Gamma9 Delta2 (γ9δ2) T cells function at the crossroads of innate and adaptive immunity, with important roles in immune responses against pathogens and carcinogenesis, making them an attractive target for cancer immunotherapy
EVICTION (NCT04243499) – a first-in-human clinical trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2021 – evaluated the efficacy of ICT01, a humanized monoclonal antibody that binds to the extracellular domain of the three BTN3A1/A2/A3 isoforms, inducing the activation of γ9δ2 T cells and leading to the death of several tumors in non-clinical settings. The study characterized the safety, tolerability and activity of ICT01 in a range of intravenous doses as monotherapy and in combination with pembrolizumab in patients with relapsed/refractory advanced-stage cancer.
Patients received ICT01 every three weeks with blood samples collected at various periods for flow cytometry immunophenotyping and cytokine analysis (IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13). Tumor biopsies were collected at baseline and on day 28 for immunohistochemistry (e.g., BTN3A and γ9δ2 T-cell expression), as well as for expression profiling of cancer and immunity-related genes.
Cohorts from 1 to 4 (total n = 20) for solid tumors involved doses of ICT01 ranging from 20μg to 20mg; and dose cohort 1 for patients with hematological cancer (n = 3, 200μg) was enrolled. ICT01 was well tolerated, with no dose-limiting toxicities or serious adverse events reported.
Target occupation in T cells at 30 minutes or four hours after the first dose ranged from 34% (700μg, n = 2), 79% (2mg, n = 5), 93% (7mg, n = 4) and 100% (20mg, n = 1), with γ9δ2 activated T cells (CD69+) migrating from the blood within 30 minutes from the dosage, leading to a decrease > 95% in the number of γ9δ2 circulating T cells for all four doses for 24 hours. The 2nd dose of ICT01 induced similar activation and migration of γ9δ2 T cells into the circulation. There were no effects on CD4/CD8 T cells, NK, or B cells.
The available cytokine data from cohorts 1 and 2 for solid tumors showed no cytokine release syndrome, although transient two- to three-fold increases in IFNγ, TNFα and IL-2 were observed four hours after the dose in patients with higher baseline γ9δ2 T cell counts. A five to ten-fold increase in IFNγ was observed on days 7 and 28 in cohort 2 for solid tumors, consistent with γ9δ2 T-cell activation. Digital pathology analysis of tumor biopsies of a patient with melanoma in cohort 1 demonstrated a 25x and 8x increase in CD3-TCRgamma delta++ and CD3+ cell densities, respectively, compared to baseline.
These preliminary results demonstrate, as per the authors’ conclusion, that ICT01 activates the BTN3A-mediated γ9δ2 T-cell antitumor immune response in a safe and potent manner.
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