WEDNESDAY, NOVEMBER 12, 1997

Dr. Tripathy began by discussing the relationship between cancer and immunology. In breast cancer, can the immune system recognize the cancer cells as abnormal? Can autoreactive T cells be used as a surveillance mechanism? The results in early trials seem somewhat mixed. In colon cancer and melanoma, there has been some success with interferon therapy, in bladder cancer, BCG, a tuberculosis vaccine used to stimulate an immune response has been effective. Tumor related antigens such as mutations in P53 and HER2/neu are being looked at to generate immunity, but vaccine has not been generated at this point to use in breast cancer. GCSF and GMCSF, proteins which are central to the production of cells which stimulate immune reaction, have been used in clinical trials dealing with metastatic breast cancer, and T cells activated with Interluken in passive method clinical trials have not yet been successful.

Dr. Tripathy introduced Dr. John Park and Dr. Mike Campbell, who together with Drs. Tripathy and Laura Esserman, form the core of investigators on a new project to develop vaccine therapy for breast cancer. Dr. Park explained that the prospect of a cancer vaccine is very alluring to researchers. By directing genetic agents such as HER2/neu, we can conceivably get the body's own immune system to recognize disease, currently the evidence is that patients with these antibodies circulating in their bodies do not do better with their breast cancer. Dr. Park also discussed KLH, a substance which comes from marine animals, as a potential enhancer of the immune system. He said that research shows that this substance does cause some immune response, but not enough. Another research problem is that the target must remain the same in order to make immunotherapy work. Cancer cells tend to change, and that would affect the immunotherapy. The approach of the new study will be geared to ductal carcinoma in situ (DCIS). This is because vaccine therapy is less likely to work in advanced cases. The immune system is even likely to be able to handle small amounts of cancer cells in the body before the individual displays the disease. Traditionally, new therapies are developed in advanced disease trials (Stage 4/metastatic). This is the paradigm that they want to break, want to reconfigure the ways that traditional clinical trials are done, and use this vaccine therapy as adjuvant treatment or in patients with DCIS, or in patients with genetic predisposition to breast cancer.

The basic idea of the proposal currently in submission is to move the research from the laboratory to the clinic-- to try to go from animals to people within one year. The patient would not be subjected to chronic therapy, but rather would receive the vaccine for a time, and then hopefully, the immune system would take over. This would require that the patient delay traditional therapy for a while (up to three months). It would be up to the individual to assess this risk, but it could be seen as an opportunity not to over-treat DCIS, especially since it usually takes approximately 2-3 months to get further care in any case.

Dr. Michael Campbell will direct the laboratory operations for the new grant. He will evaluate the animal models to see which are effective. Portions or all of the protein in the oncogene, HER2/neu, are currently being used in the animal studies. A strain of mice are used which are bred to develop breast cancer .The animals are vaccinated prior to developing tumors. Thus far, 50% of the animals who should develop tumors do not do so. This could be considered a cure rate of 50%. As exciting as this research seems, to develop a vaccine to the point that it would be accepted over chemotherapy or other standard treatment will take years of trials. This is why it must be tried on very early stage breast cancer, i.e. DCIS. The field needs surrogate markers (immune cells) which can be used for adjuvant therapy tests. These tests will look at how well the T cells respond to the vaccine (and how reliably they respond), so that you can prove that the markers improve outcomes. This would speed up the trials results.

The normal cellular function of HER2/neu appears to be a growth factor. Laboratory mice do not develop if it is absent. It is present in low levels in adults, a small amount in the epithelial cells, but 1000 times these low levels in cancer cells. There is no evidence that people with antibodies to HER2/neu are harmed by them.

Several questions were asked regarding the role a weak immune system might play in predisposing an individual to cancer, currently there is no direct evidence of this. It was noted that there is not a high rate of spontaneous remission in breast cancer, more in renal cell carcinoma, where the immune system has apparently ìralliedî in these cases.

Initially, the vaccine would be specific to DCIS, but it could at some later stage prevent the need for lumpectomy and mastectomy, and potentially inflammatory breast cancer. It could become a treatment for cancer that is there and also for prevention. Dr. Tripathy thinks that breast cancer may be too heterogenous to all respond to the very same vaccine.

The protocol for this clinical trial is:
standard excision of DCIS tumor(administer vaccine (delay)(re-excision of tumor

There will be an MRI before and after the vaccine to see if there has been an effect. That way you are still responding to the standard of care. MRI seems to be a very accurate way of evaluating the tumor. It is not good as a screening tool because it causes too many false positives, but it is very good at defining the extent of anatomic disease once diagnosed.

In closing Dr. Tripathy described two possible scenarios for the protocol:

Scenario #1: DCIS(Lumpectomy (+ margins)(Choose Lumpectomy or Mastectomy(Propose before next resection, get Vaccine, wait 3 months

Scenario#2: (Higher risk) Biopsy(Vaccine, wait 3 months(Lumpectomy

Announcements:

Carolene Marks and Barbara Duchon will be spearheading the Symposium on Alternative Medicine. The need everyone's help to make this a success, and encourage participation in any way that you are able. Sign up sheet was passed around for their next meeting.

Next month's topic will be: Hormonal Therapies