Background ICT01 is a first-in-class anti-BTN3A mAb that selectively activates γ9δ2 T cells, leading to remodeling of the tumor microenvironment by activated γ9δ2 T, CD8 T, and NK cells (EVICTION-NCT04243499). However, many cancer patients have very low circulating γ9δ2 T cells that limit their response to ICT01. In the EVICTION-2 trial, a novel regimen of ICT01 plus low dose subcutaneous (LDSC) IL-2 is being investigated in patients with advanced-stage solid tumors to increase the number of γ9δ2 T cells that generate a more efficacious anti-tumor immune response.
Methods ICT01 (1, 5, 20 or 75 mg, IV Q3W) is given in combination with IL-2 (Proleukin®, 1 or 2 MIU/m2, SC) on days 1–5 of the first 3 cycles and will be continued alone thereafter. Per dose combination two patients are enrolled for dose escalation based on the BOIN simulations to identify a dose regimen that safely expands γ9δ2 T cells, which will be expanded to 6 pts for recommended phase 2 dose regimens. The study received ethics approval for all sites involved.
Results Nineteen patients have completed at least one cycle of ICT01 plus IL-2. Treatment-related adverse events were mainly mild to moderate infusion-related reactions, comparable to those observed with ICT01 or IL-2 monotherapy. No dose-limiting toxicities were reported. A 2–11x increase of γ9δ2 T cell counts above baseline was observed for all 3 cycles across all cohorts peaking around day 8 to 15, which appeared greater at low doses where ICT01 was rapidly cleared, while prolonged target occupancy/activation by high doses prevented γ9δ2 T cells from remaining in the circulation. Activation, mobilization, and proliferation of CD8 T cells (2–3x) and NK cells (2–9x) cycles was similarly observed. Elevated levels of IFNγ, TNFα, IL-6 and IL-8 peaked at ~4 hours post ICT01/IL-2 dose that returned to baseline despite expansion of γ9δ2 T cells. Increased Tregs by flow cytometry appear to be greater at lower doses of ICT01, which may be similar to effects observed in NHPs. Response data by RECIST1.1 every 8 weeks and IHC of tumor biopsies collected at baseline and on Day 28 will be presented.
Conclusion ICT01 plus LDSC IL-2 produces a broad anti-tumor immune response that is durable across multiple treatment cycles, which appears different to prior attempts to expand g9d2 T cells with bisphosphonates or phosphoantigens.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.