In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2342-2342
Abstract:
Background: It is hypothesized that TLR7 agonists reprogram myeloid cells in the TME, which may lead to activation of antitumor CD8 T effector cells and subsequently tumor cell death. The orally available TLR7 agonist prodrug RO7119929 is mainly converted into its active form in the liver. Here we report preclinical data informing the clinical proof of mechanism (PoM) strategy for RO7119929, as well as confirmatory clinical data from the first-in-human, Phase I study (NCT04338685). Methods: Prior to the Phase 1 study, bulk RNA sequencing of tumor and liver tissue was performed in a RO7119929 -treated HEP55.1c mouse model and RO7119929-treated cynomolgus monkeys. Single cell and single nucleus RNA-sequencing (snRNA-seq) was also performed in RO7119929 -treated human peripheral blood mononuclear cells (PBMCs). The Phase 1 study subsequently enrolled 55 pts with advanced primary liver cancers or other solid tumors with predominant liver involvement to receive weekly RO7119929. Paired pre- and post-treatment tumor liver biopsies were assessed. Pharmacodynamic (PD) monitoring of proximal and distal TLR7-related PD markers was performed using snRNA-seq, immunohistochemistry (IHC) and flow cytometry. Results: Preclinical mouse, cynomolgus monkey as well as human derived data showed dose-dependent, TLR7 mode of action-related, immune stimulatory reprogramming of PBMCs, the TME and liver tissue via myeloid cell activation. These findings were translated into a Phase I expansion cohort to demonstrate PoM using predefined PD gating criteria. By implementing snRNA-seq of paired liver biopsies from 11 pts, clinical PoM of RO7119929 could be demonstrated on a cellular and cytokine/chemokine level. Macrophages were the predominant immune infiltrate in liver tumor tissue and showed a relative increase in numbers and a trend towards an M1-immune stimulatory phenotype reprogramming on treatment. The local induction of proximal and distal cytokines and chemokines further confirmed a general shift towards a proinflammatory TME. In addition, peripheral CD8 T cell expansion was observed in most pts analyzed. An increase in CD8 tumor-infiltrating lymphocytes (TILs) occurred in 4/9 pts (all presented with stable disease) while most pts with no TIL increase had disease progression as best response. However, a general change towards a predominant CD8 inflamed immune phenotype was not detected. There was no trend for TLR7-induced increase in PD-L1 or MHC class I expression. Conclusions: Single-agent TLR7 agonist treatment of advanced primary or metastatic liver cancers induces local inflammation of the TME by reprogramming myeloid cells. Combination therapies may be needed to increase the relocation of antitumor CD8 T effector cells to the TME and unlock the full potential of the local immune stimulatory effect. Citation Format: Carles Fabregat-Franco, Changhoon Yoo, Bruno Sangro, Camilla Qvortrup, Hyung-Don Kim, Teresa Macarulla, Mariano Ponz-Sarvisé, Chia-Chi Lin, Do-Youn Oh, Thomas Yau, Juliana Bessa, Petra C. Schwalie, Steffen Dettling, Ramona Schlenker, Natascha Riede, Elia Hall, Felix Lichtenegger, Nicole Kratochwil, Thomas Pöschinger, Zhiwen Jiang, Tianyi Jiang, Christina Godfried Sie, Audrey Yeo Te-Ying, Christina Schiff, Sabine Hoves, Michael Cannarile. RO7119929, a TLR7 agonist prodrug, induces local inflammation of the tumor microenvironment (TME) by reprogramming myeloid cells in patients (pts) with advanced primary or metastatic liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2342.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-2342
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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