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Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
Aurélien Marabelle, … , Victor Tse, Ronald Levy
Aurélien Marabelle, … , Victor Tse, Ronald Levy
Published May 24, 2013
Citation Information: J Clin Invest. 2013;123(6):2447-2463. https://doi.org/10.1172/JCI64859.
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Research Article Article has an altmetric score of 50

Depleting tumor-specific Tregs at a single site eradicates disseminated tumors

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Abstract

Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.

Authors

Aurélien Marabelle, Holbrook Kohrt, Idit Sagiv-Barfi, Bahareh Ajami, Robert C. Axtell, Gang Zhou, Ranjani Rajapaksa, Michael R. Green, James Torchia, Joshua Brody, Richard Luong, Michael D. Rosenblum, Lawrence Steinman, Hyam I. Levitsky, Victor Tse, Ronald Levy

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Figure 10

i.t. low-dose immunomodulation cures established CNS lymphoma.

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i.t. low-dose immunomodulation cures established CNS lymphoma.
The CNS l...
The CNS lymphoma burden assessed over time by bioluminescence for 1 representative mouse of each treatment group and the survival of the whole group (5 mice per group). MTX, 400 mg/kg s.c. MTX, followed by 12 mg/kg s.c. calcium leucovorin rescue started 16 hours later and given once every 2 hours for a total of 5 doses; CTX, 100 mg/kg i.p CTX for 2 subsequent days; αId, 100 mg i.p.; i.t. CpG and 1/10 or 1/100 doses of αOX40/CTLA4.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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