OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models
- 1 July 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (13), 3420-3430
- https://doi.org/10.1158/1078-0432.CCR-19-2238
Abstract
Purpose: The tumor microenvironment plays a key role in cancer development and progression and is involved in resistance to chemo- and immunotherapy. Cancer-associated fibroblast expressing fibroblast-activating protein alpha (FAP alpha) is one of the predominant stroma cell types and is involved in resistance to immunotherapy. Experimental Design: We generated OMTX705, a novel antibody-drug conjugate from a humanized anti-FAP antibody linked to a new cytolysin. Here, we studied its antineoplastic activity in vitro and in preclinical mouse models alone and in combination with chemotherapy as well as immunotherapy in PD-1-resistant tumors. Results: In Avatar models, OMTX705 showed a 100% tumor growth inhibition and prolonged tumor regressions as single agent and in combination with chemotherapy. Treatment rechallenge following treatment discontinuation induced additional tumor regression, suggesting lack of treatment resistance. In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8(+) T cells, induced complete regressions, and delayed tumor recurrence. Conclusions: These data suggest that FAP targeting with OMTX705 represents a novel and potent strategy for cancer treatment, including tumors resistant to immunotherapy, and support its clinical development.Other Versions
Funding Information
- Department of Industry, Tourism and Trade (SAF2017-84934-R)
This publication has 36 references indexed in Scilit:
- A CXCL1 Paracrine Network Links Cancer Chemoresistance and MetastasisCell, 2012
- Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretionNature, 2012
- Emerging roles of the tumor-associated stroma in promoting tumor metastasisCell Adhesion & Migration, 2012
- Fibroblasts—a key host cell type in tumor initiation, progression, and metastasisUpsala Journal of Medical Sciences, 2012
- Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic StrategyMolecular Cancer Therapeutics, 2012
- Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–αScience, 2010
- Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic CancerScience, 2009
- IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancersJCI Insight, 2008
- Microenvironmental regulation of metastasisNature Reviews Cancer, 2008
- Fibroblasts in cancerNature Reviews Cancer, 2006