Patient-specific therapeutic vaccines for non-Hodgkin's lymphoma
Faculty Disclosure: John M. Timmerman, M.D.
The presentation by Dr Timmerman includes discussion of vaccine therapy that has not been approved by the FDA and the use of GM-CSF as an off-label indication.
Presenter: John M. Timmerman, M.D.
Despite radiation therapy, chemotherapy, bone marrow and stem cell transplants, and molecularly directed therapies, the majority of non-Hodgkins lymphomas are not cured and they often prove to be fatal. B-cell lymphomas, especially follicular lymphoma, may be one of the cancers most responsive to immunotherapy These cancers have been shown to undergo spontaneous regression, they respond to non-specific immune activators, and they have a high rate of response to monoclonal antibodies.
Idiotype vaccines have been used with responses in the past. The term idiotype refers to the collection of unique antigens specific for B cell lymphomas. These surface immonoglobulins are the only markers unique to each B-cell. As lymphomas represent the monoclonal amplification of these B-cells, these surface antigens are maintained in B-cell lymphomas. Hence, these antigens can be used as attack points for immunotherapy. The advantages of using idiotype vaccines are that the therapy is truly specific to the cells targeted, there are multiple targets to attack as there are multiple antigens, and the effects of therapy can be long-lasting as there is an immune memory created.
There have been three major studies investigating idiotype vaccines. The first, done at Stanford, used a biopsy specimen of the follicular lymphomas, fused with myeloma cells to obtain the idiotype proteins (the "id"). These were then paired with a carrier protein from an animal source to induce an immune reaction. Although there were no side effects of this therapy 50% actually developed an immune response. In those with a response, there was a higher overall response to therapy and an increased survival. This led the investigators to search for a more potent method of producing an immune response. This was done by incorporating the antigen presenting dendritic cells into the vaccine. Using this method in 10 patients, tumor regressions were noted in 4/10 patients, including 2 responses that have now lasted over 5 years. Using this method in an additional 23 patients in first remission following chemotherapy, noted were responses in 65% of patients (Timmerman, Blood, 2002). This was then taken a step further by administering GM-CSF along with the antigen. GM-CSF attracts dendritic cells and other antigen-presenting cells to sites of idiotype vaccine injection, making an immune response even more likely. The NCI used GM-CSF with five idiotype vaccines in 20 patients in their first remission following PACE (prednisone, adriamycin, cyclophosphamide, etoposide) chemotherapy. Elimination of residual disease occurred in 8/11 patients.
These studies provided the rationale for two phase III studies currently underway. The first, sponsored by Genitope, is using CVP chemotherapy x8, followed by the administration of idiotype vaccine with GM-CSF (investigational arm) or the administration of the carrier protein only. The second study, sponsored by the NCI, is using idiotype vaccine with GM-CSF following PACE chemotherapy with the same control arm. The results from these studies are expected in 2005-2006.
Idiotype vaccines represent a possible step forward in treating indolent lymphomas. It is a truly personalized therapy with virtually no toxicity. The phase III trial results are eagerly awaited. Although this may cause a response in many patients, the response and clinical outcome will need to be verified with long-term follow up. As is well-known with follicular lymphoma, the natural course of disease is a waxing and waning smoldering course that often requires up to 20 years or longer to know if the patient is cured. There are many intercurrent deaths within this time period, making the future results of this therapy even more difficult to interpret. That being said, the responses are impressive and the downside (toxicity) minimal. The results are anticipated and hopefully the methods can also be translated into the treatment of more aggressive lymphomas where the course of disease is more rapidly progressing and fatal.