OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma

, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, both of Baptist Health South Florida, shed light on the excitement surrounding the use of low-intensity focused ultrasound (LIFU) in cancer and other conditions.

: Mike, you spoke very eloquently about the work you have done in helping these patients—whether it’s in the tremor space, the malignant glioma space, the glioblastoma space, [or even] more intriguingly, in the brain metastases space. What excites you most about all these categories as you approach patients for these techniques?

:  think it offers the patients an opportunity to contribute to medical science and new information that may help their fellow man in the future. Outside of the world of oncology, the use in treating patients with Alzheimer disease I think is particularly exciting because currently, we have no effective treatment.

The fact that we can open the blood–brain barrier with this type of technology even includes the possibility that for patients [with Alzheimer disease], we may combine LIFU with new medications to see whether we can get a better response at stabilizing the disease, or reversing some of their cognitive difficulties, which would be a great improvement for the patients’ quality of life. I think there are many aspects to this kind of treatment which make it exciting— using focused ultrasound waves, which is new, novel, [and] for the patients, it’s painless. I think it’s a wonderful advance for medicine in several subspecialty areas.

: Dr McDermott [spoke] to the premise of scientific research, which excites our patients when they seek these treatments. But also, this gives us an opportunity to collaborate with our colleagues and researchers, not only in the state of Florida, but [throughout the] United States and across the globe. Thank you so much, Dr McDermott, for sharing [these] exciting advancements that you’re [contributing to] as a pioneer in this field. [It’s exciting] to usher in an era of new opportunities for our patients. Thank you.

Videos

In this last episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, shed light on the excitement surrounding the use of low-intensity focused ultrasound in cancer and other conditions.

Examining LIFU–Aided Liquid Biopsy in Glioblastoma: Excitement Surrounding Focused Ultrasound Waves 

, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, both of Baptist Health South Florida, discuss the key objectives of the phase 3 LIMITLESS study (NCT05317858) examining low-intensity focused ultrasound (LIFU) with immunotherapy and chemotherapy in patients with lung cancer and brain metastases.

: Mike, as you know, there is another ongoing study [called] LIMITLESS, which is trying to look at this technology in patients with brain metastases from lung cancer. You alluded to some preclinical work [which suggested that] using LIFU may help in immune priming. Could you speak about your [previous] work [with] immunotherapy in brain tumors, and how you feel this [approach] can augment the immune checkpoint blockade in this patient population?

: Most of the work with immune checkpoint inhibitors that has been done in malignant brain tumors is with brain metastases, [and] we’ve noted some success [in] tumors such as lung cancer, melanoma, [and] renal cell cancer, for example. It has been shown that with LIFU, we can increase the concentration of some of these immunotherapy molecules by as much as 400% to 800%. The theory is that as opposed to just drug alone, if we pretreat the patients with LIFU, disrupt the blood–brain barrier, and then give the immunotherapy agents, we can dramatically increase the concentration of drug at the site exactly where we need it, which is where the brain metastasis is. We do have the option of crossing patients over in that trial, so they will receive additional therapies if follow-up imaging suggests tumor progression.

When we select patients for treatment with LIFU, we don’t have to shave the entire head of hair, but we recommend that we clip the hair short. Then, we put Vaseline in a band-like distribution to allow for the cooling unit that fits over the top of the patient’s head so that heat is not generated by the ultrasound unit, making it uncomfortable for the patients. The cold circulation is a little bit uncomfortable, but not nearly as intense as what might happen without the cooling. However, so far, the three patients we have treated for malignant gliomas have all seemingly tolerated this well. We’ve used bite block immobilization on the first three patients as opposed to applying a stereotactic frame. The frame is required for the high-intensity focused ultrasound treatments which take longer and require much more precision, given that the target is in a motor nucleus in the thalamus.

Mayo Clinic, University of Toronto, and our group have each treated three patients on the glioma trial. At the end of this month, I think we will be treating our first patient with brain metastasis using LIFU.

: Thanks so much again, Mike. As Dr McDermott alluded to, LIMITLESS is an ongoing, prospective, multicenter, open-label, randomized clinical trial that [randomly assigns] patients who have non–small cell [lung cancer and] brain metastases, who are on pembrolizumab [Keytruda] monotherapy with an amendment [that] will also allow patients to [receive] pembrolizumab and several chemotherapies together.

