TY - JOUR
T1 - Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity
AU - Pai, Chien Chun Steven
AU - Simons, Donald M.
AU - Lu, Xiaoqing
AU - Evans, Michael
AU - Wei, Junnian
AU - Wang, Yung Hua
AU - Chen, Mingyi
AU - Huang, John
AU - Park, Chanhyuk
AU - Chang, Anthony
AU - Wang, Jiaxi
AU - Westmoreland, Susan
AU - Beam, Christine
AU - Banach, Dave
AU - Bowley, Diana
AU - Dong, Feng
AU - Seagal, Jane
AU - Ritacco, Wendy
AU - Richardson, Paul L.
AU - Mitra, Soumya
AU - Lynch, Grace
AU - Bousquet, Pete
AU - Mankovich, John
AU - Kingsbury, Gillian
AU - Fong, Lawrence
N1 - Funding Information:
We thank the UCSF Flow Cytometry Core for technical help and the NIH Tetramer Core for generation of the Spas-1 tetramer. This work has been supported by National Cancer Institute (NCI) grants R01CA163012 and R01CA194511 and a Prostate Cancer Foundation Challenge Grant. This study was also supported by research funding from AbbVie.
Funding Information:
Authorship note: CCSP and DMS contributed equally to this work. GK and LF contributed equally to this work. Conflict of interest: LF received research funding from AbbVie, Merck, Roche-Genen-tech, and Bristol-Myers Squibb Inc. DMS, XL, SW, CB, D Banach, D Bowley, FD, JS, WR, PLR, SM, GL, and PB are research scientists at AbbVie Bioresearch Center. DMS, JM, and GK are former research scientists at AbbVie Bioresearch Center. License: Copyright 2019, American Society for Clinical Investigation. Submitted: July 24, 2018; Accepted: October 24, 2018. Reference information: J Clin Invest. 2019;129(1):349–363. https://doi.org/10.1172/JCI123391.
Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.
PY - 2019/1/2
Y1 - 2019/1/2
N2 - While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti- CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.
AB - While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti- CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.
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U2 - 10.1172/JCI123391
DO - 10.1172/JCI123391
M3 - Article
C2 - 30530991
AN - SCOPUS:85059413620
SN - 0021-9738
VL - 129
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - CI123391
ER -