Fusion of Flt3L to albumin (Alb-Flt3L) extended the half-life of Flt3L and improved its lymph node and tumor accumulation. I.v. Alb-Flt3L expanded cDC1s and pDCs in mouse spleens, tumors, and tumor-draining lymph nodes, and activated intratumoral T cells. Combined with radiation therapy, Alb-Flt3L induced tumor neoantigen-specific T cells and controlled TC-1 and MC38 tumors, and was superior to Flt3L. Alb-Flt3L also synergized with cisplatin chemotherapy to treat large tumors, dependent on Batf3 and type-I IFN. Efficacy was further improved with anti-PD-L1. In CD34-humanized mice, Alb-Flt3L expanded human cDCs and pDCs more so than Flt3L.
Contributed by Alex Najibi
ABSTRACT: 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 to 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 uptake and present relevant cancer antigens. To address this bottleneck, we developed a Flt3L-based therapeutic named Alb-Flt3L that demonstrated superior pharmacokinetic properties compared to Flt3L, including significantly longer half-life, accumulation in tumor and lymph node, and cross-presenting DCs 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-interferons, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DC 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.
Author Info: (1) School of Medicine, Stanford University, Stanford, United States of America. (2) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (3) Dep
Author Info: (1) School of Medicine, Stanford University, Stanford, United States of America. (2) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (3) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (4) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (5) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (6) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (7) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (8) Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, United States of America. (9) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (10) Flow Cytometry Core, NIH, NEI, Bethesda, United States of America. (11) Department of Obstetrics and Gynecology, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea, Republic of. (12) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (13) Department of Pathology, Johns Hopkins University, Baltimore, United States of America. (14) Department of Pathology, Johns Hopkins University, Baltimore, United States of America.
