CEA-targeted engineered IL2: Clinical confirmation of tumor targeting and evidence of intra-tumoral immune activation.

Abstract

3016 Background: CEA-IL2v (RG7813) is an engineered IL-2 variant (IL-2v) with abolished IL-2Rα (CD25) binding fused to an antibody targeting Carcinoembryonic Antigen (CEA). The molecule was designed to improve the pharmacological and safety profile of IL-2 and enable tumor targeting. Methods: In an ongoing Phase I trial of CEA-IL2v (ranges 0.1 – 40 mg flat dose IV; schedule q1W and q2W) in patients (pts) with advanced and/or metastatic solid CEA+ tumors, extensive pharmacodynamic monitoring in peripheral blood as well as immunohistochemical (IHC) and flow cytometric (FC) analysis of pre- and on-treatment biopsy specimens (day + 4) were performed, including tests for effector (CD8+) and helper T cell (CD4+) percentage and density. In a sub-study, biodistribution was analyzed using PET imaging of 89Zr-CEA-IL2v at doses of 6 and 30 mg. Results: Of the 11 pts treated at 30 mg, 4 had sequential tumor biopsies evaluable both by IHC and FC. An increase in the median density (IHC) of CD8+ T cells from 62.5 (7 - 90) [median (range)] to 104.2 (7 - 255) cells/ mm2 was observed in 3/4 subjects after the 1st dose. No relevant change in the density of CD4+ T cells was detected. FC analysis confirmed the increase in CD8:CD4 ratio in the same 3/4 patients: from 0.88 (0.57 - 1.24) to 4.54 (0.36 - 7.47). Effects in peripheral blood included strong lymphocyte expansion that was mostly driven by Natural Killer (NK) and CD8+ T cells. Medians and ranges for the 11 pts before and 4 days after dosing were: NK: 168 (range: 52 - 337) vs. 655 (206 - 1569) cells/µl; CD8+: 340 (19 - 464) vs. 831 (78 – 3754) cells/µl. While there was no clear evidence of CEA-mediated tumor accumulation at 6 mg in the first 6 pts, intra-tumoral accumulation of 89Zr-CEA-IL2v was observed in 2/2 pts at 30 mg. Additional studies are ongoing. Conclusions: Collectively, these data support the concept that reduced affinity of CEA-IL2v for IL2R-alpha together with high-affinity binding to CEA enables tumor targeting. These findings suggest that CEA-IL2v is the first tumor-targeted cytokine, which increases immune infiltration and activates NK and T cells both in the periphery and within tumors. Clinical trial information: NCT02004106.