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

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 1 st 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.