Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.

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Embargo End Date

ICR Authors

Furness, Andrew
 Turajlic, Samra
 Larkin, James

Authors

Arce Vargas, F
Furness, AJS
Solomon, I
Joshi, K
Mekkaoui, L
Lesko, MH
Miranda Rota, E
Dahan, R
Georgiou, A
Sledzinska, A
Ben Aissa, A
Franz, D
Werner Sunderland, M
Wong, YNS
Henry, JY
O'Brien, T
Nicol, D
Challacombe, B
Beers, SA
Melanoma TRACERx Consortium,
Renal TRACERx Consortium,
Lung TRACERx Consortium,
Turajlic, S
Gore, M
Larkin, J
Swanton, C
Chester, KA
Pule, M
Ravetch, JV
Marafioti, T
Peggs, KS
Quezada, SA

Document Type

Journal Article

Date

2017-04-18

Date Accepted

2017-02-09

Abstract

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

Citation

Immunity, 2017, 46 (4), pp. 577 - 586

DOI

10.1016/j.immuni.2017.03.013

URI

https://repository.icr.ac.uk/handle/internal/635

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

CELL PRESS

ISSN

1074-7613

eISSN

1097-4180

Collections

Clinical Studies

Research Team

Melanoma and Kidney Cancer

Notes