Michael Roth, Ph.D.
University of California, Los Angeles

Breast cancer now affects one out of every nine women in the United States and is a leading cause of cancer death. While surgery, radiation and chemotherapy are very effective at curing woman when their cancers are caught at an early stage, these therapies are rarely effective when used in patients with more advanced disease. New approaches are needed. One such approach is to use the body’s own immune system to fight the cancer, so called "cancer immunotherapy". Our research focuses on how to stimulate the immune system so that it will recognize breast cancer cells as abnormal and destroy them. There are several steps to this process. First, we must find something that is unique about breast cancer cells that will act like a flag to identify them. We believe that a specific protein, the HER-2/neu protein, fulfills this need. HER-2/neu is a protein that is found on very few types of cells and usually in very small amounts. However, about one-third of the cases of breast cancer produce excessive amounts of HER-2/neu - as much as 50 to100 times the normal amount. By directing the immune system to recognize HER-2/neu as abnormal, we hope that it will preferentially destroy breast cancer cells and not normal cells. The next step in our work is to figure out how to program the immune system so that it will indeed recognize this HER-2/neu protein. This is done by feeding pieces of HER-2/neu protein to a special type of white blood cell, called a dendritic cell. A dendritic cell is capable of taking up these pieces of HER-2/neu and programming the immune system to respond to it. We have recently developed ways to grow these dendritic cells from patient’s blood and we will determine the best way to load them with pieces of the HER-2/neu protein. This is a difficult process because just the right "piece" must be found and it differs from one person to another. We can simplify this task by using genetic engineering. We will take the gene that tells the body how to make the HER-2/neu protein and insert it into dendritic cells. In this manner, each person’s dendritic cells will be able to make just the right piece of HER-2/neu necessary to stimulate the immune system. By the end of our study, we will be able to put all of these steps together and test whether or not the immune system can be programmed to recognize and destroy breast cancer cells. Preliminary results are very encouraging. If we are successful, we will have developed a new way to treat breast cancer that is painless and long lasting.

Breast cancer often progresses despite surgery, radiation and/or chemotherapy. New types of treatment are needed. The goal of this research is to develop methods for stimulating a patient’s own immune system so that it recognizes and destroys their breast cancer. The advantages to such a treatment are that it 1) would not use any toxic drugs or radiation; 2) that the immune system can be trained to recognize the tumor cells and not harm any normal tissue; 3) that it will treat all sites of disease throughout the entire body; and 4) that the effects should be long lasting. An important marker that can be used by the immune system to detect breast cancer is called the HER-2/neu protein. Our research uses blood from breast cancer patients and develops methods for stimulating their white blood cells to recognize and destroy breast cancer cells that over-express this HER-2/neu protein.

The first scientific aim of this proposal was to determine whether important immune-stimulating cells, called "dendritic cells", could be grown and activated from the blood of patients with breast cancer. We have demonstrated that fully functional dendritic cells can be grown from most patients. The second aim of this study was to test a variety of potential tumor markers, peptide tumor antigens, to determine which ones can be used by dendritic cells to stimulate an immune response. At least two of these peptide antigens appear capable of stimulating the immune system - although more patients need to be evaluated before drawing any firm conclusions. The third aim was to evaluate different immune-stimulating hormones (cytokines) to determine the optimal ones for boosting the immune response. We have identified three such cytokines as important for this purpose - IL-2, IL-7 and IL-12. The mechanisms responsible for these effects are undergoing further evaluation. In addition, another cytokine, IL-I 0, is being investigated for its ability to enhance the effects of IL2 and IL-7. Finally, in the last scientific aim, different approaches for genetic engineering are being evaluated so that the genes encoding for these cytokines and tumor antigens can be directly inserted into dendritic cells. This would empower the dendritic cells with all of the information and tools needed to stimulate an immune response against breast cancer. We have identified at least two effective mechanisms for using gene therapy to modify dendritic cells and gene-modified cells appear to be better immune stimulators.

By the end of this research we will have enough information to begin testing dendritic cell immune therapy to treat patients with breast cancer. This should offer new hope and improved recovery for patients that have failed other treatments.

 Progress Report Year 2 (1998)

Breast cancer often breaks through the body's natural defenses and spreads beyond the breast. We are working on ways to stimulate the immune system so that it can recognize the spread of breast cancer and contain it. The immune system is composed of different types of white blood cells, each with a specific function, which circulate throughout the entire body. Dendritic cells are the type of immune cells which first interact with the tumor, process small pieces of it called "tumor antigens", and then use these antigens to stimulate the rest of the immune response. Cancers appear to inactivate dendritic cells - thereby short-circuiting the immune response before it ever gets started.

Using blood samples and tumor cells from cancer patients we are actively examining why and how dendritic cells are ‘turned off’. This will lead to new strategies for preventing immune suppression and restoring a patient's natural defenses. In addition, we have demonstrated that immature dendritic cells can be taken out of the blood of patients with breast cancer, activated in culture with the aide of potent growth factors, and their activity restored. Using these re-energized dendritic cells in conjunction with other important growth factors, called cytokines, we are examining ways to stimulate the body's immune responses. One cytokine, called interleukin-7 (IL-7), appears particularly promising. We are examining several aspects of immune activation in detail including (i) the best conditions for growing active dendritic cells, (ii) the best antigens for them to use in order to recognize the tumor, and (iii) the best combination of growth factors for enhancing the overall effectiveness of the immune response. As part of this strategy we are looking at gene therapy. For this we are inserting the gene for IL-7 directly into dendritic cells, which allows them to make their own IL-7 and to more efficiently stimulate the rest of the immune system. We are actively testing new types of gene therapy that might accomplish our goals with even better results.

By the end of this research we will have identified many important parts of the immune response to breast cancer, we will have identified new ways to enhance the immune response, and we will have set the stage for using dendritic cells as a form of immune treatment for patients with advanced disease that has spread outside of the breast.

Publications:

Click on the Number to View Publication Abstract

1. Kitchen SG, Korin YD, Roth MD, Landay A, Zack JA. Costimulation of naive CD8(+) lymphocytes induces CD4 expression and allows human immunodeficiency virus type 1 infection. J Virol 1998 Nov;72(11):9054-60.

2. Paquette RL, Hsu NC, Kiertscher SM, Park AN, Tran L, Roth MD, Glaspy JA. Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol 1998 Sep;64(3):358-67.