Abstract
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 α (FAPα) is one of the predominant stroma cell types and is involved in resistance to immunotherapy. 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. 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. 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.
Highlights
Solid tumors frequently exhibit a significant stromal reaction, called desmoplasia, formed by a variety of stromal cells and dense extracellular matrix
In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8þ T cells, induced complete regressions, and delayed tumor recurrence. 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
On the basis of this rationale, we developed a novel antibody–drug conjugate (ADC) molecule to target FAP-expressing cancer-associated fibroblasts (CAF)
Summary
Solid tumors frequently exhibit a significant stromal reaction, called desmoplasia, formed by a variety of stromal cells and dense extracellular matrix. This component may represent up to 20%–60% of the total tumor mass [1]. Cancer-associated fibroblasts (CAF) are frequently observed within the stroma of various cancers, including breast, lung, colon, and pancreatic carcinomas [2, 3]. Interacting coordinately with the different components of the stroma, CAFs have been associated with multiple cancer properties including neoangiogenesis, tumor progression, metastasis, impairment of drug delivery, and immunosuppression [3,4,5,6,7,8,9,10,11,12].
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