There are four main types of vaccines in trials:
DNA vaccines
Idiotype "Protein" vaccines
Dendritic cell vaccines
Heat shock proteins vaccine
In all cases there is need for tumor cells, collected usually by lymph node biopsy and the vaccine is made specifically for each patient.
The DNA vaccines are the simplest to explain but they are also the least studied. To prepare these vaccines RNA is extracted from a tumor sample (node or even FNA-Fine Needle Aspiration), the RNA corresponding to the idiotype protein is identified and sequenced, and that sequence is integrated into another piece of DNA (vector). The vector containing the sequence for the idiotype protein is injected in the patient's arm or leg.
The hope is that somehow the patient's immune system will start to recognize the idiotype protein as strange. As far as I know, no results have been published concerning trials in lymphoma patients with these vaccines. However, studies in animal models strongly suggest that they will be effective. If they become effective this will be a major advance as they are "very cheap" by comparison with the remaining types.
The Idiotype "protein" vaccines (I am giving them this name, but they are worldwide referred only as the idiotype vaccines, because they were the first to be developed and for a many years they were the only available). The initial procedure is exactly as described before. However, instead of injecting the vector with DNA into the patient's arm or leg, the vector is put inside of a bacteria (transformation) or a virus. There are bacteria (or virus) will them produce a lot of Idiotype protein that the scientists will collect and inject in the specific patient.
Note: there are many ways of producing protein and I am not trying to explain all. Also, the original process used in the first trial published by Dr. Levy was much more complicated. These idiotype vaccine have already produced dramatic long-term clinical remissions for patients with NHL (Hsu FJ. Caspar CB. Czerwinski D. Kwak LW. Liles TM. Syrengelas A. Taidi-Laskowski B. Levy R.Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma-long-term results of a clinical trial. Blood. 89 (9):3129-35, 1997).
Furthermore, one study has shown that the idiotype vaccination can induce even molecular remissions (a hope for a cure) (Bendandi M. Gocke CD. Kobrin CB. Benko FA. Sternas LA. Pennington R. Watson TM. Reynolds CW. Gause BL. Duffey PL. Jaffe ES. Creekmore SP. Longo DL. Kwak LW. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.
Nature Medicine. 5 (10):1171-7, 1999 Oct.).
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The dendritic cell vaccine is the most complex and expensive process. It is also probably the most promising. However, because of the costs and because it requires a more advanced technology is only being studied at very specific places and the number of patients accepted
in these trials are even smaller than in other vaccine trials.
The first part of the process is essentially the same as described for the "protein" vaccines however after the idiotype protein is collected from bacteria this protein is used in vitro to stimulate the patient's dendritic cells. Dendrite cells circulate in our blood and can be collected by apheresis.
Dendritic cells alert the immune system of any bacteria or viruses that are in a person's body. In the dendritic vaccine patient's dendritic cells are collected, grown in a solution that contained large amounts of patient's idiotype protein (made in bacteria, for example). Therefore, these cells are "educated" in vitro to recognize the patient's idiotype protein as foreign and reinfused into the patient.
The dendritic vaccine has shown to be effective even if the patients do not obtain CR (Hsu FJ. Benike C. Fagnoni F. Liles TM. Czerwinski D. Taidi B. Engleman EG. Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nature Medicine. 2(1):52-8, 1996 Jan.).
Important: Theoretically, these vaccines may help in any patient with a lymphoma derived from a B-cell. Although most of the studies published and clinical trials concer follicular NHL, similar trials are also including intermediate grade, mantle cell lymphoma and others.
Heat Shock Proteins Vaccine "The versatility of heat shock proteins in the treatment of cancer derives from their normal physiological role in cells. HSPs play a role in protein trafficking, whereby they keep other proteins in their correct shape and location. When these molecular chaperones are purified from cells, they bring along with them small fragments, or peptides, derived from other proteins expressed in that cell, providing a molecular "fingerprint" of the cell's content. Vaccination with the HSP-peptide complexes purified from cancer cells has the potential to specifically stimulate the immune system to attack cells bearing those peptides, i.e., the cancer cells themselves." Source: slip.net/~mcdavis
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Below is a technical subject explained in plain language by Lurdes. Different methods have been developed to create a vaccine that can "teach" the immune system about a specific protein target on the patients tumor. The idiotype is a good target protein because it's not expressed anywhere else but on the patient's tumor cells. The job of isolating this protein and fusing it with another molecule called KLH is an exceptional technical feat. The following description by Lurdes explains that the idiotype itself is complex and has multiple targets within it. -Karl
Polyclonal can be very confusing because it may signify different things.
An immune response against most proteins is usually polyclonal. David was talking about a protein as a string of beads. Imagine that a specific Id from patient A has 5 blue beads followed by 5 red beads followed by 5 green beads. If each stretch of 5 beads is immunogenic an immune response composed of 3 different antibodies (one against green, another against red, another against blue) might occur. Because there is more than one antibody it is called polyclonal.
Imagine now that patient A has more than one type of Id (her tumor has different clones). In this case even if a single antibody is made for each different Id, the response is called polyclonal.
Therefore, when someone tells you that their vaccine has a polyclonal effect you need to ask "is that against different Ids or against different parts of the same Id?"
This is extremely important if a patient has more than a single Id. The original vaccine was derived from a hybridoma, it was only against a single Id, but it was against several different parts of that Id. That's why is was called polyclonal.
In my mind the most important thing is that a vaccine is able to produce an immune response against the different parts of a given protein. For example, let's take the specific Id I described before (5 beads blue, 5 red, 5 green). When a patient has different Ids, they raise by mutations in previous Ids. Let's say one blue bead changed to a black bead. If that was the case the antibodies made against the blue beads might not recognize this mutant, but the antibodies made against red and green will still recognize the mutant protein.
Another comment: The reason why the "old vaccine" is not being followed is because it is extremely time consuming, expensive and has a high rate of failures. Furthermore, it might be worse than some of the "new vaccines". Both the Genitope and Favrille are in my opinion highly promising. However, as you said we do not have data. We are the "mice". One can choose to wait until data is available or until he/she progresses, but that can be too late. Alternatively, one can take the risk of taking a vaccine that does not seem to have major risks but might do nothing. Each of us need to weight the pros
and cons.
- Lurdes Q
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