Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets
- 16 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (12), 1204-1217
- https://doi.org/10.1038/s43018-020-00143-y
Abstract
Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA201189, R01CA180913, 1U01CA154967, P30 CA015704, 1U01CA154967, P30 CA015704)
This publication has 58 references indexed in Scilit:
- A Cancer Vaccine Induces Expansion of NY-ESO-1-Specific Regulatory T Cells in Patients with Advanced MelanomaPLOS ONE, 2012
- Integrated NY-ESO-1 antibody and CD8+T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumabProceedings of the National Academy of Sciences of the United States of America, 2011
- Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1Journal of Clinical Oncology, 2011
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Response definition criteria for ELISPOT assays revisitedCancer Immunology, Immunotherapy, 2010
- In Vivo Role of Flt3 Ligand and Dendritic Cells in NK Cell HomeostasisThe Journal of Immunology, 2010
- CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefitProceedings of the National Academy of Sciences of the United States of America, 2008
- Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant gliomaSeminars in Immunology, 2008
- A Modular Analysis Framework for Blood Genomics Studies: Application to Systemic Lupus ErythematosusImmunity, 2008
- Repression of Flt3 by Pax5 is crucial for B-cell lineage commitmentJournal of Bone and Joint Surgery, 2006