Based on a phase 1 dose escalation study, Pul and Notohardjo et al. reported that a single intradermal injection of tremelimumab (anti-CTLA-4) at the primary tumor excision site of patients with clinical stage I/II melanoma was safe and well tolerated. Intradermal anti-CTLA-4 systemically decreased activated Treg frequencies, increased conventional T cell activation and central memory conversion, and induced migratory dendritic cell subset activation in the sentinel LN. Systemic melanoma-specific T cell responses against NY-ESO-1 and MART-1 detected in responders were associated with increased T cell activation and memory T cell differentiation.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Amsterdam UMC location Vrije Universiteit, Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, Netherlands. Amsterdam UMC location Vrije Universiteit, Surgical Oncology, D
Author Info: (1) 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. (2) 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. (3) 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. (4) 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. (5) 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. (6) 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. (7) 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. (8) 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. (9) 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. (10) 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. (11) Pfizer Inc., San Diego, CA, USA. (12) Department of Surgical Oncology, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, Netherlands. (13) 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. (14) 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.
