Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity

被引:101
作者
Pai, Chien-Chun Steven [1 ]
Simons, Donald M. [2 ]
Lu, Xiaoqing [2 ]
Evans, Michael [3 ]
Wei, Junnian [3 ]
Wang, Yung-hua [3 ]
Chen, Mingyi [4 ]
Huang, John [1 ]
Park, Chanhyuk [1 ]
Chang, Anthony [1 ]
Wang, Jiaxi [1 ]
Westmoreland, Susan [2 ]
Beam, Christine [2 ]
Banach, Dave [2 ]
Bowley, Diana [2 ]
Dong, Feng [2 ]
Seagal, Jane [2 ]
Ritacco, Wendy [2 ]
Richardson, Paul L. [5 ]
Mitra, Soumya [2 ]
Lynch, Grace [2 ]
Bousquet, Pete [2 ]
Mankovich, John [5 ]
Kingsbury, Gillian [2 ]
Fong, Lawrence [1 ,6 ]
机构
[1] UCSF, Sch Med, Dept Hematol & Oncol, San Francisco, CA USA
[2] AbbVie Biores Ctr, Worcester, MA USA
[3] UCSF, Sch Med, Dept Radiol & Biomed Imaging, San Francisco, CA USA
[4] Univ Texas Southwestern Med Ctr Dallas, Sch Med, Dept Hematopathol, Dallas, TX 75390 USA
[5] AbbVie Inc, N Chicago, IL USA
[6] UCSF, Helen Diller Family Comprehens Canc Ctr, Parker Immunotherapy Inst, San Francisco, CA USA
关键词
REGULATORY T-CELLS; IMMUNE CHECKPOINT BLOCKADE; ADVERSE EVENTS; CTLA-4; IPILIMUMAB; EFFECTOR; MELANOMA; DISEASE; MICE; ANTIBODIES;
D O I
10.1172/JCI123391
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 Fc gamma R-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.
引用
收藏
页码:349 / 363
页数:15
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