Combining Hypomethylating and Immuno-Oncology Agents

Hypomethylating agents (HMAs) are epigenetic modifiers that have been shown to activate immune responses in preclinical studies. This is hypothesized to enhance secretion of interferon, induce T-cell activity, modulate dendritic cells, and lead to malignant cell death. It is also hypothesized that HMAs reactivate epigenetically silenced tumor suppressor genes.1-7

Expression of PD-L1 may help tumor cells evade immune responses. Interaction of PD-L1 with PD-1 expressed on T cells has been shown in vitro to dampen the T-cell response.8-9

Preclinical studies have demonstrated that inhibiting signaling of the PD-1–PD-L1 pathway increases immune activation and anti-tumor immune functions.10-13

Both HMAs and anti–PD-L1 antibodies activate the immune system via different pathways.1-7,10-12 Combining anti–PD-L1 antibodies with HMAs is hypothesized to overcome tumor-mediated immune escape and enhance the anti-tumor effects and immune activation induced by HMAs.1,14,15

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

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  5. Goodyear O, et al. Blood. 2012;119:3361-3369.
  6. Costantini B, et al. Haematologica. 2013;98:1196-1205.
  7. Frikeche J, et al. Exp Hematol. 2011;39:1056-1063.
  8. Sznol M, Chen L. Clin Cancer Res. 2013;19:1021-1034.
  9. McDermott DF, Atkins MB. Cancer Med. 2013;2:662-673.
  10. Görgün G, et al. Clin Cancer Res. 2015;21:4607-4618.
  11. Kondo A, et al. Blood. 2010;116:1124-1131.
  12. Ray A, et al. Leukemia. 2015;29:1441-1444.
  13. He J, et al. Sci Rep. 2015;5:13110.
  14. Li H, et al. Oncotarget. 2014;3:587-598.
  15. Heninger E, et al. Front Immunol. 2015;6:29.