Abstract CT024: γ9δ2 T-cell (γδTC) activation and azacitidine-venetoclax (AV) for older/unfit adults with newly diagnosed (ND) acute myeloid leukemia (AML) induces high rates of complete remission (CR): Preliminary efficacy, safety, pharmacodynamics

Abstract Background: AML impairs immunosurveillance by circumventing target recognition and subsequent cytotoxic T cell responses, which is partly counteracted by immunomodulatory effects of AV and indicates a potential role of further immunotherapy for AML. ICT01 is a first-in-class humanized, Fc-disabled anti-butyrophilin 3A monoclonal antibody, selectively inducing γδTCA that promotes direct anti-leukemic cytotoxicity and immunomodulation via IFNγ/TNFα release. γδTC are known to drive anti-leukemic efficacy in the post-transplant setting. In humans, γδTCA by ICT01 was dose dependent, safe, tolerable and modestly effective. Preclinical studies revealed that ICT01-mediated γδTCA was maintained under AV co-administration and induced synergistic anti-leukemic efficacy and favorable immunomodulatory effects in-vivo (AML model with adoptive γδTC transfer), supporting further clinical investigation of the combination. Methods: ND-AML pts ≥ 75 years old or unfit to receive intensive chemotherapy were randomized 1:1 to AV plus either 10 mg (ICT01LOW) or 75 mg ICT01 (ICT01HIGH) Q4W. We assessed cytogenetics, NGS, comprehensive PD in peripheral blood (PB) and bone marrow (BM), safety, and anti-tumor efficacy. Results: Of 40 pts randomized, 28 had conclusive disease assessments as of 16Dec2024, median age was 75 yrs (range 64‒87), and the majority had established (ELN 2024) and emerging adverse risk characteristics suggestive of a poor response to AV. Median number of BM blasts was 40% (range 5‒98%). No DLT was reported, and all pts had at least one adverse event; no new safety signal was observed, and 30-day mortality was 3%. Grade 3/4 febrile neutropenia was seen in 18 pts (45%) and neutropenia in 23 pts (58%). ICT01 reproducibly induced rapid γδTCA and γδTC migration from PB, followed by increased serum IFNγ/TNFα reflective of downstream immune-cell effects. γδTC counts in both PB and BM returned to near baseline values during ICT01LOW dosing and became almost undetectable during continued ICT01HIGH dosing. ICT01LOW exhibited a favorable benefit-risk profile with 88% CR/CRi (69% CR, 19% CRi) and fewer infectious complications, while PD effects seen with ICT01HIGH suggestive of activation-induced γδTC death upon repeated dosing were associated with less efficacy (75% CR/CRi [42% CR, 33% CRi]). Notably, response rates to ICT01LOW were high both in pts with known/emerging adverse (mtTP53 and mtASXL1, CR 50%, CR/CRi 75%, N=8) and favorable (mtNPM1 and mtIDH1/2, CR 80% and CR/CRi 100%, N=4) molecular risk. Updated results with additional pts will be presented at the meeting. Conclusions: For AV combination, the recommended Phase 2 dose is 10 mg ICT01 Q4W. Both ICT01 regimens were safe and very well tolerated and generated very high CR and CR/CRi rates across molecular AML subtypes. Citation Format: Abhishek Maiti, Pierre Peterlin, Daniel Morillo, Jose-Miguel Torregrosa-Diaz, Matthew Ulrickson, Agustin Penedo, Aude De Gassart, Eisabeth Wieduwild, Emmanuel Valentin, Maelle Mairesse, Patrick Brune, Katrien Lemmens, Stephan Braun, Daniel Olive, Naval G. Daver, Sylvain Garciaz, Pierre-Yves Dumas. γ9δ2 T-cell (γδTC) activation and azacitidine-venetoclax (AV) for older/unfit adults with newly diagnosed (ND) acute myeloid leukemia (AML) induces high rates of complete remission (CR): Preliminary efficacy, safety, pharmacodynamics (PD) and dose selection of ICT01 in the phase 1 study EVICTION [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT024.