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

In this fourth episode of 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, 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.

Ahluwalia: 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?

McDermott: 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.

Ahluwalia: 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.