Immunotherapy: Open Access
Open Access

5-Azacytidine Therapy in the Immunogenicity of Acute Myeloid Leukemia

Curtis Pondman^{* *}Correspondence: Curtis Pondman, Department of Immunology, University of Melbourne, Parkville, Victoria, Australia, Email:

Author info »

Description

The majority of leukemia cases are Acute Lymphocytic Leukemia (ALL), a blood disease that is the most prevalent cancer in children and teenagers. Acute Myeloid Leukemia (AML) and chronic lymphocytic leukemia are among the most common types of leukemia, yet 90% of all cases are diagnosed in adulthood. Intense chemotherapy has been the go-to treatment for primary AML for decades, with early response rates reaching 80% for individuals under the age of 60. However, due to relapse, long-term survival rates are still low, with a 40-50% longterm survival rate for patients under the age of 50 and less than 10% for patients above the age of 50. Many patients over 65 are also ineligible for chemotherapy or hematopoietic stem cell transplants because of their afflictions.

Dysregulation of epigenetic gene silencing and activation is an emerging characteristic of AML and a growing number of other cancer forms. While the majority of AML mutations affect genes that control epigenetic gene expression and processing, this contributes to the great variety of gene expression patterns between patients and the relatively low mutational burden of AML. For AML patients who are not candidates for chemotherapy or Hematopoietic Stem Cell Transplant (HSCT), the use of Hypomethylating Agents (HMAs) to therapeutically reexpress tumor suppressor and tumor antigen genes is presently the first line of treatment. For Myelodysplastic Syndrome (MDS) and AML, the overall response rates to the frequently used HMAs 5-Azacytidine (5-Aza) and Decitabine (DAC) are approximately 50% and 15-20%, respectively. The response rate rises to 66% following the FDA's approval of 5-Aza in combination with the BCl-2 inhibitor Venetoclax, significantly improving overall survival; nonetheless, about 50% of patients experience a relapse within two years. HMA in conjunction with immune checkpoint antibodies is being researched to fight proleukemic immune responses and extend the effectiveness of HMA therapy. Some trials have shown minor gains in response rate but higher toxicity when compared to HMA alone.

Numerous gene alterations and expression patterns have been linked to the clinical response of AML to HMA therapy, but the precise mechanisms of primary resistance or relapse are still poorly understood. Additionally, research on the impact of HMA treatment on the immunological milieu have shown mixed results regarding T-cell action and are lacking information regarding a number of innate immune subsets, which may imply both pro- and anti-tumor immune responses to HMA treatment. To assist shed light on the processes of interaction between HMAs, leukemic cells, and the immune milieu, leukemia models that recapitulate hypermethylation and sensitivity/resistance to HMAs are needed. Pre-clinical research using immunecompetent animals can support clinical findings, identify novel biomarkers of response and resistance, and inspire the development of hypothesis-driven therapy regimens for the treatment of human AML.

Compared to correlative gene expression analysis in primary human samples, immune competent mouse models support more mechanistic studies of disease progression (e.g., genetic manipulation, specific cell depletion), and patient-derived xenograft or human cell line models using humanized mice lack fully functioning immunsystems. Transplantable mouse models of leukemia have many advantages.

Conclusion

We investigated how HMA therapy affected leukemia cells and found that both transgenic and endogenous gene expression were significantly reprogrammed. We discovered an interesting phenomenon: whereas 5-Aza therapy increases the immunogenicity of leukemia cells and upregulates genes linked to antigen presentation, we also noticed concurrent overexpression of immunological checkpoint proteins on the surface of both innate and adaptive immune subsets. We come to the conclusion that 5-Aza therapy may have a double-edged effect, inhibiting immune-suppressive pathways to reduce efficacy and boost resistance while also having anti-leukemic effects. Our HMA treatment model will be essential for future work in assessing novel combinatorial strategies utilizing HMAs. Our findings strongly recommend immune checkpoint blockade therapy in addition to concurrent treatment, which may give clarity and support to clinical trials examining this particular combination.