Imaging Agent from Scorpion Venom May Improve Brain Tumor Resection

Michael Vlessides

May 30, 2019

An imaging agent derived from scorpion venom may offer neurosurgeons a novel imaging technique to improve surgical resection of gliomas.

New phase 1 study data show tozuleristide (BLZ-100) — a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore, indocyanine green — provided a viable fluorescence signal in both high- and low-grade glial tumors. Signal intensity in high-grade tumors was found to improve with increasing doses of tozuleristide, regardless of the time of dosing relative to surgery.

"This was an escalating-dose trial where we increased the dose of tozuleristide

from 3 mg to 30 mg," principal investigator Adam Mamelak, MD, told Medscape Medical News. "And we showed was that there were no serious toxicities at doses up to 30 mg."

"The other exciting finding was that if we saw fluorescence, it was always a tumor," added Mamelak, director of the Functional Neurosurgery Program at Cedars Sinai Medical Center in Los Angeles, California. "And if we didn't see fluorescence, it was largely not a tumor."

The study was published online May 9 in Neurosurgery.

A Surgical Challenge

Surgery remains one of the primary treatment modalities among patients with malignant brain tumors. Of these, tumor resection offers the greatest chance of long-term and progression-free survival.

Nevertheless, surgeons are often challenged in distinguishing tumors from normal brain tissue, because of their similar appearance and the infiltrative nature of brain tumors. With that in mind, novel intraoperative imaging technologies may help surgeons identify tumor margins in real time, an innovation that may ultimately lead to more complete — and precise — resection.

Although MRI and CT are currently used in surgical planning, previous research has shown that the accuracy of both methods is limited when tissues are shifted during surgery, making these techniques less reliable as tumor resection progresses.

MRI and ultrasound can be used intraoperatively during tumor resection, but have been shown to be challenged by poor resolution, prolonged operative times, high cost, and disruption of surgical workflow.

In light of such shortcomings, some clinicians have turned to fluorescence-guided surgery, an emerging technology that combines detection devices with fluorescent contrast agents.

Tozuleristide is one such contrast agent, a peptide/fluorophore conjugate in development that selectively binds to neoplastic tissue and fluoresces in the near-infrared range. Interestingly, the peptide component of tozuleristide is a 36 amino acid synthetic peptide that is derived from chlorotoxin in scorpion venom.

No Toxicity

Preclinical toxicology research indicates that tozuleristide was well-tolerated, and preclinical imaging studies show it selectively binds to human and animal tumors with good tumor-to-background signal.

"These studies demonstrated that tozuleristide appears to bind to glioma cells of all different grades, but not normal tissues," said Mamelak.

The current study included 17 adult patients (ages 18-75) with grade 1-4 glioma and an indication for surgical resection. Individuals with recurrent disease were eligible for the trial if their previous brain surgery was performed at least 3 months prior to the study surgery.

The researchers used a 3+3 dose-escalation design to identify the maximum dose of tozuleristide tolerated by patients. The experimental agent was administered as an IV bolus injection over 1 to 5 minutes, between 3 and 29 hours prior to surgery. The dose was stopped or modified if potential adverse drug reactions posed a health risk.

"The purpose of this phase 1 trial was to 'dose find' and show that the agent is not toxic," said Mamelak. "That's what the FDA mandated and that's how the study was designed."

Participants all underwent standard craniotomy according to clinical criteria and surgeon-preferred method. They were monitored for at least 7 days after surgery for safety monitoring and for at least 30 days for serious adverse event reporting. Laboratory tests were conducted at screening and pre-surgery, as well as 24 hours after surgery and 7 days post-dose.

Fluorescence signals in both tumor and nontumoral tissues were measured in situ in the surgical cavity and ex vivo through tissue specimens removed at the time of surgery. Three independent reviewers scored images for each case.

The trial showed that tozuleristide was well-tolerated by participants. Indeed, patients reported no dose-limiting toxicities. Similarly, the maximum tolerated dose was not identified, as dose escalation continued to the maximum pre-specified dose level of 30 mg.

No Uptake in Some Tumors?

Nine participants experienced treatment-emergent adverse events, though none was deemed to be related to tozuleristide. Similarly, three serious adverse events were reported in three patients, though none were considered by the investigators to be related to tozuleristide.

With respect to pharmacokinetics, tozuleristide's half-life increased with doses between 3 mg and 24 mg, but not at the 30-mg dose. This, the investigators note, indicates that the agent is rapidly cleared from blood 1 to 2 hours after injection.

