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

Chien Chun Steven Pai, Donald M. Simons, Xiaoqing Lu, Michael Evans, Junnian Wei, Yung Hua Wang, Mingyi Chen, John Huang, Chanhyuk Park, Anthony Chang, Jiaxi Wang, Susan Westmoreland, Christine Beam, Dave Banach, Diana Bowley, Feng Dong, Jane Seagal, Wendy Ritacco, Paul L. Richardson, Soumya Mitra & 5 others Grace Lynch, Pete Bousquet, John Mankovich, Gillian Kingsbury, Lawrence Fong

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Abstract

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.

Original languageEnglish (US)
Article numberCI123391
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - Jan 2 2019

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Immunotherapy
Neoplasms
Inbred C57BL Mouse
CTLA-4 Antigen
CD8 Antigens
T-Lymphocytes
Tumor Microenvironment
Serine Proteases
Neoplasm Antigens
Gastrointestinal Tract
Anti-Idiotypic Antibodies
Binding Sites
Tissue Donors
Inflammation
Lung
Membranes
Antibodies
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pai, C. C. S., Simons, D. M., Lu, X., Evans, M., Wei, J., Wang, Y. H., ... Fong, L. (2019). Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. Journal of Clinical Investigation, 129(1), [CI123391]. https://doi.org/10.1172/JCI123391

Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. / Pai, Chien Chun Steven; Simons, Donald M.; Lu, Xiaoqing; Evans, Michael; Wei, Junnian; Wang, Yung Hua; Chen, Mingyi; Huang, John; Park, Chanhyuk; Chang, Anthony; Wang, Jiaxi; Westmoreland, Susan; Beam, Christine; Banach, Dave; Bowley, Diana; Dong, Feng; Seagal, Jane; Ritacco, Wendy; Richardson, Paul L.; Mitra, Soumya; Lynch, Grace; Bousquet, Pete; Mankovich, John; Kingsbury, Gillian; Fong, Lawrence.

In: Journal of Clinical Investigation, Vol. 129, No. 1, CI123391, 02.01.2019.

Research output: Contribution to journalArticle

Pai, CCS, Simons, DM, Lu, X, Evans, M, Wei, J, Wang, YH, Chen, M, Huang, J, Park, C, Chang, A, Wang, J, Westmoreland, S, Beam, C, Banach, D, Bowley, D, Dong, F, Seagal, J, Ritacco, W, Richardson, PL, Mitra, S, Lynch, G, Bousquet, P, Mankovich, J, Kingsbury, G & Fong, L 2019, 'Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity', Journal of Clinical Investigation, vol. 129, no. 1, CI123391. https://doi.org/10.1172/JCI123391
Pai, Chien Chun Steven ; Simons, Donald M. ; Lu, Xiaoqing ; Evans, Michael ; Wei, Junnian ; Wang, Yung Hua ; Chen, Mingyi ; Huang, John ; Park, Chanhyuk ; Chang, Anthony ; Wang, Jiaxi ; Westmoreland, Susan ; Beam, Christine ; Banach, Dave ; Bowley, Diana ; Dong, Feng ; Seagal, Jane ; Ritacco, Wendy ; Richardson, Paul L. ; Mitra, Soumya ; Lynch, Grace ; Bousquet, Pete ; Mankovich, John ; Kingsbury, Gillian ; Fong, Lawrence. / Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 1.
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AU - Evans, Michael

AU - Wei, Junnian

AU - Wang, Yung Hua

AU - Chen, Mingyi

AU - Huang, John

AU - Park, Chanhyuk

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AU - Wang, Jiaxi

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