CA is a CEA-specific antibody fused to IL2v with abolished CD25 binding. Compared to wildtype (wt) IL-2, CA was designed to preferentially expand natural killer (NK) and CD8 T cells but not T regulatory cells (Tregs), to be retained within CEA+ tumors, and for improved PK.
In this FIH phase I study, PK/PD analyses were performed using samples from solid tumor patients treated weekly (QW) or biweekly (Q2W) with 6 – 40 mg CA monotherapy IV. Methods: PK - population modeling; PD analysis of baseline (BL) and on-treatment (OT) samples; flow cytometry of peripheral blood monocytes (PBMCs); immunohistochemistry (IHC) on tumor biopsies; PD-L1 expression using SP142 assay; measurement of plasma cytokines and sCD25.
During cycle 1, CA exhibited prolonged exposure (8-fold) vs. wt IL2. Following multiple cycles, serum exposure showed typical target-mediated drug disposition kinetics, likely due to clearance by IL-2 receptor-expressing cells. In PBMCs from patients treated QW x 4, a significant increase in the absolute number of NK cells and CD8 T cells was seen (median of 13- and 2.3-fold, respectively). By contrast, moderate or no increase was seen in the absolute number of CD4 T or Tregs (median of 1.5- and 1.2-fold). Similar but less prominent changes were observed in patients treated Q2W. Treatment was accompanied by upregulation of the activation marker CD314 (NKG2D), which was undetectable on more than 20% of NK cells in 9 of 39 patients at BL, suggesting increased functional activity of NK cells in the affected patients. A transient increase in the level of various cytokines was seen, peaking 24 hours after administration. Changes in the level of sCD25 correlated with drug exposure. OT biopsies showed an increase in the number of infiltrating Ki67+ CD8 T cells and PD-L1+ immune cells (median of 3.5- and 3-fold, n = 11).
PK data confirmed that CA has longer exposure than wt IL2. PD data demonstrated preferential expansion and reinvigoration of NK and CD8+ T cells in both PBMCs and tumors. This data suggest that CA can be a potent combination partner for cancer immunotherapies targeting CEA+ solid tumors.
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd
F. Hoffmann-La Roche Ltd
I. Melero: Advisory board: Bristol-Myers, Roche-genentech, AstraZeneca, Lilly, Merck Serono, Bayer, Genmab, Alligator, Bioncotech, Tusk Grants from: Roche-Genetech, Bristol Myers, Bioncotech. J. Tabernero: Advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. V. Teichgräber: A permanent employee of F Hoffmann La Roche Ltd. With stock options L. Jukofsky: A Roche employee with stocks options. E. Rossmann: A permanent Roche employee with stocks options. G. Babitzki: A Roche employee. A. Patricia Silva: F.Hoffman-La Roche employee. M. Canamero: Roche employee with stock options. C. Boetsch: An employee of Roche with stock options. S. Evers: An employee and shareholder of Roche. J. Charo: The author is an employee and stockholder of Roche. All other authors have declared no conflicts of interest.