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

NCT06874257 | Recruiting

• 2 other identifiers: TALETE-20233000506
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

AML (Acute Myelogenous Leukemia)

Outcome Measures

Primary Outcomes (5)

• Pan-tissue AHR signature

  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.

  At visit 1 (T1, diagnosis), and after the second cycle with azacitidine and venetoclax (T2, 2 months after treatment initiation)

• IFN-y pathway response

  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.

  At visit 1 (T1), and after the second cycle with azacitidine and venetoclax (T2, 2 months after treatment initiation)

• Immunometabolic shift in T-cells

  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.

  At visit 1 (T1), and after the second cycle with azacitidine and venetoclax (T2, 2 months after treatment initiation)

• Clinical response

  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

  After the second cycle with azacitidine and venetoclax (T2, 2 months after treatement initiation )

• Survival (Aim 4)

  OS (%, months) and RFS (%, months)

  At follow-up (up to 12 months)

Study Arms (1)

Patien with AML

The study will include untreated and newly diagnosed unfit-to-chemotherapy, adult AML patients candidate to receive the combination of venetoclax plus azacitidine according to standard clinical practice, and independently of the participation to the study. The patients will be enrolled at the time of disease diagnosis. For healthy donors, a total of 60 buffy coats will be collected in time period of 24 months. Patients who will not receive any treatment will be excluded from the study

Biological: Laboratory tests and in vitro studies

Interventions

Laboratory tests and in vitro studies BIOLOGICAL

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.

Patien with AML

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The planned population size for the study is of 60 prospectively enrolled AML patients. The project outcomes will be evaluated at T2 and correlated with CR and refractoriness obtained at T2 and with survival data obtained at follow-up. Power analysis conducted using Stata 17 indicated that a sample size of n=60 allows at least 0.90 power for the estimation of a linear regression model with 4 to 10 covariates and an expected R2 of 0.30 to 0.75 with α=0.05. This linear regression model will include as dependent an immune microenvironment variable measured at T2, and as exposure the treatment variable. By including among covariates the baseline values of the dependent variable we expect to obtain high R2 values

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• IRCCS Azienda Ospedaliero-Universitaria di Bologna: lead

Study Sites (1)

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, 40138, Italy

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Bone Marrow, Plasm, blood, Osteo medullary biopsy

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Antonio Curti, MD

  IRCCS Azienda Ospedaliero-Universitaria di Bologna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Antonio Curti, MD

CONTACT

+39 0512144074; antonio.curti2@unibo.it

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Target Duration: 12 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2024
• First Posted: March 13, 2025
• Study Start: April 17, 2024
• Primary Completion: October 31, 2025
• Study Completion (Estimated): October 31, 2026
• Last Updated: March 13, 2025

Record last verified: 2024-12

Locations

IT (1)