Armored CAR T cells safe, clinically active in advanced pediatric liver cancer
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A novel armored chimeric antigen receptor T-cell therapy targeting the glypican-3 protein showed antitumor activity among children with advanced liver cancer, according to preliminary results of a phase 1 trial presented at the virtual American Society of Gene and Cell Therapy Annual Meeting.
The armored glypican-3 (GPC3) CAR T-cell therapy also exhibited an acceptable safety profile.
Glypican-3 is heavily expressed by multiple liver tumors but normally absent in healthy tissue, making it an attractive target for CAR T-cell therapy, according to David Steffin, MD, assistant professor at Baylor College of Medicine.
“For all liver tumors, two-thirds of those who relapse or are refractory to initial treatment died of their disease,” Steffin said during a presentation. “As a result, we need to develop novel therapies to overcome this obstacle.”
The primary objective of the phase 1 dose-escalation portion of the trial was to evaluate the safety of GPC3 CAR T cells among children aged 1 to 18 years with relapsed or refractory liver cancer and establish a recommended dose of cells for the phase 2 portion of the study. Secondary objectives included measuring CAR T-cell persistence and antitumor activity, as well as examining changes in gene and protein expression of cells within the tumor microenvironment to identify potential immune escape mechanisms.
Researchers graded toxicity according to Common Terminology Criteria for Adverse Events version 5 and evaluated CAR T-cell activity at 4 to 6 weeks after infusion based on RECIST version 1.1.
All patients received lymphodepletion chemotherapy before infusion with GPC3 CAR T cells.
Steffin and colleges presented interim results of the first three patients — girls aged 3, 7 and 13 years — enrolled and treated with the lowest-level dose (1 × 107 cells/m2) of GPC3 CAR T-cells in the study. Complete safety and treatment response evaluations were available for two of the girls.
Results showed no infusion-related or serious adverse events and no dose-limiting toxicities.
The greatest toxicities were hematologic and likely related to lymphodepletion chemotherapy, Steffin said. Other mild adverse events included headache, fatigue and rash, all of which resolved without additional intervention, he added.
All three girls had evidence of CAR T cells in peripheral blood, with two showing greater than 40-fold CAR T-cell expansion by the second week after infusion, as revealed by reverse transcription polymerase chain reaction. Researchers observed evidence of circulating CAR T cells for at least 4 weeks after infusion.
The two girls with complete evaluations showed a greater than 60% decrease in alpha-fetoprotein levels, a known marker of liver tumors.
Antitumor response assessment showed one girl had progressive disease at week 5 after infusion, although her primary lesion size remain unchanged and multiple metastatic lung lesions either decreased in size or disappeared. The second girl had stable disease of a single mediastinal mass at 5 weeks after infusion. Imaging is pending for the third girl.
“Even at this lowest dose level, we have been able to demonstrate that the treatment has been safe thus far with some efficacy,” Steffin said.
The trial continues to enroll patients, he added, and new enrollees will receive higher doses. Another ongoing trial is using the same CAR construct for adults with liver cancer. – by Drew Amorosi
Reference:
Steffin DHM, et al. Abstract 486. Presented at: ASGCT Annual Meeting; May 11-15, 2020 (virtual meeting).
Disclosure: Steffin reports no relevant financial disclosures.
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