Scientific publications
CD40 Agonist Targeted to Fibroblast Activation Protein α Synergizes with Radiotherapy in Murine HPV-Positive Head and Neck Tumors.
Sara Labiano 1, Vincent Roh 2, Céline Godfroid 1, Agnès Hiou-Feige 2, Jackeline Romero 3, Eva Sum 4, Moritz Rapp 5, Gael Boivin 3, Tania Wyss 1 6, Christian Simon 2, Jean Bourhis 3, Pablo Umaña 4, Christine Trumpfheller # 4, Genrich V Tolstonog # 2, Marie-Catherine Vozenin # 3, Pedro Romero # 7
Abstract
Purpose: The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV+-HNSCC) is rising worldwide and although current therapeutic modalities are efficient in the majority of patients, there is a high rate of treatment failures. Thus, novel combination approaches are urgently needed to achieve better disease control in patients with HPV+-HNSCC. We investigated the safety and therapeutic efficacy of a novel fibroblast activation protein (FAP)-targeted CD40 agonist (FAP-CD40) in combination with local hypofractionated radiation in a syngeneic HPV+-HNSCC model.
Experimental design: Using an established orthotopic model, we treated tumor-bearing mice with local hypofractionated radiotherapy (2 × 6 Gy) alone or in combination with a systemic administration of the FAP-CD40 antibody. Following up the mice, we evaluated the changes in the tumor microenvironment (TME) by immunofluorescence, FACS, and NanoString RNA analysis.
Results: The suboptimal radiotherapy regimen chosen failed to control tumors in the treated mice. The FAP-CD40 administered in monotherapy transiently controlled tumor growth, whereas the combined therapy induced durable complete responses in more than 80% of the tumor-bearing mice. This notable efficacy relied on the radiotherapy-induced remodeling of the TME and activation of the CD8+ T-cell-cDC1 axis and was devoid of the systemic toxicity frequently associated with CD40-targeted therapy. Moreover, the robust immunologic memory developed effectively prevented tumor relapses, a common feature in patients with HNSCC.
Conclusions: Our study provides proof of concept, as well as mechanistic insights of the therapeutic efficacy of a bispecific FAP-CD40 combined with local radiotherapy in a FAP+-HNSCC model increasing overall survival and inducing long-term antitumor immunity.
CITA DEL ARTÍCULO Clin Cancer Res. 2021 Jul 15;27(14):4054-4065. doi: 10.1158/1078-0432.CCR-20-4717. Epub 2021 Apr 26.
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