Acute myeloid leukemia (AML) remains one of the most aggressive blood cancers, particularly affecting older adults or patients with significant comorbidities who are often ineligible for intensive chemotherapy. While the introduction of the azacitidine (Vidaza®; Bristol-Myers Squibb) and venetoclax (Venclexta®; Genentech/Abbvie)(Aza-Ven-) combination has become a standard first-line treatment for these patients, durable responses are limited, and more than 50% of the patients experience relapse within the first year. [1] The medical need for more effective and more tolerable treatments remains high, especially for patients with high-risk genetic mutations.
Immunotherapy Highlights a New Approach in Myeloid Leukemia
In recent years, attention has turned to γ9δ2 T cells, a unique subset of T cells that exhibit both innate and adaptive immune characteristics. These cells are capable of recognizing and killing malignant cells independently of major histocompatibility complex (MHC) presentation. Their presence in the tumor microenvironment has been associated with improved prognosis across several cancer types. [2][3] until recently, selectively activating γ9δ2 T cells for therapeutic purposes remained a challenge.
ImCheck Therapeutics, a clinical-stage biotechnology company based in Marseille, France, is pioneering the butyrophilin (BTN) superfamily as a new class of immuno-modulatory targets.
ImCheck’s lead candidate is ICT01, a first-in-class humanized monoclonal antibody that targets butyrophilin 3A (BTN3A). It selectively activates γ9δ2 T cells, unleashing their cytolytic potential and triggering the activation of CD8+ T cells and natural killer (NK) cells. This multi-faceted immune response drives direct cytotoxicity against AML blasts, offering a promising new immunotherapeutic strategy for hematologic malignancies as well as solid tumor indications.[2][3]
Preclinical evidence suggests that this strategy may synergize with Aza-Ven treatment by enhancing immune-mediated antitumor responses. Venetoclax is a BCL2 inhibitor that promotes apoptosis by blocking a protein that cancer cells use to evade cell death.[4] Azacitidine is a hypomethylating agent that interferes with DNA replication and repair, thereby increasing the visibility of cancer cells to the immune system.[5] Venetoclax works synergistically with ICT01-activated γ9δ2 T cells, while azacitidine enhances antigen recognition on AML blasts (see figure 1.0). Together, this triple combination amplifies the cytolytic capacity of γ9δ2 T cells against leukemic cells,[6] laying the groundwork for a promising new therapeutic strategy.
Fig 1.0: Azacitidine-venetoclax sensitize AML blasts mounting synergistic ICT01-mediated anti-leukemic effect via activated γ9δ2 T, NK and CD8 cells.
“γ9δ2 T cells represent an exciting new immunotherapeutic avenue, especially for diseases like AML where traditional treatments fall short,” said Stephan Braun, MD, PhD, Chief Medical Officer of ImCheck Therapeutics.
“By unlocking the potential of γ9δ2 T cells, we hope to expand the reach and effectiveness of modern immunotherapy,” Braun added.
Clinical Evaluation of ICT01 in AML: Results from the EVICTION Study
ImCheck presented updated interim data from its ongoing Phase 1/2a EVICTION trial (NCT04243499) during an oral session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. [7]
The data support the potential of ICT01 to meaningfully enhance the effectiveness of Aza-Ven in older or unfit AML patients. At the data cut-off on January 20, 2025, 45 patients aged 51 to 87 were enrolled. A total of 29 patients received 10 mg of ICT01 and 16 patients received 75 mg of ICT01, each administered intravenously every 4 weeks in combination with azacitidine and venetoclax (Aza-Ven) and continued until disease progression or unacceptable toxicity. A total of 39 patients were evaluable for efficacy analysis.
Fig 2.0: EVICTION phase IIa in Group F (AML) study design
Key outcomes include:
- High response rates: ICT01 at the proposed 10 mg dose, in combination with Aza-Ven, achieved a 96% composite complete remission (CRc) rate and 74% complete remission (CR) rate in newly diagnosed AML patients.
- Clear signs of immune activation: ICT01 at the 10 mg dose provided optimal activation of γ9δ2 T cells and a downstream immune cascade, supporting its role in enhancing Aza-Ven efficacy, and confirming it as the proposed dose for further clinical development.
- Durable benefit: At a median follow-up time of 8.5 months, patients in the 10 mg ICT01 arm showed high response rates that were associated with a longer duration of response and an improved 9-month overall survival. While these time-to-event data are encouraging, they remain preliminary because the majority of patients are still on treatment.
- Activity in high-risk populations: Among evaluable patients, the majority had adverse- or intermediate-risk mutations (e.g., TP53, MECOMr, NRAS), typically associated with poor response to Aza-Ven alone. Notably, patients with TP53-mutated AML achieved 60% CR and 83% CRc rates.
