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Combination of Chemotherapy and T-Cell Immunotherapy May Provide Novel Treatment Strategy for Glioblastoma

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Key Points

  • The combination of decitabine and T-cell immunotherapy in the treatment of glioblastoma in mouse models has demonstrated antitumor activity against the cancer and was about 50% effective at curing the disease in the mice.
  • The study demonstrated that engineered T-cell receptor–induced T cells migrate through the parenchyma of the brain, eliciting enhanced therapeutic benefit after systemic delivery in mice harboring intracranial gliomas.
  • A combination of epigenetic modulation and targeted immunotherapy provides a novel systemic treatment strategy for malignant gliomas.

A preclinical study has found that a combination of decitabine and T-cell immunotherapy demonstrated antitumor activity against glioblastomas in mouse models and was about 50% effective at curing the disease. The results, reported by Everson et al in Neuro-Oncology, show an innovative, clinically feasible strategy in the treatment of glioblastoma. If the results in studies in other brain tumor models are promising, the researchers will test this novel systemic treatment strategy for malignant gliomas in human clinical trials.

Study Methodology

The researchers used human glioblastoma cell cultures to induce expression of the New York-Esophageal Squamous Cell Carcinoma (NY-ESO-1) gene, following in vitro treatment with the demethylating agent decitabine. The researchers then investigated the phenotype of NY-ESO-1–specific lymphocytes using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay.

Finally, the researchers examined the in vivo application of this immune therapy using an intracranially implanted xenography model for in situ T-cell trafficking, survival, and tissue studies.

Study Results

The investigators found that the treatment of intracranial glioma–bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1–specific lymphocytes along white matter tracks to these tumors in the brain.

Similarly, NY-ESO-1–specific adoptive T-cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. The transfer of NY-ESO-1–specific T cells systemically was superior to intracranial administration, and resulted in significantly extended and long-term survival of the animals.

“Brain cancer cells are very good at evading the host immune system, because they do not express specific targets that can be recognized by immune cells,” said Linda M. Liau, MD, PhD, Professor and Vice Chair of Neurosurgery at UCLA Jonsson Comprehensive Cancer Center, and a coauthor of this study, in a statement. “By treating glioblastoma cells with decitabine, we found that we can unmask targets on the tumor cell that can be recognized by killer T cells. Once these targets are uncovered, we can then administer T cells that are genetically programmed to attack tumor cells with the new targets.”

The researchers plan to verify these study findings in other brain tumor models and if the results are promising, they will test this novel systemic treatment strategy for malignant gliomas in human clinical trials.

Dr. Liau and Robert M. Prins, PhD, of UCLA Jonsson Comprehensive Cancer Center, are co-corresponding authors for the Neuro-Oncology study.

Funding for this study was provided by the National Institutes of Health, the Eli & Edyth Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, the STOP Cancer Foundation, the Jonsson Comprehensive Cancer Center Foundation, and the AANS Neurosurgery Research Education Fund. The study authors reported no potential conflicts of interest.

 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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