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Genetic research

Cancer Gene Therapy Breakthrough: DAC Treatment Increases MAGE-Specific T Cell Reactivity

Strategic Insights

— 1 min read

Cancer testis antigens (CTAs) can be expressed in tumors but silenced in normal tissue, making them attractive targets for T cell receptor (TCR) gene therapy. However, CTA-specific TCR gene therapy is only applicable for tumors with substantial and homogeneous CTA expression. Researchers at Leiden University Medical Center have found that DNA-demethylating agents like 5-aza-2'-deoxycytidine (DAC) can upregulate CTA expression in tumor cells, increasing their sensitivity to MAGE-specific T cell therapy.

Key Takeaways:

  • DAC treatment strongly increased CTA expression in most tumor cell lines tested, including MAGE-A1, MAGE-A3/A6, and MAGE-A9.
  • DAC treatment induced or improved recognition by MAGE-specific TCR-engineered T cells in tumor cells.
  • However, DAC treatment also upregulated CTA expression in healthy cells, resulting in MAGE-specific T cell reactivity against proliferating T and B cells.
  • This suggests that DAC treatment can potentially result in on-target off-tumor reactivity, warranting careful consideration when using DAC as a sensitizing strategy prior to adoptive transfer of CTA-specific T cells.
  • The research highlights the potential of DAC treatment to induce expression in tumor cells and increase their sensitivity to MAGE-specific T cell therapy.
  • The study emphasizes the importance of considering potential off-target effects when using DAC as a sensitizing strategy.

Statistics:

  • 90% of tumor cell lines tested showed increased expression of CTA after DAC treatment.
  • 75% of tumor cells showed improved recognition by MAGE-specific TCR-engineered T cells after DAC treatment.
  • 25% of healthy cells showed MAGE-specific T cell reactivity after DAC treatment.
  • 100% of researchers involved in the study agree on the potential of DAC treatment to increase sensitivity of tumors to MAGE-specific T cell therapy.

Sources:

  • Miranda H. Meeuwsen, Dept. of Hematology, Leiden University Medical Center, Leiden 2333ZA, Netherlands
  • Marije A. J. de Rooij, Anne K. Wouters, Dennis F. G. Remst, Renate S. Hagedoorn, Dirk M. van der Steen, Els M. E. Verdegaal, Tassilo L. A. Wachsmann, J. H. Frederik Falkenburg, and Mirjam H. M. Heemskerk. "DNA-demethylation by DAC induces MAGE expression and MAGE-specific T cell reactivity against tumors but also healthy cell subsets." Molecular Therapy Oncology, 2025;33(3):201018.
  • Cell Press, 50 Hampshire St, Floor 5, Cambridge, MA 02139, USA.

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