2011 SABCS, San Antonio Breast Cancer Symposium, 6-10 December, San Antonio, USA
Use of neutrophils to prevent lung metastases in breast cancer patients
Dr Robert Benezra – Memorial Sloan-Kettering Cancer Center, New York, USA
We’ve been studying the role of the innate immune system on breast cancer metastasis progression and we’ve found that there’s a component of the innate immune system, called neutrophils, which seem to be able to inhibit the growth or the seating of breast cancer metastatic cells primarily in the lung, which is where we’ve looked first. This is a big surprise since most people when they think of an immune response to cancer, they’re thinking of acquired immunity – B cells and T cells and this is the first example of an innate immune component, namely neutrophils as a means or mechanism of inhibiting metastasis. Neutrophils typically target bacterial cells and this is something that they’ve been entrained to do by the primary tumour, to actually kill metastatic cells.
It turns out that there are certain factors, chemokines, secreted by the tumours which facilitate their growth at the primary site but have the collateral effect of entraining neutrophils to actually kill cells at the metastatic site. The question obviously is why does that happen and we’re first studying exactly what these chemokines do to neutrophils but having exposed these neutrophils to these chemokines we find that they can attach themselves to tumour cells and actually, in a process called degranulation, release a burst of hydrogen peroxide which actually kills the metastatic cells. Now it’s important to note that it has to be done, we can only do this when the tumour cells are at low density. If they grow to a large size, like in the primary tumour, they secrete a factor called TGF-β which blocks this killing activity. So we think the neutrophils are only effective at the metastatic site because there’s a very low tumour density in these early metastatic lesions. In fact, we have no effect on advanced metastatic lesions so if we’re thinking about this as a potential therapy, we have to get the tumours down to a reasonable size before actually treating them with neutrophils.
Radiation chemotherapy, we’re actually trying to model that now in the mouse where we take an animal with advanced metastatic disease, try to reduce the size of the tumour and then treat with neutrophils and see whether or not we can eradicate the metastatic lesions. Another strategy is, based on what I mentioned about TGF-β, which is that TGF-β blocks the activity of these neutrophils to kill so if you put in a TGF-β blocker you might be able to enhance the killing activity of the tens. There are, in fact, some TGF-β blocking compounds in early clinical development so we can think about doing combination therapies of adding back neutrophils, particularly to patients that are at high risk of metastatic progression with and without TGF-β inhibitors.
Are studies planned?
We’re close to thinking about this in a clinical setting. It’s not like a drug, these are cells which we can harvest from the patient themselves, entrain them with these chemokines ex vivo, so we don’t even have to expose the patients to these chemokines which have lots of different potential side effects, and then just put the neutrophils back into the patient which is great, there should be essentially no toxicity, at least in principle. But these are the types of trials we’re thinking about doing, showing that there’s no toxicity and then ultimately seeing whether or not we can delay the time to progression in patients that are at high risk from metastatic disease.
We think it’s a new line of potential therapeutics, treating neutrophils with various chemokines in combination with other drugs and seeing whether or not we can delay the time to progression, particularly in patients at high risk. So, yes, it’s a new way of looking at it.