Targeting Acute Myeloid Leukemia Immunosuppressive Microenvironment by combinedIDO1 Inhibition and PD-1 Blockade

Summary

The combination of azacitidine and venetoclax is currently considered a therapeutic strategy innovative in AML through the addition of new compounds (triplet therapies), including inhibitors of the immune checkpoint inhibitors. Despite strong motivation, the clinical results of these approaches have been disappointing overall. The mechanisms leading to treatment failure of immunotherapies in AML are poorly elucidated as the effects on the AML microenvironment induced by basic azactidine and venetoclax therapy are largely unknown. In particular, the activity of the IDO1 enzyme as a potential mechanism of microenvironment resistance has been scarcely studied. The products of the IDO1-catalysed pathway activate the signalling of the AHR in mesenchymal stem cells and enhance their immunosuppressive effects, including the ability to reprogram the phenotype of M1/M2 macrophages. Furthermore, activation of the AHR by by products of the IDO1 pathway kinurenine-promotes tolerogenic dendritic cells and the generation of regulatory T cells. Based on this rationale, TALETE-2023 will aim to analyse the leukaemia immune microenvironment through multiomics (epigenomics transcriptomics, proteomics, metabolomics) and assess its contribution to the effect of the combination of azacitidine and venetoclax.

Eligibility

Inclusion Criteria:

* Subject is ≥ 18 years of age
* Subject has a new diagnosis of AML according to World Health Organization 2022 criteria
* Subject is ineligible for intensive induction chemotherapy according to investigator assessment
* Subject will undergo front-line treatment with azacitidine and venetoclax according to normal clinical practice
* Subject providing signed written informed consent according to ICH/EU/GCP and national local laws

For healthy donors:

* Age ≥ 18 years
* Subject providing signed written informed consent according to ICH/EU/GCP and national local laws

Exclusion Criteria:

For patients:

* Subject has acute promyelocytic leukemia
* Subject has known AML with central nervous system involvement
* Subject has not initiated treatment with azacitidine and venetoclax

For healthy donors:

None

Conditions2

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