First CLTX-Directed CAR T-Cell Therapy Expands Landscape of Tumor-Selective CAR T cells in Glioblastoma

The first chimeric antigen receptor (CAR) T-cell therapy to utilize chlorotoxin (CLTX) to direct T cells to target cancer cells in the brain has been developed at City of Hope and demonstrated antitumor activity in a preclinical study. Based on these findings, a first-in-human clinical trial has opened enrollment at City of Hope for patients with recurrent or progressive glioblastoma (NCT04214392).¹

With this new approach to CAR T-cell therapy, CLTX is used as part of a CAR construct to redirect cytotoxic T cells at glioblastoma. In the preclinical study, the antitumor activity was robust and specific in mouse models.²

CLTX binding was found in a greater proportion of tumor and patient-derived glioblastoma cells when investigators evaluated the treatment with other CAR immunotherapy targets, such as IL13Ra2, HER2, and EGFR.^1,2Binding CLTX includes glioblastoma stem-like cells that were associated with seed tumor recurrence.

CLTX-CAR T cells were able to recognize and kill broad populations of glioblastoma cells. At the same time, the T cells ignored the nontumor cells in the brain and other organs, demonstrating that this therapy is highly effective in selectively killing human glioblastoma cells in both cell-based assays and animal models.

“Much like a scorpion uses toxin components of its venom to target and kill its prey, we’re using chlorotoxin to direct the T cells to target the tumor cells with the added advantage that the CLTX-CAR T cells are mobile and actively surveilling the brain looking for appropriate targets,” Michael Barish, PhD, said in a statement. “We are not injecting a toxin, but exploiting CLTX’s binding properties in the design of the CAR. The idea was to develop a CAR that would target T cells to a wider variety of GBM tumor cells than the other antibody-based CARs.”

Barish, chair of the Department of Development and Stem Cell Biology at City of Hope, initiated the development of this CAR T-cell product to target glioblastoma cells. He added, “The notion is that the higher the proportion of tumor cells that one can kill at the beginning of treatment, the greater the probability of slowing down or stopping GBM growth and recurrence.”

The study opening at the City of Hope is a phase I clinical trial that will evaluate the feasibility and safety of CLTX-directed CAR T-cell therapy for patients with glioblastoma. To be included in the study, patients must have an ECOG performance status ≤2, a Karnofsky performance status of ≥60%, and a life expectancy of at least 4 weeks. The patients should have grade IV glioblastoma or grade II/III malignant glioma that had a radiographic progression that is consistent with stage IV.

The primary end point is dose-limiting toxicity, while secondary end points include cytokine levels, progression-free survival, disease response, and overall survival, among others.

While glioblastoma is among the deadliest cancers, it is also the most common type of brain cancer. However, this disease is difficult to treat when the tumor disseminates throughout the brain. The study team at the City of Hope plans to bring the CLTX-directed CAR T-cell therapy to patients with glioblastoma in hopes of improving outcomes. Patients are currently being screened for enrollment to the first-in-human clinical trial.

References:

1. From scorpion to immunotherapy: City of Hope scientists repurpose nature’s toxin for first-of-its kind CAR T cell therapy to treat brain tumors [news release]. Duarte, CA: City of Hope; March 4, 2020.https://story.cision.com/r/3gErsD. Accessed March 6, 2020
2. From scorpion to immunotherapy: City of Hope scientists repurpose nature’s toxin for first-of-its kind CAR T cell therapy to treat brain tumors [news release]. Duarte, CA: City of Hope; March 4, 2020.https://story.cision.com/r/3gErsD. Accessed March 6, 2020.