The [hypothesis] is that noninvasive disruption of the blood–brain barrier using the LIFU can either increase drug delivery, which is probably more important for the chemotherapeutic agents, but also lead to this immune-priming mechanism, which can make the immunotherapy even more effective.

The [goal] of the study will be to see whether there is an increase in the objective response rate in the LIFU arm combined with the chemotherapy or immunotherapy compared with just chemotherapy or immunotherapy given to these patients, which would be a standard of care…In terms of response rates, we hope [to] go from 30% to as high as 60%. The trial will use a Bayesian design in that we can treat anywhere from 100 patients to up to 400 patients to get an idea of the efficacy [of such an approach].

Check back next Tuesday for the final episode in the series.

In this fourth episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, discuss the key objectives of the phase 3 LIMITLESS study (NCT05317858) examining low-intensity focused ultrasound with immunotherapy and chemotherapy in patients with lung cancer and brain metastases.

Examining LIFU–Aided Liquid Biopsy in Glioblastoma: Raising the Bar With the LIMITLESS Trial 

, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, both of Baptist Health South Florida, discuss the LIBERATE study (NCT05383872) examining low-intensity focused ultrasound (LIFU) in patients with glioblastoma.

: Thank you for sharing that, Mike. The first patient that [Dr McDermott] treated in the state of Florida was part of a bigger trial called LIBERATE; this is an FDA approval study [that will include] up to 50 patients who will [receive] LIFU. The intent of that trial is to see at least a two-fold increase in the circulating [tumor] DNA [ctDNA] of patients with glioblastoma, whether they are newly diagnosed or [have] recurrent [disease].

[In this] study, [we are looking] at the level of ctDNA in these patients before the procedure is done. Then, after the procedure is performed, we [will] collect blood at 30 minutes, an hour, and a couple hours after that. The FDA approval discussion [established that the trial would be successful] if [we observe] a two-fold increase in the level of ctDNA, and there is more than 75% concordance between what we find in terms of genomics of ctDNA that matches up with the surgery that neurosurgeons like Dr McDermott will do for patients [when] clinically indicated.

The trial is ongoing at multiple sites in North America, including Miami Cancer Institute, Mayo Clinic, and NYU [Langone]. The study is also open at University of Maryland, [as well as] a site in Toronto at Sunnybrook [Research Institute]. Numerous other sites are in the process of opening it.

Check back next Tuesday for the next episode in the series.

In this third episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, discuss the LIBERATE study (NCT05383872) examining low-intensity focused ultrasound in patients with glioblastoma.

Examining LIFU-Aided Liquid Biopsy in Glioblastoma: Key Objectives of the LIBERATE Trial

, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, both of Baptist Health South Florida, discuss the success observed with low-intensity focused ultrasound (LIFU) in essential tremors and the hope for this approach in brain cancer.

: Great, congratulations on some groundbreaking work. I know we’ve seen numerous patients with essential tremors really getting instantaneous benefit from high-intensity focused ultrasound. Could you talk to us a little bit about how you’ve seen patients derive benefit from this technology?

: My colleague, Justin Sporrer, MD, of Baptist Health South Florida, has treated over 100 patients with essential tremor since September 2021, when it was FDA approved and approved by Medicare. The benefit of this approach has been very dramatic, and as you said, it’s instantaneous.

We are using LIFU for targeting newly diagnosed or recurrent malignant gliomas 24 hours before surgery, collecting blood samples at 1, 2, and 3 hours after sonication, and then tissue biopsies at surgery. We’ve treated three patients on a clinical protocol for the liquid biopsy, as it’s called, using the low-intensity transducer to disrupt the blood–brain barrier in the hopes that we may be able to find small circulating tumor DNA [ctDNA] molecules in the patient’s circulation after the blood–brain barrier disruption. We’re correlating that with histochemical features that we derived from biopsies of the patient’s brain at the time of surgery. These are patients with newly diagnosed or recurrent gliomas, and they have surgery within 24 hours of LIFU.

