Dr. Leisha Emens is at the Johns Hopkins Kimmel Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy. She specializes in cancer immunotherapy, and her research is focused on combining breast cancer vaccine and immune checkpoint blockade strategies with traditional cancer therapies and newer targeted agents for greater patient benefit.
Her current BCRF research with collaborator Dr. Elizabeth Jaffee is focused on employing multiple strategies to increase tumor immunity and survival in a laboratory model of breast cancer. The best strategies will lead to clinical trials testing the most potent combination immunotherapy in patients with recurrent breast cancer.
In recognition of Triple Negative Breast Cancer Day on March 3, BCRF spoke with Dr. Emens about the renewed excitement around cancer immunotherapy and what role it might play in breast cancer, particularly triple negative breast cancer (TNBC).
BCRF: What are the challenges in developing targeted therapies for TNBC?
Dr. Emens: From a clinical point of view, we treat breast cancer as three major classes:
Cancers that have a well-known driver pathway are the best candidates for effective targeted therapies. Examples include anti-estrogen therapies for ER/PR-positive breast cancers and anti-HER2 therapies in the HER2-positive breast cancers. In the case of TNBC, however, there is not an obvious driver pathway to target. So, we lack targeted therapies for this type of breast cancer. TNBC is further complicated by the fact that it consists of a variety of subtypes, making it a very complex set of diseases that we are only just beginning to understand. Within each of these subtypes, there may be driver pathways that could be therapeutic targets, but as of yet, none have been well validated clinically.
BCRF: Why have we seen such resurgence in immunotherapy?
Dr. Emens: The main driver of this progress has been the discovery of the role of PD-1 and PD-L1 in immune regulation and the development of agents that can target this pathway. Because these agents, called immune checkpoint inhibitors, treat the immune system rather than treating the tumor directly, they have applicability to multiple tumor types. PD-1/PD-L1 seems to be a foundational pathway regulating immune response in multiple tumor types and has been the driving force underlying the interest and excitement in cancer immunotherapy. PD-1 is a receptor expressed on activated T-cells and PD-L1 is expressed both on tumor cells, as well as on immune cells within the tumor microenvironment. When the two receptors interact, they create signals that suppress tumor immunity. Tumors that evade tumor immunity through the PD-1 pathway will often have immune cells within the microenvironment (sometimes referred to as tumor infiltrating lymphocytes- TILs) that are held in check by activation of this pathway. Blocking this pathway with PD-1/PD-L1 inhibitors, releases the T- cells so that they can mediate a tumor response. Multiple drugs that target PD-1 or PD-L1 are under active investigation. None have been approved for breast cancer yet, but several – pembrolizumab (KEYTRUDA®), atezolizumab (TECENTRIQ®) and avelumab– have shown activity in breast cancer, particularly TNBC.
Another important immune checkpoint regulator is the CTLA-4 (Cytotoxic T Cell Lymphocyte Associated Protein-4) pathway. CTLA-4 suppresses immune cell activation, and so plays a role very early in immune cell response. Ipilumibab (Yervoy®), was the first FDA-approved cancer immune therapy in melanoma and is being tested in other cancers, including TNBC, both as a single agent, as well as in combination with standard therapies and other immune therapies.
BCRF: Patients with TNBC are often good candidates for PD1/PDL1 therapies, but there is still a relatively low response rate of 20 percent or less. What do we need to do to improve the response to these therapies?
Dr. Emens: There are multiple reasons why a patient may not respond to these therapies. There might be multiple layers of immune regulation active in the tumor immune microenvironment, so blocking the PD-1 pathway is not sufficient to relieve the immune suppression. Some promising combination approaches are emerging that include combining PD-1 therapy with agents that target metabolic pathways in the tumor microenvironment. Another reason patients may not respond is due to a lack of T-cells in the tumor-immune microenvironment. In these cases, we need strategies to prime a T-cell response and combinations of anti- PD-1 therapy with chemotherapy or radiation therapy, or vaccines may be effective. Another scenario may be that the T-cells don’t have access to the tumor, so developing strategies to attract these T-cells into the tumor will be critical in removing this barrier to PD-1- targeted therapies.
