Successes and challenges in designing combination immunotherapy clinical trials for breast cancer
Prof Leisha Emmens - Johns Hopkins Kimmel Cancer, Baltimore, USA
The challenge with breast cancer is that historically it has been considered to be somewhat of a non-immunogenic tumour so it has been somewhat challenging to develop immunotherapies in that space. I started translating immunotherapies into the clinic back in the early 2000s and had developed a wholesale breast cancer vaccine that secretes GM-CSF, GVAX. We tested it in combination with low doses of chemotherapy as well as trastuzumab in two different trials that are designed to support the vaccine’s ability to induce a tumour specific T-cell response. In the first trial we treated 28 women with ER positive metastatic breast cancer and we sequenced the vaccine with a range of low doses of cyclophosphamide and doxorubicin where the cyclophosphamide was being used to mitigate the influence of regulatory T-cells and doxorubicin was used to promote effector T-cells. The goal of that study was to identify the doses of chemotherapy that could maximise the level of immunity induced by the vaccine. We identified a dose of cyclophosphamide of 200mg/m2 as the best dose to support vaccine induced immunity and that’s lower than the dose that has been traditionally used in vaccine trials. We’ve taken that dose forward in other trials of similar vaccines at Johns Hopkins.
Are you currently working on any novel combinations?
We had our vaccine trial that was in combination with both cyclophosphamide and trastuzumab. The trastuzumab was at standard doses and that also looked very active. Last year at AACR I presented the first data of more than a handful of patients for atezolizumab, the anti-PD-L1 agent, in patients with metastatic triple negative breast cancer. They were pre-selected and as a single agent in that small group of patients there was a response rate of about 19%. That agent is moving forward into different combinations in a variety of different cancer types. One trial is testing it with an IDO inhibitor; there’s another trial that’s testing it for HER2 positive metastatic breast cancer as well as early stage breast cancer in combination with standard HER2 directed therapy where the PD-L1 is given with trastuzumab and pertuzumab or with trastuzumab emtansine in metastatic disease and with those agents in a window study in the neoadjuvant setting as well.
How do you manage patient expectations towards their cancer?
As I started off the interview I said that historically breast cancer has been considered a non-immunogenic type of cancer so it has been challenging to translate immunotherapies into that disease. There’s accumulating data to suggest that breast cancer can be immunogenic, in particular there are two sub-types of breast cancer, HER2 positive breast cancer as well as triple negative breast cancer, that appear to be associated with higher T-cell infiltrates at diagnosis than, for example, luminal breast cancer or ER positive breast cancer. So those two subtypes in particular are very attractive for developing immunotherapies just because of that. Those higher T-cell infiltrates are associated with improved clinical outcomes, better complete pathologic response, or a higher likelihood of complete pathologic response, for neoadjuvant therapy as well as longer progression free and overall survival if women have higher T-cell infiltrates at diagnosis. That’s less likely for the ER positive or luminal cancers.
What future treatment developments do you hope to see?
The trials that I mentioned are Genentech sponsored trials; I think those are very interesting immuno-oncology combinations, anti-PD-L1 and IDO inhibition together as well as anti-PD-L1 with standard HER2 based therapy. There are going to be more and more interesting immuno-oncology agents that come out and I think the biggest challenge for the field is determining a strategy for transforming non-responders into patients that can potentially respond to immunotherapy. There are a variety of different ways to do that, some standard chemotherapies can do that, radiation therapy can do that and there are emerging agents that can really modulate the tumour microenvironment to make it more conducive to T-cell activity as well. So I think the most potent things to come along will likely depend in part on the specific tumour type as well as the baseline immune profile of the tumour itself.
What is your take-home message?
It’s a very exciting time in cancer research and particularly in cancer immunotherapy for patients with all types of cancer. I’m firmly convinced that we’re going to be able to make cancer immunotherapy a reality for the vast majority of patients and the strategy, as I mentioned, for different diseases will vary somewhat depending on the baseline immune infiltrates that are present as well as the biology of the tumour itself. So the future for cancer immunotherapy will tend to be more one of personalised medicine where you really do an in-depth profile of the immune biology of that tumour and really tailor the type of immunotherapy to the biology of that particular cancer.