Most people think of ultrasound as an imaging modality. Yet, there are many other clinical uses for the high frequency soundwaves. Focused ultrasound waves can promote the opening of the blood-brain barrier, and they can be used to ablate fibroids, among other uses. Yet the potential of ultrasound in clinical medicine is far from fully realized, as new uses and studies evaluating them are rapidly sprouting, and a particularly interesting one involving checkpoint inhibitors to treat stage IV metastatic breast cancer is about to begin. To get a sense for how ultrasound can improve cancer care in combination with checkpoint inhibitors, we spoke with Jessica Foley, Ph.D., the Chief Scientific Officer of the Focused Ultrasound Foundation.
Medgadget: Checkpoint inhibitors help a patient’s immune system to not be deceived by cancer cells’ attempts at disguising themselves as healthy cells. There’s already a few of these types of drugs on the market (ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo)), but their effectiveness can vary greatly from patient to patient. Where do you think focused ultrasound fits in the equation?
Jessica Foley, Ph.D.: Efficacy may be improved for patients with a baseline immune response (e.g. biomarkers expressed; tumor microenvironment) prior to treatment, potentially elicited by radiation or other ablative therapies including focused ultrasound. Ablative therapies – radiation, radiofrequency, cryoablation, laser, and focused ultrasound – have demonstrated the ability to stimulate an immune response in preclinical and clinical studies. In addition, therapies such as radiation have demonstrated clinical success when used in combination with immunotherapy, by providing the initial immune response (i.e. response to release of tumor antigens or changes in the tumor microenvironment) that immunotherapy can then enhance. Similarly, focused ultrasound could potentially be effective in combination with immunotherapy. Given its non-invasiveness, use of non-ionizing radiation, and ability for conformal and precise ablation with no dose limitations, focused ultrasound could be more appealing for this combination therapy than other ablative modalities.
Medgadget: There’s some indication that focused ultrasound may help increase the effectiveness of checkpoint inhibitors. What is the evidence for this and what is the current explanation for this mechanism?
Foley: Focused ultrasound applied to a tumor can cause the release of tumor antigens that can awaken the immune system so it can begin to fight the tumor. Promising preclinical studies in models of breast cancer, melanoma, pancreatic cancer, and glioma (among others) have demonstrated that focused ultrasound can initiate a powerful anti-tumor immune response either alone or in combination with immunotherapeutics such as checkpoint inhibitors. The specific mechanisms – i.e. specific changes to the tumor microenvironment, specific tumor antigens released following FUS exposure – are under investigation. Focused ultrasound can also be used to increase the delivery of immunotherapeutics through better penetration into the target tumors.
Medgadget: Theraclion recently received a green light to combine focused ultrasound with the pembrolizumab to treat patients with stage IV metastatic breast cancer. Can you give us an idea of how the therapy will be administered in this trial?
Foley: This pilot study will be completed at the University of Virginia (PI: Patrick Dillon). The goal is to evaluate the use of high-intensity focused ultrasound (HIFU) combined with pembrolizumab in patients with metastatic breast cancer. One-half of participants will be randomized to receive the first dose of pembrolizumab after HIFU treatment and one-half of participants will be randomized to receive their first dose of pembrolizumab before HIFU treatment. For both groups of patients, HIFU ablation will target 50 percent of the tumor, up to 3cm. (Description of the study taken from https://www.fusfoundation.org/clinicaltrials/breast-cancer-clinical-trials)
Medgadget: What are the goals of this clinical trial and is there an expectation that it will help explain how focused ultrasound helps improve the effectiveness of the checkpoint inhibitor, if it in fact does so?
Foley: The goal is to evaluate the use of high-intensity focused ultrasound (HIFU) combined with pembrolizumab in patients with metastatic breast cancer. Preclinical studies have shown that the timing of the delivery of focused ultrasound and the delivery of immunotherapy plays a key role in the success of the combination approach (in various tumor models including breast cancer). This first clinical investigation into the combination of FUS with a checkpoint inhibitor could further assess the importance of timing. Although not an intended outcome of the trial, it could potentially demonstrate whether this combination approach that includes focused ultrasound treatment of a primary tumor could induce an immune response to also treat metastatic tumors (i.e. abscopal effect).
Medgadget: Do you believe that focused ultrasound can improve the functionality of checkpoint inhibitors?
Foley: Yes. Despite the demonstrated benefits of checkpoint inhibitors on tumor regression and increased overall survival, these therapies are effective in only 20-40 percent of patients. We think there is a lot of potential for the combination approach to enable more patients to be “responders” to treatment and for the treatment effect to be more robust and sustained. Preclinical studies have started to demonstrate this, but the research is still early stage and a lot of questions including a better understanding of the specific characteristics of the immune response produced by FUS (via detailed immune assessment protocols) still need to be answered. The Foundation is supporting projects to try to get to these answers.
Medgadget: Since ultrasound has been shown to be successfully used to open the blood brain barrier, do you think that the same therapy session combining ultrasound and immunotherapy can potentially improve how brain tumors are treated?
Foley: Yes. Focused ultrasound can temporarily make the blood-brain barrier and/or the blood-tumor barrier more permeable to therapies that are typically too large to penetrate these barriers. This includes immunotherapies that have recently been shown to have a beneficial effect in mouse models of GBM and metastatic brain cancer. Focused ultrasound could potentially not only enable higher concentrations of immunotherapies to reach brain tumors, but the energy itself could initiate an anti-tumor immune response that could be enhanced and sustained by immunotherapy. The Foundation has created a multi-site consortium to streamline efforts and accelerate progress in using FUS to induce an anti-tumor immune response for treatment of glioblastoma. The project brings together seven research sites in North America to investigate the effects of different FUS modalities (i.e. parameters of energy delivery) on the immune system, each using the same animal model of GBM. Results are expected within the next few months and should demonstrate the modality – or modalities – that are promising to assess in larger translational studies and/or in combination with specific immunotherapeutics.
Medgadget: What are some of the other research goals that the Focused Ultrasound Foundation is working on now? And what challenges do you hope to be able to tackle in the not too distant future?
Foley: The Foundation has established a partnership with the Cancer Research Institute with the goal of advancing the development of new focused ultrasound and cancer immunotherapy treatments. Both organizations recognize the intersection of the latest developments in FUS therapy and cancer immunotherapy offers a highly promising opportunity for combination approaches to treat a variety of cancers. As a key component of the partnership, CRI and FUSF will establish a joint fund to support research to move towards new combination therapies. A panel of advisors with expertise in FUS and cancer immunology/immunotherapy will determine critical unanswered research questions. A request for applications (RFA) will then be issued to encourage future projects to address these knowledge gaps. After review and assessment, FUSF and CRI will share the costs of funding the chosen project(s); CRI will administer the grants within this joint program.
The Foundation is supporting several ongoing preclinical projects to elucidate the characteristics of the immune response induced by focused ultrasound, and how this response varies with different modalities of FUS application, in tumor models of GBM (see section above about multi-site consortium), melanoma, breast cancer, and pancreatic cancer.