PT  - JOURNAL ARTICLE
AU  - Kelly-Anne Masterman
AU  - Oscar L Haigh
AU  - Kirsteen M Tullett
AU  - Ingrid M Leal-Rojas
AU  - Carina Walpole
AU  - Frances E Pearson
AU  - Jonathon Cebon
AU  - Christopher Schmidt
AU  - Liam O'Brien
AU  - Nikita Rosendahl
AU  - Ghazal Daraj
AU  - Irina Caminschi
AU  - Eric H Gschweng
AU  - Roger P Hollis
AU  - Donald B Kohn
AU  - Mireille H Lahoud
AU  - Kristen J Radford
TI  - Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141<sup>+</sup> dendritic cells to activate naïve and memory NY-ESO-1-specific CD8<sup>+</sup> T cells
AID  - 10.1136/jitc-2020-000691
DP  - 2020 Jul 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e000691
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e000691.short
4100  - http://jitc.bmj.com/content/8/2/e000691.full
SO  - J Immunother Cancer2020 Jul 01; 8
AB  - Background Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs.Methods Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells.Results CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro.Conclusions These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.