of T cells, so called "helper" T cells (Th) and the "Cytoxic" T cells (CTL). For a variety of historic reasons an excessive emphasis has been placed on CTL. Many vaccine attempts have focused exclusively on CTL, ignoring Th. We have formulated an approach that specifically recruits Th as well as CTL. We think this greatly enhances vaccine efficacy.

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