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Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer

van Hooren, Luuk; Sandin, Linda C; Moskalev, Igor; Ellmark, Peter LU ; Dimberg, Anna; Black, Peter; Tötterman, Thomas H and Mangsbo, Sara M (2017) In European Journal of Immunology 47(2). p.385-393
Abstract

Checkpoint blockade of CTLA-4 results in long-lasting survival benefits in metastatic cancer patients. However, patients treated with CTLA-4 blockade have suffered from immune-related adverse events, most likely due to the breadth of the induced T-cell activation. Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown s.c., peritumoral (p.t.) injection of anti-CTLA-4 treatment was equally effective as intravenous or s.c. (nontumor bearing flank) administration. Notably, p.t. injection was associated with lower circulating antibody levels and decreased IL-6 serum levels as compared... (More)

Checkpoint blockade of CTLA-4 results in long-lasting survival benefits in metastatic cancer patients. However, patients treated with CTLA-4 blockade have suffered from immune-related adverse events, most likely due to the breadth of the induced T-cell activation. Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown s.c., peritumoral (p.t.) injection of anti-CTLA-4 treatment was equally effective as intravenous or s.c. (nontumor bearing flank) administration. Notably, p.t. injection was associated with lower circulating antibody levels and decreased IL-6 serum levels as compared to systemic treatment. Ultrasound-guided intratumoral anti-CTLA-4 antibody treatment of orthotopically growing MB49 tumors resulted in tumor regression, with more than tenfold reduction in systemic antibody levels as compared to i.v. or s.c. administration, in line with the compartmentally restrained nature of the bladder. Local anti-CTLA-4 therapy in combination with anti-PD-1 therapy resulted in complete responses, superior to each therapy alone. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bladder cancer, Checkpoint inhibitors, CTLA-4, Immunotherapy, Local low-dose, MB49, PD-1
in
European Journal of Immunology
volume
47
issue
2
pages
385 - 393
publisher
John Wiley & Sons
external identifiers
  • scopus:85006725021
  • wos:000394839800018
ISSN
0014-2980
DOI
10.1002/eji.201646583
language
English
LU publication?
yes
id
e149f8d5-9e5d-4d70-b20f-0ec51bba3d53
date added to LUP
2017-02-01 07:29:31
date last changed
2018-01-07 11:47:16
@article{e149f8d5-9e5d-4d70-b20f-0ec51bba3d53,
  abstract     = {<p>Checkpoint blockade of CTLA-4 results in long-lasting survival benefits in metastatic cancer patients. However, patients treated with CTLA-4 blockade have suffered from immune-related adverse events, most likely due to the breadth of the induced T-cell activation. Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown s.c., peritumoral (p.t.) injection of anti-CTLA-4 treatment was equally effective as intravenous or s.c. (nontumor bearing flank) administration. Notably, p.t. injection was associated with lower circulating antibody levels and decreased IL-6 serum levels as compared to systemic treatment. Ultrasound-guided intratumoral anti-CTLA-4 antibody treatment of orthotopically growing MB49 tumors resulted in tumor regression, with more than tenfold reduction in systemic antibody levels as compared to i.v. or s.c. administration, in line with the compartmentally restrained nature of the bladder. Local anti-CTLA-4 therapy in combination with anti-PD-1 therapy resulted in complete responses, superior to each therapy alone. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.</p>},
  author       = {van Hooren, Luuk and Sandin, Linda C and Moskalev, Igor and Ellmark, Peter and Dimberg, Anna and Black, Peter and Tötterman, Thomas H and Mangsbo, Sara M},
  issn         = {0014-2980},
  keyword      = {Bladder cancer,Checkpoint inhibitors,CTLA-4,Immunotherapy,Local low-dose,MB49,PD-1},
  language     = {eng},
  number       = {2},
  pages        = {385--393},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer},
  url          = {http://dx.doi.org/10.1002/eji.201646583},
  volume       = {47},
  year         = {2017},
}