Imperial College London
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DrJunIshihara

Faculty of Engineering, Department of Bioengineering

Lecturer
 
 
 
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Contact

 

j.ishihara Website CV

 
 
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Location

 

86 Woodlane London W12 0BZSir Michael Uren HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ishihara:2019:10.1126/scitranslmed.aau3259,
author = {Ishihara, J and Ishihara, A and Sasaki, K and Lee, SS-Y and Williford, J-M and Yasui, M and Abe, H and Potin, L and Hosseinchi, P and Fukunaga, K and Raczy, MM and Gray, LT and Mansurov, A and Katsumata, K and Fukayama, M and Kron, SJ and Swartz, MA and Hubbell, JA},
doi = {10.1126/scitranslmed.aau3259},
journal = {Science Translational Medicine},
pages = {1--13},
title = {Targeted antibody and cytokine cancer immunotherapies through collagen affinity},
url = {http://dx.doi.org/10.1126/scitranslmed.aau3259},
volume = {11},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti–cytotoxic T lymphocyte antigen 4 antibody (αCTLA4) + anti–programmed death ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4 + αPD-L1 combination therapy and IL-2, for example, eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD–IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD–IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast cancer model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically administered tumor drugs with high translational promise.
AU  - Ishihara,J
AU  - Ishihara,A
AU  - Sasaki,K
AU  - Lee,SS-Y
AU  - Williford,J-M
AU  - Yasui,M
AU  - Abe,H
AU  - Potin,L
AU  - Hosseinchi,P
AU  - Fukunaga,K
AU  - Raczy,MM
AU  - Gray,LT
AU  - Mansurov,A
AU  - Katsumata,K
AU  - Fukayama,M
AU  - Kron,SJ
AU  - Swartz,MA
AU  - Hubbell,JA
DO  - 10.1126/scitranslmed.aau3259
EP  - 13
PY  - 2019///
SN  - 1946-6234
SP  - 1
TI  - Targeted antibody and cytokine cancer immunotherapies through collagen affinity
T2  - Science Translational Medicine
UR  - http://dx.doi.org/10.1126/scitranslmed.aau3259
UR  - https://stm.sciencemag.org/content/11/487/eaau3259/tab-pdf
UR  - http://hdl.handle.net/10044/1/83775
VL  - 11
ER  -
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