Those of us who have been in the immunotherapy field for a long time are enthusiastic about the possibility of combining vaccines with PD-1 directed therapies in order to jump start the immune response. We often use the analogy of PD-1 as putting the brakes on the immune system and anti-PD-1 therapy as taking away the brakes. A similar analogy of vaccines plus PD-1 -directed therapy would be using the vaccine to press on the immune accelerator at the same time as taking off the brake with immune checkpoint inhibitors. It is very likely that one reason vaccines have not been successful is that the PD-1 pathway is such a dominant force driving immune suppression, so that even with the vaccine-induced T-cell production, they are still held in check by the PD-1 pathway.
BCRF: What are we learning from the ongoing trials that can inform making immunotherapy a more viable approach for a broader spectrum of cancers?
Dr. Emens: We know that not all tumor types are the same and that every patient’s tumor is going to be unique. One reason that TNBC is more susceptible to immune therapy is that these tumors tend to have more genetic mutations, referred to as mutational load. These mutations cause the tumor cells to produce unique antigens that look foreign to the immune system. For some tumors, the mutational load may be important and for others that may not be the case. It might be that a personalized vaccine composed of these unique antigens could work well to induce T-cells in patients with TNBC who do not have sufficient T-cells in the tumor immune microenvironment at diagnosis.
We still need to learn a lot to be able to predict which patients may respond to immunotherapy. We know that the presence of PD-L1 in the tumor microenvironment is a good– but not perfect– predictor of response. Some patients without PD-L1 in their tumors can also respond to immunotherapy, so we need to know more about what is driving their tumor immunity.
BCRF: What do you think are the major milestones in improving our understanding of the immune-biology of breast cancer?
Dr. Emens: Overall, I think it’s going to be quite complex and that being able to personalize an immune therapy strategy to a patient’s tumor in real time is going to be critical for maximum benefit and the greatest likelihood of success. Collecting biopsies from initial diagnosis and again after immune therapy will help us to identify the biomarkers that can predict which patients are good candidates for a particular immune approach and which are not, and will help identify targets for effective combination immunotherapy approaches. Our hope is that we will find a profile within the tumor microenvironment that can also be detected by profiling the blood. Detecting a biomarker that can predict response to immunotherapy through a blood assay would reduce the need for tissue biopsies.
BCRF: What has changed in immune oncology and what are you most excited about?
Dr. Emens: The main advance driving clinical progress has been the discovery of the role of PD-1 and PD-L1 in immune regulation and the development of agents that can target that pathway in the clinic. Because these agents treat the immune system rather than treating the tumor directly, they can work for multiple types of cancer. The challenge now is to convert patients who don’t respond into patients who do. The best opportunity to do that is through combination immunotherapy. Using approaches to profile the immune microenvironment and personalize these strategies to each patient is going to be critical in moving forward.
I am particularly excited about some of the immune therapy combinations that are currently being tested. As we move these forward we have remain aware that these therapies bring with them unique side effects. These immune checkpoint pathways are normal pathways of immune regulation that typically prevent autoimmune diseases. They are high-jacked by cancers to avoid detection by the immune system. It is not surprising then that some of the side effects we see are autoimmune-related side effects. The risk of side effects is likely to increase when we combine multiple immune therapies. In spite of that, I think there is great promise for combination immune therapies and it is a high priority in the field to develop these strategies quite rapidly.
Read more about Dr. Emens’ BCRF research and collaboration with Dr. Elizabeth Jaffee here.
Interested in learning about about triple negative breast cancer? Dr. Vonderheide along with BCRF researcher Dr. Leisha Emens recently shared their insights on TNBC research with us. Read their in-depth conversation here.
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