- Favorable safety profile: The combination treatment was clinically well manageable, with a low 30-day mortality rate of 4% (all deaths unrelated to ICT01) and a low rate of infectious complications. The most frequent adverse events of Grade ≥3 were febrile neutropenia, neutropenia, thrombocytopenia, and sepsis, reported as unrelated to ICT01 and consistent with the known hematological toxicity of Aza-Ven.
“The consistency and depth of responses we are seeing across patient subgroups, including those with historically poor prognoses like TP53-mutated AML, are truly encouraging,” said Abhishek Maiti, MD, Assistant Professor of Leukemia at The University of Texas MD Anderson Cancer Center and principal investigator in the EVICTION study.
“These data support the potential of ICT01 to significantly enhance the efficacy of current frontline regimens while maintaining a manageable safety profile,” Maiti added.
Based on pharmacodynamic, efficacy, and safety data, the 10 mg dose has been confirmed as the proposed dose for further clinical investigation. Enrollment in the ICT01 high-dose arm was discontinued in December 2024. The decision was based on both higher response rates and the pharmacodynamic requirement for recovery of circulating γ9δ2 T cells with repeated 10 mg dosing, as compared to the lower response rates and sustained depletion of γ9δ2 T cells observed with the 75 mg dose.
Next Steps and Broader Clinical Development
Based on the encouraging Phase 1/2a data, ICT01 is now being advanced into a randomized Phase 2 trial in AML. In addition, ImCheck is planning to broaden its clinical program to include patients with myelodysplastic syndrome (MDS), a related blood cancer that can progress to the more aggressive AML, and where BTN3A is also expressed on leukemic blasts and in the tumor microenvironment. In parallel, ImCheck is exploring ICT01’s potential in select solid tumor indications. Both are important steps supporting the company’s overall mission to transform treatments across oncology, autoimmune, and infectious diseases by unlocking the power of γ9δ2 T cells.
Clinical trials
First-in-Human Study of ICT01 in Patients With Advanced Cancer (EVICTION) – ClinicalTrials.gov ID NCT04243499
Highlights of Prescribing information
Azacitidine (Vidaza®; Bristol-Myers Squibb) [Prescribing Information]
Venetoclax (Venclexta®; Genentech/Abbvie)[Prescribing Information]
References
[1] DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971. [Article]
[2] Gentles AJ, Plevritis SK, Majeti R, Alizadeh AA. An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis. Nat Commun. 2015 Sep 10;6:8489. doi:10.1038/ncomms9489. PMID: 26373200; PMCID: PMC4722652 [Article]
[3] Tosolini M, Pont F, Poupot M, Vergez F, Nicolau-Travers ML, Vermijlen D, et al. Assessment of tumor-infiltrating TCRVγ9Vδ2 γδ lymphocyte abundance by deconvolution of human cancers microarrays. Oncoimmunology. 2017;6(7):e1284723. doi:10.1080/2162402X.2017.1284723. PMID: 28405516; PMCID: PMC5489573 [Article]
[4] Proposed mode of action, Abbvie product information [Website]
[5] Cruijsen M, Lübbert M, Wijermans P, Huls G. Clinical Results of Hypomethylating Agents in AML Treatment. J Clin Med. 2015;4(1):1–17. doi:10.3390/jcm4010001. [Article]
[6] Wieduwilt MJ, Dumas PY, Maiti A, et al. Evaluation of ICT01, a γ9δ2 T Cell-Activating Monoclonal Antibody, Combined with Venetoclax and Azacitidine in 1L AML (EVICTION Study). Blood. 2023 Nov 2;142(Suppl 1):1552. doi: 10.1182/blood-2023-172008. [Article]
[7] Pierre Yves Dumas, Abhishek Maiti, Pierre Peterlin, Daniel Morillo, Jose Miguel Torregrosa-Diaz, Matthew Ulrickson, Agustin Penedo, Aude De Gassart, Emmanuel Valentin, Maelle Mairesse, Patrick Brune, Katrien Lemmens, Daniel Olive, Stephan Braun, Naval Daver, Sylvain Garciaz. γ9δ2 T-cell activation (γδTCA) with ICT01 combined with azacitidine-venetoclax (AV) for older/unfit adults with newly diagnosed (ND) AML: Preliminary efficacy and dose selection in phase 1/2 study EVICTION. ASCO 2025 Jun 2; 10.1200/JCO.2025.43.16_suppl.6507 [Abstract]
Featured image: © 2016 – 2025 ASCO/Todd Buchanan. Used with permission
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