Induction of cancer testis antigen expression in circulating acute myeloid leukemia blasts following hypomethylating agent monotherapy

Abstract

Cancer testis antigens (CTAs) are promising cancer associated antigens in solid tumors, but in acute myeloid leukemia, dense promoter methylation silences their expression. Leukemia cell lines exposed to HMAs induce expression of CTAs. We hypothesized that AML patients treated with standard of care decitabine (20mg/m2 per day for 10 days) would demonstrate induced expression of CTAs. Peripheral blood blasts serially isolated from AML patients treated with decitabine were evaluated for CTA gene expression and demethylation. Induction of NY-ESO-1 and MAGEA3/A6, were observed following decitabine. Re-expression of NY-ESO-1 and MAGEA3/A6 was associated with both promoter specific and global (LINE-1) hypomethylation. NY-ESO-1 and MAGEA3/A6 mRNA levels were increased irrespective of clinical response, suggesting that these antigens might be applicable even in patients who are not responsive to HMA therapy. Circulating blasts harvested after decitabine demonstrate induced NY-ESO-1 expression sufficient to activate NY-ESO-1 specific CD8+ T-cells. Induction of CTA expression sufficient for recognition by T-cells occurs in AML patients receiving decitabine. Vaccination against NY-ESO-1 in this patient population is feasible.

Dendritic Cell Therapies for Hematologic Malignancies

“…Expression of such cancer testis antigens may vary across different disease states. For example, expression of the cancer testis antigens NY-ESO-1 and MAGEA3/A6 increases on leukemic blasts following treatment with the hypomethylating agent decitabine in human patients with acute myelogenous leukemia 18 . Likewise, expression of the cancer testis antigen NXF2 is increased on neoplastic lymphocytes after the administration of decitabine in patients with chronic lymphocytic leukemia 19 .…”

EWSR1-FLI1 Activation of the Cancer/Testis Antigen FATE1 Promotes Ewing Sarcoma Survival

“…The mechanisms that activate the expression of CT antigens are poorly defined. While DNA demethylation is thought to contribute significantly to expression in cancer cells and is exploited clinically, the specific factors that activate transcription following demethylation have been poorly described (25,49,50). Here, we report EWSR1-FLI1 as the first chimeric oncogenic transcription factor to directly activate CT antigens.…”

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

“…However, we believe that combinatorial approaches are the most promising strategy to further enhance immune responses and hence clinical benefit. Epigenetic modifiers such as DNA methyltransferase inhibitors and histone deacetylase inhibitors are suitable combination partners because of an enhancement in antigen processing and presentation of malignant cells . In the setting of myelodysplastic syndrome, the combination of vaccination against NY‐ESO‐1 and decitabine resulted in an increased antigen‐specific immune response .…”

“…Epigenetic modifiers such as DNA methyltransferase inhibitors and histone deacetylase inhibitors are suitable combination partners because of an enhancement in antigen processing and presentation of malignant cells. [22][23][24][25] In the setting of myelodysplastic syndrome, the combination of vaccination against NY-ESO-1 and decitabine resulted in an increased antigen-specific immune response. 26 In our hands, the combination of next-generation DC vaccination with 5azacytidine resulted in a striking increase in local and systemic immune responses.…”