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.
Findings
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.
References:
Legal Notice: All content of this portal has been developed and will be constantly updated by Oncologia Brasil, independently and autonomously, without any interference from the sponsoring companies and without any obligation of its professionals in relation to the recommendation or prescription of products of one of the companies. The information provided on this portal does not replace the relationship between the internet user and the doctor. Always consult your doctor.