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

Condition(s) studied

Investigational drug(s) / intervention(s)

Laboratory tests and in vitro studies: Cell models, co-culture condition set-up and functional validation, Single-cell RNA sequencing and NGS, Metabolomics analysis, metabolomics validation and intracellular metabolomics analysis, Metabolic ImmunoProfiling and epigenetic profile, CyTOF immune and signaling profiling, Monocyte, macrophages and MSCs in vitro assays.

Study 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

Primary outcome measure(s)

• Pan-tissue AHR signature — At visit 1 (T1, diagnosis), and after the second cycle with azacitidine and venetoclax (T2, 2 months after treatment initiation)
  Pan-tissue AHR signature levels will be measured by using iterative cycles of computational biology analyses and experimental validation (24). In particular, the levels of expression will be detected and a cutoff for differentially expressed genes will be set at log2 fold change.
• IFN-y pathway response — At visit 1 (T1), and after the second cycle with azacitidine and venetoclax (T2, 2 months after treatment initiation)
  Expression level of IFN-y in AML cells (% of positive cells) and IDO1 in MSCs (mRNA levels) will be measured. IDO1 expression will be measured in relation to BM Treg infiltration (25).A cutoff for IFN-y and IDO1 expression will be set at 30% with fold-change\>2 at T2 over T1.
• Immunometabolic shift in T-cells — At visit 1 (T1), and after the second cycle with azacitidine and venetoclax (T2, 2 months after treatment initiation)
  The effects of IDO1 inhibitor for the metabolic re activation of effector T cells will be measured via mTOR activation. We will measure the following parameters as percentages(%): 1) glucose dependence, 2) mitochondrial dependence 3) glycolytic capacity and 4) fatty acid and AA oxidation capacity to determine the metabolic status. The fold change between T2 and T1 of these 4 parameters will be evaluated.
• Clinical response — After the second cycle with azacitidine and venetoclax (T2, 2 months after treatement initiation )
  1. Complete Remission (CR): BM blasts \<5%; absence of circulating blasts or blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 x 109 * L (1,000/μL); platelet count ≥100 x 109 * L (100,000/μL) 2. CR with partial hematologic recovery (CRh): ANC ≥0.5 x 109 * L (500/μL) and platelet count ≥50 x 109 * L (50,000/μL), otherwise all other CR criteria met 3. CR with incomplete hematologic recovery (CRi): All CR criteria except for residual neutropenia \<1.0 x 109 * L (1,000/μL) or thrombocytopenia \<100 x 109 * L (100,000/μL) 4. Refractoriness: No CR, CRh or CRi
• Survival (Aim 4) — At follow-up (up to 12 months)
  OS (%, months) and RFS (%, months)

Trial sites (1)

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