Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade

Yadavilli, S; Waight, JD; Brett, S; Bi, M; Zhang, T; Liu, YB; Ellis, C; Turner, DC; Hahn, A; Shi, H; Seestaller-Wehr, L; Jing, J; Xie, Q; Shaik, JS; Ji, X; Gagnon, R; Fieles, W; Hook, L; Grant, S; Hopley, S; DeYoung, MP; Blackwell, C; Chisamore, M; Biddlecombe, R; Figueroa, DJ; Hopson, CB; Srinivasan, R; Smothers, J; Maio, M; Rischin, D; Olive, D; Paul, E; Mayes, PA; Hoos, A; Ballas, M

Author(s): Yadavilli, S; Waight, JD; Brett, S; Bi, M; Zhang, T; Liu, YB; Ellis, C; Turner, DC; Hahn, A; Shi, H; Seestaller-Wehr, L; Jing, J; Xie, Q; Shaik, JS; Ji, X; Gagnon, R; Fieles, W; Hook, L; Grant, S; Hopley, S; DeYoung, MP; Blackwell, C; Chisamore, M; Biddlecombe, R; Figueroa, DJ; Hopson, CB; Srinivasan, R; Smothers, J; Maio, M; Rischin, D; Olive, D; Paul, E; Mayes, PA; Hoos, A; Ballas, M;
Details: Publication Year 2023-08,Volume 3,Issue #8,Page 1564-1579
Journal Title: Cancer Research Communications
Publication Type: Research article
Abstract: In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. SIGNIFICANCE: Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.
Publisher: American Association for Cancer Research
Keywords: Humans; Animals; Mice; *Antibodies, Monoclonal/pharmacology; *Ambulatory Care Facilities; Immune Checkpoint Inhibitors; Immunoglobulin G; Inhibition, Psychological
Department(s): Medical Oncology
PubMed ID: 37593752
Publisher's Version: https://doi.org/10.1158/2767-9764.CRC-22-0293
Open Access at Publisher's Site: https://doi.org/10.1158/2767-9764.Crc-22-0293
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-14 12:42:07

Last Modified: 2023-11-14 12:43:26