Academic Journal
Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic Treg reduction and effector T cell activation
| العنوان: | Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic Treg reduction and effector T cell activation |
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| المؤلفون: | van Pul, Kim M., Notohardjo, Jessica C. L., Fransen, Marieke F., Koster, Bas D., Stam, Anita G. M., Chondronasiou, Dafni, Lougheed, Sinéad M., Bakker, Joyce, Kandiah, Vinitha, van den Tol, M. Petrousjka, Jooss, Karin, Vuylsteke, Ronald J. C. L. M., van den Eertwegh, Alfons J. M., de Gruijl, Tanja D. |
| المصدر: | van Pul , K M , Notohardjo , J C L , Fransen , M F , Koster , B D , Stam , A G M , Chondronasiou , D , Lougheed , S M , Bakker , J , Kandiah , V , van den Tol , M P , Jooss , K , Vuylsteke , R J C L M , van den Eertwegh , A J M & de Gruijl , T D 2022 , ' Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic Treg reduction and effector T cell .... |
| سنة النشر: | 2022 |
| الوصف: | Preclinical studies show that locoregional CTLA-4 blockade is equally effective in inducing tumor eradication as systemic delivery, without the added risk of immune-related side effects. This efficacy is related to access of the CTLA-4 blocking antibodies to tumor-draining lymph nodes (TDLNs). Local delivery of anti-CTLA-4 after surgical removal of primary melanoma, before sentinel lymph node biopsy (SLNB), provides a unique setting to clinically assess the role of TDLN in the biological efficacy of locoregional CTLA-4 blockade. Here, we have evaluated the safety, tolerability, and immunomodulatory effects in the SLN and peripheral blood of a single dose of tremelimumab [a fully human immunoglobulin gamma-2 (IgG2) mAb directed against CTLA-4] in a dose range of 2 to 20 mg, injected intradermally at the tumor excision site 1 week before SLNB in 13 patients with early-stage melanoma (phase 1 trial; NCT04274816). Intradermal delivery was safe and well tolerated and induced activation of migratory dendritic cell (DC) subsets in the SLN. It also induced profound and durable decreases in regulatory T cell (Treg) frequencies and activation of effector T cells in both SLN and peripheral blood. Moreover, systemic T cell responses against NY-ESO-1 or MART-1 were primed or boosted (N = 7), in association with T cell activation and central memory T cell differentiation. These findings indicate that local administration of anti-CTLA-4 may offer a safe and promising adjuvant treatment strategy for patients with early-stage melanoma. Moreover, our data demonstrate a central role for TDLN in the biological efficacy of CTLA-4 blockade and support TDLN-targeted delivery methods. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1126/sciimmunol.abn8097 |
| الاتاحة: | https://research.vumc.nl/en/publications/2f0e8e0c-4ce6-46f6-8208-8a315c5e1b13 https://doi.org/10.1126/sciimmunol.abn8097 http://www.scopus.com/inward/record.url?scp=85134854372&partnerID=8YFLogxK |
| Rights: | info:eu-repo/semantics/restrictedAccess |
| رقم الانضمام: | edsbas.FB7722AC |
| قاعدة البيانات: | BASE |
| DOI: | 10.1126/sciimmunol.abn8097 |
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