|Julia Draznin Maltzman, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
= Julia Draznin Matlzman, MD, Senior Editor, OncoLink
OncoLink had the opportunity to interview Dr. Brian Czerniecki about his unique approach to ductal carcinoma in situ (DCIS) a pre-malignant breast lesion. Dr. Czerniecki is a breast cancer surgeon who also has a keen interest in clinical trials. He is particularly interested in tumor vaccines and tumor immunology. He is currently the principle investigator for a novel vaccine trial for patients with DCIS. The currently available vaccine trials are all for stage IV, advanced disease. What is unique about Dr. Czernieckis trial is that it examines the efficacy and safety of vaccines in a much earlier setting, even before invasive cancer is present. The results from this trial are particularly exciting as they open the door for the use of vaccines as cancer prevention tools as opposed to treatment of late stage disease.
Please tell me about your trial.
BC: This is a vaccine, made with autologous white blood cells, primed against the Her/2neu peptide. See, whereas estrogen receptor-expressing tumors can be treated with anti-estrogen drugs such as Tamoxifen, and some of the newer regiments, the Her/2neu over-expressing DCIS do not have an analogous option.
A patient who is found to have an abnormal mammogram or ultrasound will be asked to undergo a core needle biopsy. To be eligible for the trial, the biopsy must show DCIS that overexpresses the Her/2neu protein. We would also need to obtain a MUGA scan (a heart function test), a breast MRI and a ductal lavage of the affected breast prior to and following the vaccine administrations. The MUGA scan is a precautionary measure to ensure that vaccine therapy will not affect cardiac function. The MRI scan will document extent of visible disease and we will be able to compare it before and after treatment to see if immune therapy had any affect on the DCIS itself. And, the ductal lavage is a side aim. We would like to see if we could identify malignant Her/2neu expressing cells in the milk ducts of the breast. If so, this could be used as a powerful diagnostic tool that would complement if not replace biopsy. Certain types of white blood cells will be collected from the patient by a process called leukophoresis before treatment can begin. These white blood cells will be primed in the laboratory to recognize and mount an immune attack against the Her/2neu protein.
The vaccine itself is actually composed of dendritic cells (a type of white blood cell) primed against the Her/2neu. There are four vaccines, administered weekly under controlled and monitored conditions. We will need to inject the vaccine directly into the lymph nodes where most immune reactions take place. At the conclusion of the four doses, the patient will undergo conclusive surgery as per their own decision. It may be either a lumpectomy or a mastectomy and has no bearing on the trial.
So what are you looking for? What is your end point?
BC: We are looking for immune system activation. We want to see that the vaccine was able to prime the patients own immune system mainly the patients T-cells, to go and destroy all cells that overexpress Her/2neu. There are a number of assays we could do to test for T-cell activation. We are particularly interested in CD4 and CD8 cells. These are the helper T cells and the cytotoxic T cells that do the dirty work.
Is that why you also collect white blood cells by way of leukopheresis at the conclusion of the study? To be able to harvest the white blood cells and examine them for activation?
BC: Yes. Exactly.
Why do you prefer to inject directly into the lymph nodes? Why not under the skin or in the vein? Dendritic cells should find their way to the lymph nodes anyway?
BC: Yes, they do, but the dendritic cells we are injecting are activated. The idea is to present the dendritic cells to the patients T-cells as quickly as possible. If we just injected them under the skin, it may take hours for the dendritic cell to find its way to the lymph node. For the purposes of this study we need to ensure that we have T cell activation. Plus, dendritic cells make all kinds of cytokines (hormones-like substances necessary for T-call activation) that help activate the immune system such as IL-12 for example. However, they only make it for a short period of time. It is possible that the dendritic cell will no longer be activated and primed by the time it finds and reaches a lymph node. By then it is no longer producing cytokines and will not activate the immune system, as we would like to see.
Are there any animal models that support the use of vaccines in breast cancer?
BC: Yes. Her/2neu transgenic mice, those that have been genetically engineered to over express Her/2neu develop breast cancer 100% of the time at about week 16 of life. DCIS needs Her/2neu to survive. It is the driving force and thought to be what is responsible for transforming DCIS into invasive cancer.
Do these mice develop other types of cancers also? Her/2nue is commonly expressed on other types of malignancies.
BC: Not that I know of. In any case, they die of breast cancer
What is the significance of Her/2neu overexpression on DCIS? I am sure you are aware that a higher percentage of DCIS over expresses Her/2nue than invasive cancers.
BC: Like I said, it is what drives DCIS. Long time ago, we used to think that breast cancer develops in steps: from low grade DCIS to intermediate to high to eventually invasive cancer. Now we know that this is probably not the case. High grade DCIS probably leads to aggressive invasive tumors and low-grade DCIS likely leads to more indolent invasive breast cancers. When you look at the high grade DCIS, about 70% of them over express Her/2nue. Furthermore, when you sample lymph nodes in DCIS patients, the ones with positive nodes are almost always the ones with the high grade DCIS, the Her/2nue positive ones. So maybe if we could prevent the Her/2nue from driving the proliferation of disease and the growth of cancer by the use of this vaccine, we could prevent women from getting aggressive breast cancer.
It is conceivable that the invasive cancer no longer needs the Her/2nue to drive its proliferation and growth. It has broken through and invaded. Perhaps that is why there are fewer invasive cancers with the Her/2nue marker than there are DCIS cases.
Do you think that the four-week delay in surgical therapy for DCIS would deter some potential patients?
BC: No. When women opt for plastic surgery following lumpectomy, often times it takes 4-6 weeks to get that scheduled anyway. As surgeons, we try to get the invasive cancer cases done as quickly as possible. DCIS often gets done 4-6 weeks after the diagnosis.
As you know, the treatment of DCIS is varies widely. There are many variations in how oncologists approach this problem. Do you have any comments about this? Is there a wrong way to treat DCIS for example?
BC: I think that this is probably true. Much of it depends on patient preference and the extent of disease. You have lumpectomy, lumpectomy followed by radiation, and even mastectomy. Mastectomy rates in the south and west of the country are probably higher than in the east. There is no wrong way to treat it. This is a decision that must be arrived at after careful consideration of all aspects medical and personal. What is wrong is to ignore high grade DCIS. That would be wrong -- especially in young people. Young people tend to recur so often that you really need to consider all options very carefully.
What do you see as the future of vaccines for breast cancer? Where do you hope this will take us?
BC: Well, we dont have them right yet. We need to get the vaccines to work first. And, they will. We need to figure out how to knock down self-tolerance but not so much that we evoke autoimmunity. The problem now is that malignant cells escape immunity due to self-tolerance. The immune system does not recognize the cells as being sick just as self. It is the same issue for all cancers for which vaccines have been used: breast, melanoma, and prostate. We used to think that melanoma was the perfect disease for vaccines because the antigen was so accessible. But it is accessible in breast too.
In the ideal world, we would use this vaccine for invasive breast cancer prevention for patients who may have been diagnosed with DCIS. Hopefully there would be an adjuvant therapy application as well, but to use it for prevention gets closer to the true meaning of a vaccine. You want to prevent the disease before you have it rather than try to treat it once it is in its advanced stages. It is very difficult to activate the immune system once the disease is wide spread.
How long has the trial been open?
BC: Since October.
: How many patients do you hope to accrue?
Good luck to you and keep us posted on your results. We are fortunate that such cutting edge research is happening right here at Penn.
For more information or to see if you are eligible for Dr. Czerneickis trials please see the OncoLink/EmergingMed Cancer Clinical Trials Matching Service