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

Author:

Yadavilli Sapna1ORCID,Waight Jeremy D.1ORCID,Brett Sara2ORCID,Bi Meixia1ORCID,Zhang Tianqian1ORCID,Liu Yao-Bin1ORCID,Ellis Catherine1ORCID,Turner David C.1ORCID,Hahn Ashleigh1ORCID,Shi Hong1ORCID,Seestaller-Wehr Laura1ORCID,Jing Junping1ORCID,Xie Qing1ORCID,Shaik Jafar Sadik1ORCID,Ji Xiao1ORCID,Gagnon Robert1ORCID,Fieles William1ORCID,Hook Laura2ORCID,Grant Steven2ORCID,Hopley Stephanie1ORCID,DeYoung M. Phillip1ORCID,Blackwell Christina1ORCID,Chisamore Michael3ORCID,Biddlecombe Robert2ORCID,Figueroa David J.1ORCID,Hopson Christopher B.1ORCID,Srinivasan Roopa1ORCID,Smothers James1ORCID,Maio Michele4ORCID,Rischin Danny56ORCID,Olive Daniel7ORCID,Paul Elaine1ORCID,Mayes Patrick A.1ORCID,Hoos Axel1ORCID,Ballas Marc1ORCID

Affiliation:

1. 1GSK, Collegeville, Pennsylvania.

2. 2GSK, Stevenage, Hertfordshire, United Kingdom.

3. 3Merck & Co., Inc., Rahway, New Jersey.

4. 4University of Siena and Center for Immuno-Oncology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

5. 5Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

6. 6Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

7. 7CRCM, Immunity and Cancer, Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille Université, UM105, CNRS, UMR7258, Marseille, France.

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.

Funder

GlaxoSmithKline

Publisher

American Association for Cancer Research (AACR)

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