Now, we don’t offer any potential therapeutic benefit from the LIFU, but it may help future patients. If we identify these molecules with consistency and sensitivity, those molecules could be used to help with diagnosis and to monitor the effects of treatment. There is a theoretical possibility that release of other protein compounds during the treatment may stimulate the immune system and lead to an indirect immune response to the tumor, which may prolong the time of tumor control.

In this second episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, discuss the success observed with low-intensity focused ultrasound in essential tremors and the hope for this approach in brain cancer.

Examining LIFU-Aided Liquid Biopsy in Glioblastoma: Deriving Benefit From the Technology

, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, both of Baptist Health South Florida, explain how low-intensity focused ultrasound (LIFU) works and the rationale for examining its use in cancer and other conditions.

: Hello everyone. My name is Manmeet Ahluwalia. I serve as the deputy director and Fernandez Family Foundation Endowed Chair in cancer research, as well as the chief of medical oncology and chief scientific officer of the Miami Cancer Institute, which is part of Baptist Health. I’m pleased to be joined today by my dear friend and incredible colleague, Dr Michael McDermott.

: Thank you Manmeet. For those in the audience, I currently serve as the chief medical executive officer of Miami Neuroscience Institute. I’m in charge of neurosurgery, neurology, physiatry, and acute rehab services for patients with conditions of the central and peripheral nervous system. I hold the Irma & Kalman Bass Endowed Chair in clinical neuroscience. It’s our pleasure to be able to offer medical services to the patients in South Florida.

: Thank you so much, Mike. Today, we are gathered via Zoom to talk about low frequency ultrasound and its use in brain tumors. Mike, you’ve been working on this technology recently. Could you explain to our viewers how this technology works? Also, could you talk about non-oncologic avenues where you have used this [technology] to help patients?

: There are two different frequencies—LIFU and high-intensity focused ultrasound—for medical applications in the brain. A high-intensity focused ultrasound is more energetic and can make lesions in the brain over a period of 50 minutes. Currently, that is used for essential tremor that is disabling and some cases of Parkinsonian-associated tremor, which is disabling. We use LIFU for brain tumor applications with attempts to open the blood–brain barrier and release tumor-associated DNA into the circulation and for non-tumor applications particularly for investigation of the effects on memory function in patients with diagnosed Alzheimer disease. Both of these applications of LIFU are done in the setting of a clinical research trial.

Currently, there’s a state-of-Florida–funded research study for Alzheimer disease that’s planned to accrue 25 patients at several sites. We are one of those sites; I’m the co-principal investigator with Patricia Junquera, MD, FAPA. Once the patients are screened, and we can identify an amyloid-positive site in the brain that may be a good target for us, then we can treat those sites with LIFU. We treat the patient, in that setting, three different times, one week apart, targeting the PET Tau amyloid-positive areas, up to six sites and 40 cc in total volume.

We use a contrast agent from the cardiac ultrasound world called Definity; that is essentially a lipid bilayer sphere containing small gas bubbles. The ultrasound waves that pass through the blood vessels in the brain where the Definity microbubbles are, releases the gases from the microbubbles, which transiently disrupts the blood–brain barrier for about 24 hours.

There is preclinical evidence to suggest that the disruption of the blood–brain barrier is safe, not harmful, and it allows for clearance of some of the Tau proteins. As such, the hypothesis is that repeated treatments will allow for clearance of Tau, which may in some way affect cognitive abilities, and that with clearance, cognitive abilities will either stabilize or improve.

In this first episode of OncChats: Examining LIFU–Aided Liquid Biopsy in Glioblastoma, Manmeet Singh Ahluwalia, MD, MBA, FASCO, and Michael W. McDermott, MD, explain how low-intensity focused ultrasound works and the rationale for examining its use in cancer and other conditions.

Michael W. McDermott, MD

Articles

Examining LIFU–Aided Liquid Biopsy in Glioblastoma: Excitement Surrounding Focused Ultrasound Waves

Examining LIFU–Aided Liquid Biopsy in Glioblastoma: Raising the Bar With the LIMITLESS Trial

Examining LIFU-Aided Liquid Biopsy in Glioblastoma: Key Objectives of the LIBERATE Trial

Examining LIFU-Aided Liquid Biopsy in Glioblastoma: Deriving Benefit From the Technology

Examining LIFU-Aided Liquid Biopsy in Glioblastoma: Overview and Rationale