MONTREAL – Adding an immunostimulatory cytokine to chimeric antigen receptor–T cells (CAR-T) improved the adaptive immunotherapy’s activity against aggressive pediatric brain malignancies both in vitro and in animal models, an investigator reported.
CAR-T cells engineered to express interleukin-15 (IL-15), an inducer of T-cell proliferation and survival, were associated with significantly longer progression-free survival (PFS) and overall survival in mouse models of glioma, compared with regular CAR-T cells, said Giedre Krenciute, PhD, of Baylor College of Medicine in Houston.
Dr. Giedre Krenciute
The improved T-cell persistence, however, still resulted in the eventual loss of both targeted and nontargeted tumor-associated antigens and tumor recurrence, Dr. Krenciute noted.
The results suggest that T-cell persistence is critical for antitumor activity, and that it will be necessary to perform antigen profiling of recurrent tumors in order to develop follow-on therapies targeting multiple tumor-associated antigens, she said.
Her team had previously reported on the development of a CAR-T cell directed specifically against the IL-13 receptor alpha-2, which is expressed at high frequency in diffuse intrinsic pontine glioma and glioblastoma tumors but not in normal brain tissues.
In preclinical models, the construct had potent antiglioblastoma activity. However, the T-cells had only limited persistence, and tumors positive for IL-13 receptor alpha-2 recurred.
To see whether they could improve on T-cell persistence, they took their CARs back to the shop and modified them with a retroviral vector to express IL-15 transgenes. They then tested the altered cells in vitro using standard assays and found that the addition of IL-15 did not change the T-cell phenotype or affect the cells’ cytotoxicity.
The addition of IL-15 significantly improved the persistence of the T cells when they were injected into the tumors of mice with human glioblastoma xenografts (P less than .05), and this persistence translated into a near-doubling of PFS, compared with regular CAR-T cells (media, 84 days vs. 49 days; P = .008), as well as improved overall survival (P = .02).
Of 10 mice that received the IL-15–expressing CAR-Ts, 4 were free of glioma through at least 80 days of follow-up.
Of five mice with recurring gliomas, three had down-regulated expression of the IL-13 receptor alpha-2 target, indicating immune escape, and all recurring tumors had reduced expression of the human epidermal growth factor receptor-2 antigen, which is associated with gliomas.
The investigators are currently test-driving a new CD20-targeted CAR, transduced to express IL-15, and have seen good expansion and persistence of the T cells for up to 15 days in culture, with in vivo tests in the planning stage, Dr. Krenciute said.
The work is supported by the National Institutes of Health, Alex’s Lemonade Stand Foundation, the James S. McDonnell Foundation, and the American Brain Tumor Association. The laboratory, the Center for Cell and Gene Therapy at Baylor, has or had research collaborations with Celgene, Bluebird Bio, and Tessa Therapeutics, and investigators at the center hold or have applied for patents in T-cell and gene-modified T-cell therapies for cancer.