From the Journals

CLTX-CAR T cells exhibit preclinical activity and move on to a clinical trial


 

FROM SCIENCE TRANSLATIONAL MEDICINE

Chlorotoxin (CLTX)-directed chimeric antigen receptor (CAR) T cells demonstrated activity against glioblastoma in a preclinical study and will soon be tested in a clinical trial.

“We sought to develop a CAR T cell using chlorotoxin peptide as the tumor-targeting domain,” wrote Dongrui Wang, a PhD candidate at City of Hope National Medical Center in Duarte, Calif., and colleagues. Their report is in Science Translational Medicine.

“CLTX has been established to bind broadly and specifically to glioblastoma and other neuroectodermal tumors while showing minimal cross-reactivity with nonmalignant cells,” the researchers noted.

The team evaluated CLTX binding capacity in 23 tumor samples from 15 glioblastoma patients, in patient-derived glioblastoma cell lines, and in orthotopic mouse xenograft models. These experiments showed that CLTX could bind to a high percentage of patient tumors as well as to most glioblastoma cells within a tumor.

In the design phase, the researchers engineered a peptide-bearing CAR, which overcame previous barriers of other glioblastoma-directed CARs, including antigen escape and tumor heterogeneity.

The team evaluated the antitumor activity of CLTX-CAR T cells in two orthotopic mouse xenograft models. Intracranial administration of CLTX-CAR T cells controlled tumor growth and extended survival in both models. All mice originally bearing PBT106-TS tumors became tumor-free and remained so for more than 170 days. However, only a subset of mice bearing PBT003-4-TS tumors experienced similar long-term tumor-free survival.

The researchers assessed potential off-target effects of CLTX-CAR T cells in normal human cells. The team observed limited binding of CLTX-CAR T cells to embryonic kidney cells, peripheral blood mononuclear cells, and neural progenitor cells, suggesting minimal off-target activity.

Further toxicity experiments demonstrated that, even at high doses, CLTX-CAR T cells were tolerated in mouse models, suggesting high potency for tumor cells and low risk of systemic toxicity.

Additional preclinical experiments elucidated mechanisms of CLTX-CAR T-cell function, namely the essential role of matrix metalloproteinase 2 expression for cell activation.

The researchers acknowledged that a key limitation of this study was the use of glioblastoma xenograft models, which may not fully represent tumor activity in glioblastoma patients.

Nevertheless, the researchers concluded that “CLTX-CAR T cells present a strategic combination of selective yet ubiquitous tumor targeting and are a candidate for clinical development as anti-glioblastoma immunotherapy.”

In fact, City of Hope is now screening patients for a clinical trial of CLTX-CAR T cells for the treatment of recurrent or progressive glioblastoma (NCT04214392).

The preclinical research was funded by the Ben and Catherine Ivy Foundation and the National Institutes of Health. Two authors disclosed financial affiliations with Mustang Bio.

SOURCE: Wang D et al. Sci Transl Med. 2020 Mar 4. doi: 10.1126/scitranslmed.aaw2672.

Next Article: