Looking to Scorpion Venom for GBM Treatment

When engineered into chimeric antigen receptor (CAR) T cells, chlorotoxin (CLTX)—a peptide component of the deathstalker scorpion's venom—may help pinpoint glioblastoma (GBM) cells for destruction. This concept, developed by researchers at City of Hope Comprehensive Cancer Center in Duarte, CA, has shown preclinical promise and will soon enter a first-in-human study (Sci Transl Med 2020;12:eaaw2672).

CLTX “probably helps scorpions deliver poison into their prey's nervous system, while not being toxic itself—which is loosely reminiscent of how we're applying it now,” says Michael Barish, PhD, a co–senior author. “It's evolved through predator–prey relationships to have rather exquisite specificity, with useful therapeutic outcomes for us.”

CLTX's binding affinity for GBM and other neuroectodermal tumors, sparing normal tissue, was established a couple of decades ago, says co–senior author Christine Brown, PhD. Since then, it's been developed as ¹³¹I-conjugated radiotherapy for high-grade glioma, used to coat nanoparticles for targeted drug delivery, and turned into a fluorescence imaging tool, enabling more precise brain tumor resection. The imaging tool, called “Tumor Paint,” was created by James Olson, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, WA. “It's his work we're building on,” Brown notes. “We wanted to get from tumor binding to tumor killing, by exploiting CLTX in CAR T cells.”

Graduate student Dongrui Wang was tasked with achieving this goal, which involved going beyond the familiar terrain of antibody-based constructs (commonly targeting CD19) to ligand–receptor CARs. “We did have some experience” with the latter, he says, but pioneering an optimal design to incorporate a peptide toxin targeting the membrane-associated protein MMP2, a crucial part of CLTX's receptor complex, was challenging.

Interestingly, Wang observes that “our construct worked much better with CD28 as a costimulatory domain,” instead of 4-1BB. Possible reasons why remain unknown, but the field “has had this idea for a while now that 4-1BB is a preferable design,” Brown notes, “and our data seem to suggest something different.”

In patient-derived xenograft models, potent anti-GBM activity and tumor regression were seen with CLTX–CAR T cells, Wang says—even when there was minimal expression of IL13Rα2, HER2, or EGFR, three key GBM antigens. The therapy was also active against glioma stem cells, a subpopulation that often seeds recurrence. Treatment was well tolerated, with no off-target effects or other toxicities.

Encouraging preclinical safety aside, CLTX–CAR T cells' potential immunogenicity in humans “is difficult to model,” Brown says, “so it will be an important end point” in the phase I trial. “We're screening patients based on tumor MMP2 expression,” she adds, “because that's essential for CAR T recognition and targeting.”

Antonio Iavarone, MD, of Columbia University in New York, NY, considers CLTX–CAR T cells “a novel approach that should allow more comprehensive targeting of a highly heterogeneous cancer.” In general, GBM remains a poor candidate for immunotherapy, but Iavarone and others are gradually unearthing features, in small subsets of patients, that may better predict benefit. He therefore lauds patient stratification, such as Brown's team is doing, as “absolutely key” (Commun Biol 2, 135 [2019]).

“The more molecular profiling up front, the more likely that even if a given trial turns out negative, it will still be informative,” Iavarone says. He hopes for clinical efficacy with CLTX–CAR T cells but thinks concurrent immune checkpoint inhibition may well be necessary, based on the researchers having shown that one route of treatment resistance is PD-L1 induction.

“Once we've shown our therapy is safe in people, we do want to start a combination study,” Brown agrees. She's encouraged that despite the disease's seeming intractability, “there are more CAR T trials for GBM than any other solid tumor. It should accelerate our understanding of what can be achieved, therapeutically, for this population.” –Alissa Poh

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