Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets

Nina Bhardwaj; Philip A. Friedlander; Anna C. Pavlick; Marc S. Ernstoff; Brian R. Gastman; Brent A. Hanks; Brendan D. Curti; Mark R. Albertini; Jason J. Luke; Ana B. Blazquez; Sreekumar Balan; Davide Bedognetti; Joseph M. Beechem; Andrea S. Crocker; Leonard D’Amico; Patrick Danaher; Thomas A. Davis; Thomas Hawthorne; Bruce W. Hess; Tibor Keler; Lisa Lundgren; Chihiro Morishima; Nirasha Ramchurren; Darawan Rinchai; Andres M. Salazar; Bob A. Salim; Elad Sharon; Laura A. Vitale; Ena Wang; Sarah Warren; Michael J. Yellin; Mary L. Disis; Martin A. Cheever; Steven P. Fling

doi:10.1038/s43018-020-00143-y

Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets

Nina Bhardwaj, Philip A. Friedlander, Anna C. Pavlick, Marc S. Ernstoff, Brian R. Gastman, Brent A. Hanks, Brendan D. Curti, Mark R. Albertini, Jason J. Luke, Ana B. Blazquez, Sreekumar Balan, Davide Bedognetti, Joseph M. Beechem, Andrea S. Crocker, Leonard D’Amico, Patrick Danaher, Thomas A. Davis, Thomas Hawthorne, Bruce W. Hess, Tibor KelerLisa Lundgren, Chihiro Morishima, Nirasha Ramchurren, Darawan Rinchai, Andres M. Salazar, Bob A. Salim, Elad Sharon, Laura A. Vitale, Ena Wang, Sarah Warren, Michael J. Yellin, Mary L. Disis, Martin A. Cheever, Steven P. Fling

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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.

Original language	English
Pages (from-to)	1204-1217
Number of pages	14
Journal	Nature Cancer
Volume	1
Issue number	12
DOIs	https://doi.org/10.1038/s43018-020-00143-y
State	Published - Dec 2020

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Bhardwaj, N., Friedlander, P. A., Pavlick, A. C., Ernstoff, M. S., Gastman, B. R., Hanks, B. A., Curti, B. D., Albertini, M. R., Luke, J. J., Blazquez, A. B., Balan, S., Bedognetti, D., Beechem, J. M., Crocker, A. S., D’Amico, L., Danaher, P., Davis, T. A., Hawthorne, T., Hess, B. W., ... Fling, S. P. (2020). Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets. Nature Cancer, 1(12), 1204-1217. https://doi.org/10.1038/s43018-020-00143-y

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title = "Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets",

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.",

author = "Nina Bhardwaj and Friedlander, {Philip A.} and Pavlick, {Anna C.} and Ernstoff, {Marc S.} and Gastman, {Brian R.} and Hanks, {Brent A.} and Curti, {Brendan D.} and Albertini, {Mark R.} and Luke, {Jason J.} and Blazquez, {Ana B.} and Sreekumar Balan and Davide Bedognetti and Beechem, {Joseph M.} and Crocker, {Andrea S.} and Leonard D{\textquoteright}Amico and Patrick Danaher and Davis, {Thomas A.} and Thomas Hawthorne and Hess, {Bruce W.} and Tibor Keler and Lisa Lundgren and Chihiro Morishima and Nirasha Ramchurren and Darawan Rinchai and Salazar, {Andres M.} and Salim, {Bob A.} and Elad Sharon and Vitale, {Laura A.} and Ena Wang and Sarah Warren and Yellin, {Michael J.} and Disis, {Mary L.} and Cheever, {Martin A.} and Fling, {Steven P.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = dec,

doi = "10.1038/s43018-020-00143-y",

language = "English",

volume = "1",

pages = "1204--1217",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

number = "12",

}

Bhardwaj, N , Friedlander, PA, Pavlick, AC, Ernstoff, MS, Gastman, BR, Hanks, BA, Curti, BD, Albertini, MR, Luke, JJ, Blazquez, AB, Balan, S, Bedognetti, D, Beechem, JM, Crocker, AS, D’Amico, L, Danaher, P, Davis, TA, Hawthorne, T, Hess, BW, Keler, T, Lundgren, L, Morishima, C, Ramchurren, N, Rinchai, D, Salazar, AM, Salim, BA, Sharon, E, Vitale, LA, Wang, E, Warren, S, Yellin, MJ, Disis, ML, Cheever, MA & Fling, SP 2020, 'Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets', Nature Cancer, vol. 1, no. 12, pp. 1204-1217. https://doi.org/10.1038/s43018-020-00143-y

TY - JOUR

T1 - Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets

AU - Bhardwaj, Nina

AU - Friedlander, Philip A.

AU - Pavlick, Anna C.

AU - Ernstoff, Marc S.

AU - Gastman, Brian R.

AU - Hanks, Brent A.

AU - Curti, Brendan D.

AU - Albertini, Mark R.

AU - Luke, Jason J.

AU - Blazquez, Ana B.

AU - Balan, Sreekumar

AU - Bedognetti, Davide

AU - Beechem, Joseph M.

AU - Crocker, Andrea S.

AU - D’Amico, Leonard

AU - Danaher, Patrick

AU - Davis, Thomas A.

AU - Hawthorne, Thomas

AU - Hess, Bruce W.

AU - Keler, Tibor

AU - Lundgren, Lisa

AU - Morishima, Chihiro

AU - Ramchurren, Nirasha

AU - Rinchai, Darawan

AU - Salazar, Andres M.

AU - Salim, Bob A.

AU - Sharon, Elad

AU - Vitale, Laura A.

AU - Wang, Ena

AU - Warren, Sarah

AU - Yellin, Michael J.

AU - Disis, Mary L.

AU - Cheever, Martin A.

AU - Fling, Steven P.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s43018-020-00143-y

DO - 10.1038/s43018-020-00143-y

M3 - Article

C2 - 35121932

AN - SCOPUS:85096062622

SN - 2662-1347

VL - 1

SP - 1204

EP - 1217

JO - Nature Cancer

JF - Nature Cancer

IS - 12

ER -

Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets

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