Local delivery of low-dose anti-CTLA-4 to the melanoma lymphatic basin leads to systemic T reg reduction and effector T cell activation.

Autor:	van Pul KM; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Amsterdam UMC location Vrije Universiteit, Surgical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Notohardjo JCL; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Fransen MF; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam UMC location Vrije Universiteit, Pulmonary Diseases, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands., Koster BD; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Stam AGM; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Chondronasiou D; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Lougheed SM; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Bakker J; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Kandiah V; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., van den Tol MP; Amsterdam UMC location Vrije Universiteit, Surgical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., Jooss K; Pfizer Inc., San Diego, CA, USA., Vuylsteke RJCLM; Department of Surgical Oncology, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, Netherlands., van den Eertwegh AJM; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands., de Gruijl TD; Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands.; Cancer Center Amsterdam, Cancer Immunology, Amsterdam, Netherlands.; Amsterdam Institute for Infection and Immunology, Cancer Immunology, Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Science immunology [Sci Immunol] 2022 Jul 15; Vol. 7 (73), pp. eabn8097. Date of Electronic Publication: 2022 Jul 15.
DOI:	10.1126/sciimmunol.abn8097
Abstrakt:	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 (T reg ) 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.
Databáze:	MEDLINE
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