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.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1158/1078-0432.CCR-20-4717 | DOI Listing |
Transl Oncol
December 2024
School of Chemical Engineering and Technology, Tianjin University, Tianjin, PR China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, PR China. Electronic address:
Bispecific antibodies (BsAbs) represent a promising strategy for cancer immunotherapy. Challenges in immunotherapy include inefficient early events in the immune response cycle, such as antigen presentation and T cell priming. Background stimulation of CD40 with agonistic antibodies is a promising strategy to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs).
View Article and Find Full Text PDFHum Immunol
December 2024
Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:
The field of cancer immunotherapy has experienced remarkable advancements in the treatment of human cancers over recent decades. Therapeutic cancer vaccines have been employed to elicit antitumor immune responses through the generation of specific reactions against tumor-associated antigens. Although preclinical studies have demonstrated hopeful results and at least one product is approved for clinical use, the overall efficacy of cancer vaccines remains restricted.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
TNF receptor-associated factors (TRAFs) function as intracellular adaptor proteins utilized by members of the TNF receptor superfamily, such as CD40. Among the TRAF family proteins, TRAF5 has been identified as a potential regulator of CD40. However, it remains unclear whether TRAF5 regulates the generation of germinal center (GC) B cells and antigen-specific antibody production in the T-dependent (TD) immune response.
View Article and Find Full Text PDFJ Immunother Cancer
November 2024
INSERM, IMRB U955, Université Paris-Est Créteil Val de Marne, Créteil, France
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!