Ex vivo imaging studies showed that 12 of the 17 tumors demonstrated positive fluorescence. At tozuleristide doses of at least 9 mg or higher, all 6 high-grade tumors showed positive fluorescence ex vivo. Interestingly, 4 of 8 low-grade tumors also showed positive fluorescence ex vivo at these doses.

The investigators also performed flat-bed scans on the tissue samples, which control for variables such as camera distance and ambient light. These data correlated with ex vivo imaging results and demonstrated a clear positive association between tozuleristide dose and fluorescence intensity.

Nevertheless, fluorescence in low-grade tumors was less consistent, as a relationship between dose and signal was not apparent.

"The caveat here is there were some cases where there was no fluorescence; the tumors didn't take up any fluorescent signal at all and it wasn't clear if that was because our imaging system wasn't perfect or if there is a subset of tumors that just doesn't take up enough of the tozuleristide," Mamelak said.

Promise of Greater Low-Grade Tumor Detection

The findings are consistent with previous research on tozuleristide and help demonstrate that imaging with the agent can be reliably performed on the day of surgery or 1 day postoperative.

"Administering tozuleristide a few hours before the start of surgery allows for sufficient tumor uptake and clearance of unbound drug from the blood for optimal imaging," — a finding that is "consistent with the observed half-life in blood of [approximately] 30 minutes," the authors write.

Investigators also found fluorescence-positive examples among tumors ranging from grade 1 to 4, a finding that suggests tumor grade does not influence tozuleristide uptake.

Nevertheless, future research might consider using optimal tozuleristide doses and including detailed molecular analysis, which may help identify which tumor types demonstrate consistent fluorescence.

Although the investigators urged caution when interpreting the results of the phase 1 study, they were most encouraged by the agent's demonstrated fluorescence in half of the non-enhancing low-grade gliomas.

"The ability to identify low-grade glioma and infiltrating margins of low-grade tumor remains one of the great promises for fluorescence-guided surgery," they write.

"Neither fluorescein nor indocyanine green demonstrates meaningful fluorescence for these tumors, and 5-ALA has also proven disappointing with less than 20% of low-grade tumors showing uptake," they add.

Given that ongoing efforts with tozuleristide will likely include more uniform drug-dosing regimens and will utilize imaging technology optimized for neurosurgery, greater detection of low-grade gliomas is a reality in the future.

Potential for Improved Survival

In an accompanying commentary, Alireza M. Mohammadi, MD, from the Cleveland Clinic in Ohio, said that extent of resection is known to impact survival outcomes after glioma surgery.

"Intraoperative imaging and neuronavigation are tools that are being used for this purpose," commented Mohammadi, who was not involved in the study. "However, there are limitations associated with them, like prolonged operative times, high cost, and disruption of surgical workflow. Fluorescence-guided surgery is a cheaper technique to improve extent of resection and is proven to be effective, at least for centers [for which] intraoperative magnetic resonance imaging was deemed not to be cost effective."

Mohammadi noted that although the study demonstrated that tozuleristide was safe and had acceptable results in ex vivo imaging, in situ imaging yielded less-promising results. This, he said, would need to be investigated and fixed for phase 2 and phase 3 trials.

"Especially if this agent is going to be used for fluorescence-guided surgery like 5-aminolevulinic acid and indocyanine green, its major use will be intraoperative and not ex vivo," Mohammadi said. "Overall, this is a strong first step and we will stay tuned for phase 2-3 results."

Study investigator Mamelak explained that while the novel technique may not prove curative for individuals with glioma, it will certainly help achieve surgical success.

"For many people with gliomas — and other kinds of malignancies in the brain — I think the realistic expectation is that this approach will be able to improve the extent of how much tumor can be removed safely," he said.

"Because it turns out that this is a very tricky problem," he added. "There are many times where a little piece of the tumor is inadvertently left behind in this big messy field or there are whole areas you don't appreciate.

"So I think a technique like this would significantly increase surgical confidence in what surgeons are removing, and will result in more complete resections with less removal of normal tissues.

"Is it a cure in and of itself?" he added. "In some cases it might be, but in many cases it won't. Because in most gliomas, surgery itself is not a curative therapy. In fact, most of these tumors recur anyway, even after radiation and chemo. But the extent of resection is very highly correlated with better quality of life and longer survival.

"So I think it's yet another weapon in the armamentarium of trying to get better outcomes for patients with these tumors."

The study was sponsored by Blaze Bioscience, Inc. Mamelak disclosed that he serves as a consultant for, and is a shareholder in, Blaze Bioscience, Inc. Mohammadi has disclosed no relevant financial relationships.

Neurosurgery. Published online May 9, 2019. Abstract

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