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Intratumoral anti-CTLA-4 therapy: enhancing efficacy while avoiding toxicity.

ABSTRACT: Systemic administration of the checkpoint blockade antibody anti-CTLA4 results in severe autoimmune toxicity, limiting its clinical efficacy. Fransen and colleagues show here that peritumoral delivery of low doses of this immunomodulatory drug can trigger a systemic antitumor immune response while preventing the toxicity against other organs.

SUBMITTER: Marabelle A

PROVIDER: S-EPMC3817012 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Intratumoral anti-CTLA-4 therapy: enhancing efficacy while avoiding toxicity.

Marabelle Aurélien A Kohrt Holbrook H Levy Ronald R

Clinical cancer research : an official journal of the American Association for Cancer Research 20130821 19

Systemic administration of the checkpoint blockade antibody anti-CTLA4 results in severe autoimmune toxicity, limiting its clinical efficacy. Fransen and colleagues show here that peritumoral delivery of low doses of this immunomodulatory drug can trigger a systemic antitumor immune response while preventing the toxicity against other organs. ...[more]

PMID: 23965900

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Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''.

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Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy.

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Project description:Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors cotreated with GVAX, anti-CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcR). Anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Treg). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous Braf V600E Pten -/- melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T-cell subsets, and anti-CTLA-4 treatment led to FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral natural killer cells. Similarly, in non-small cell lung cancer (NSCLC) and melanoma patient-derived tumor tissue, Tregs had higher sCTLA-4 expression than other intratumoral T-cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Patients with cutaneous melanoma who benefited from ipilimumab, a mAb targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti-CTLA-4 plus IL15/IL15Rα complexes enhanced tumor control compared with either monotherapy.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Intratumoral TFR cells curtail anti-PD-1 treatment efficacy

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