Initial Award Abstract (1997)In this project, we intend to test whether normal cells from the blood stream of breast cancer patients called dendritic cells have the ability to stimulate immunity against breast cancer.
The dendritic cells are normally present in small numbers in the blood, and stimulate immunity very strongly against viruses, bacteria, cancer cells and other foreign invaders. Scientists have developed a way to grow these cells in large numbers outside the body within a week after removing a sample of blood and exposing the white blood cells to growth factors that encourage the growth of dendritic cells. In this research project, dendritic cells will then be exposed to a synthetic piece of a substance present on breast cancer cells called "CEA" that is present on tumors from two thirds of patients with breast cancer.
Dendritic cells will be grown for a week outside the body and then exposed to a fragment of the "CEA", followed by infusion in large numbers into the veins of patients with breast cancer that has spread widely and cannot be cured with chemotherapy, radiation or surgery.
Increasing doses of the cells will be given to groups of at least three patients with breast cancer in order to find out whether the dendritic cells cause side effects when given twice over a period of two weeks.
Stimulation of the immune system against breast cancer will be measured before and after the dendritic cells are given by removing a sample of blood for analysis in the laboratory and by other tests. Shrinkage of tumor will also be measured.
In this 2 year trial of 24 patients with metastatic breast cancer, we will ask whether patients that receive CEA dendritic cells can increase their immunity against breast cancer without side effects, and whether increased immunity against breast cancer can cause shrinkage of tumors.
The long term goal of this initial study is to find ways to educate the immune system to recognize and destroy breast cancer cells even though the presence of the tumor and the chemotherapy agents used to shrink the breast cancer have caused decreased levels of immunity.
The results of this initial CEA dendritic cell study will determine the course of future studies depending on whether shrinkage of tumor is seen, in which case a follow-up study will be performed to confirm that CEA dendritic cells are effective for the treatment of metastatic breast cancer.
If no tumor shrinkage is seen, but immunity against breast cancer is boosted, then patients will be treated with CEA dendritic cells and then have a blood sample removed to try to grow another type of white blood cell called killer T cells that can be directed against breast cancer.
This use of dendritic cells to stimulate immunity against breast cancer is supported by work showing that in the mouse and in humans, dendritic cells are the strongest stimulators of the immune system. This immunologic approach to breast cancer is an attempt to harness the body’s natural defenses to eliminate tumors by boosting the immune response directed against a substance found on cancer cells.
Final Report (1999)In our proposal, entitled "Peptide pulsed Dendritic Cell Therapy for Breast Cancer," we had two specific aims: the first aim was to perform a clinical trial in which patients whose tumors over had the tumor marker CEA were treated with their own dendritic cells, which are immune stimulating cells from the bloodstream, to which a fragment (a peptide) of the CEA marker protein was added.
The goals of the trial were to determine what side effects the dendritic cell therapy caused and to measure whether tumors shrank after treatment with CEA peptide pulsed dendritic cells. In the second specific aim we wished to measure whether the injection of dendritic cells that were pulsed with the CEA peptide caused a boosting of immunity in patients.
The results of our study are that generation of dendritic cells from patients with breast cancer that have been heavily pre treated with chemotherapy was difficult, with low yields.
The resulting dendritic cells had less of the cell surface molecules than dendritic cells from non-chemotherapy treated patients with metastatic melanoma, for example. We were able to infuse cells in 16 patients, but found that there was no evidence of tumor shrinkage in any patient. Immunologic assays revealed that the CEA peptide pulsed dendritic cells did not result in boosting of immunity in general or specifically directed against the CEA antigen with which the dendritic cells were pulsed.
This information leads us to believe that in a population of breast cancer patients that were heavily pre treated with chemotherapy, the CAP 1 CEA peptide loaded onto dendritic cells was not capable of provoking an immune response and did not cause tumors to shrink. Newer peptides that have been produced synthetically are being developed that bind more strongly to the dendritic cells and may be more capable of causing immune recognition of tumor cells.
In addition, we believe that patients that have not been previously treated with chemotherapy and have minimal disease burden are ideal candidates for dendritic cell treatment in future trials.
http://www.cbcrp.org/research/PageGrant.asp?grant_id=154
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