In situ vaccination via tissue-targeted cDC1 expansion enhances the immunogenicity of chemoradiation and immunotherapy

Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present...

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Published in:The Journal of clinical investigation 2024-01, Vol.134 (1)
Main Authors: Lam, Brandon, Kung, Yu Jui, Lin, John, Tseng, Ssu-Hsueh, Tu, Hsin-Fang, Huang, Claire, Lee, Brandon, Velarde, Esteban, Tsai, Ya Chea, Villasmil, Rafael, Park, Sung Taek, Xing, Deyin, Hung, Chien-Fu, Wu, T-C
Format: Article
Language:English
Subjects:
Albumin
Apoptosis
Cancer
Cancer vaccines
Chemotherapy
Comparative analysis
Dosage and administration
Health aspects
Patient outcomes
Radiation
Radiotherapy
Scientific equipment and supplies industry
T cells
Testing
Tumor antigens
Tumors
Vaccination
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Summary:Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI171621