To improve efficacy and safety of CD40 agonists in HPV+ HNSCC, Labiano et al. investigated a novel agonistic CD40 bispecific antibody targeting tumor stromal cell fibroblast activation protein α (FAP-CD40) in combination with local radiation (RAD). In a clinically relevant HPV+ HNSCC model, combination FAP-CD40/RAD therapy produced complete responses, tumor-specific memory, and extended survival in 83% of mice without the weight loss that occurred in a control CD40 Ab group. Efficacy correlated with extensive TME remodeling, including increased numbers of activated CD8+ T cells, decreased Tregs, and enhanced DC maturation.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland. (2) Department of Otolaryngology - Head and Neck Surgery, Lausanne University Hospital and Un
Author Info: (1) Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland. (2) Department of Otolaryngology - Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (3) Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland. (4) Department of Otolaryngology - Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (5) Laboratory of Radiation Oncology, Department of Radiation Oncology. Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (6) Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland. (7) Roche Innovation Center Munich (RICM), pRED, Penzberg, Germany. (8) Laboratory of Radiation Oncology, Department of Radiation Oncology. Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (9) Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. (10) Department of Otolaryngology - Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (11) Laboratory of Radiation Oncology, Department of Radiation Oncology. Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (12) Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland. (13) Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland. (14) Department of Otolaryngology - Head and Neck Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (15) Laboratory of Radiation Oncology, Department of Radiation Oncology. Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (16) Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland. pedro.romero@hospvd.ch.
