Abstract CT114: Preliminary phase 1a/1b results of GIGA-564, a novel intratumoral Treg-depleting anti-CTLA-4 antibody, in advanced or metastatic solid tumors

Abstract Background: Anti-CTLA-4 therapies were originally designed to block the interaction between CTLA-4 and its B7 ligands, leading to enhanced T cell costimulation. However, in preclinical studies, efficacy of anti-CTLA-4 monoclonal antibodies (mAbs) requires Fc receptor-dependent depletion of intratumoral regulatory T cells. Additionally, strong blocking of CTLA-4 binding to its B7 ligands may increase adverse events and even limit efficacy of these therapies. Thus, it is hypothesized, and supported by nonclinical studies, that an anti-CTLA-4 mAb that has minimal ability to block CTLA-4 from binding to its B7 ligands, such as GIGA-564, may increase efficacy while reducing toxicity compared to other anti-CTLA-4 therapies. Methods: This is an ongoing, first-in-human, Phase 1a/1b study of GIGA-564 in advanced, relapsed/refractory solid tumors (NCT06258304). Participants (pts) receive up to 4 cycles of GIGA-564 on Day 1 of each 3-week cycle. Phase 1a enrolled 5 escalating dose cohorts of 0. 3, 1, 3, 10, and 20 mg/kg. One pt was enrolled in the 1st cohort, and the subsequent cohorts followed a 3+3 dose escalation design. Phase 1b allows for dose expansion in up to three tolerable doses (10 pts each) and involves pre- and on-treatment biopsies. The primary objective is safety. Secondary objectives include objective response rate (ORR) by RECIST1. 1, disease control rate (DCR: CR + PR + SD), minor response (MR: ≥ 20 to 30% reduction in net tumor bulk), and pharmacokinetics. Results: As of October 9, 2025, data cutoff, 21 pts received ≥ 1 dose of GIGA-564. The most frequent cancer types were colorectal (57. 1%, n=12) and head and neck (14. 3%, n=3). The median (range) of prior anti-cancer drug therapy lines was 3 (1-10). Treatment-related adverse events (TRAEs) occurred in 33% (n=7) of participants, with 9. 5% (n=2) experiencing grade 3-4 TRAEs. The most common TRAEs were rash 14. 3% (n=3), anemia 9. 5% (n=2), and hyperthyroidism 9. 5% (n=2). Two pts had treatment-related serious adverse events at the 20mg/kg dose; one had a grade 3 pneumonitis, and another developed grade 4 hyperthyroidism followed by a grade 2 colitis. The grade 4 hyperthyroidism was the only DLT observed in the study. Fourteen pts were efficacy evaluable. The unconfirmed ORR and DCR were 14. 3% (n=2) and 57. 1% (n=8), respectively. One partial response has been confirmed. Two pts had MR. Conclusions: Preliminary data suggest that GIGA-564 has a favorable safety profile while exhibiting anti-tumor activity. More research is warranted to further explore GIGA-564. Additional clinical and correlative analyses, including changes in tumor microenvironment and peripheral immune cell subsets after GIGA-564, are underway. Citation Format: Laercio DaSilva, Jason M. Redman, Olga Titova, Anne-Marie Duggan, Victoria Jeffers, Erica Redmond, Ruchi Patel, Hoyoung M. Maeng, Nicholas Tschernia, Jennifer L. Marte, Renee N. Donahue, Evrim B. Turkbey, Daniel Prins, Wiem Lassoued, Manuk Manukyan, Michell Manu, Jeffrey Schlom, Charalampos S. Floudas, Kim Hanna, Erica Lyn Stone, James L. Gulley. Preliminary phase 1a/1b results of GIGA-564, a novel intratumoral Treg-depleting anti-CTLA-4 antibody, in advanced or metastatic solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT114.