Abstract
BackgroundAntibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma. Response to anti-PD-1 treatment requires pre-existing CD8+ T cells that are negatively regulated by PD-1-mediated adaptive immune resistance. Unfortunately, less than half of melanoma tumours have these characteristics. Combining anti-PD-1 treatment with other immunomodulating treatments to activate CD8+ T cells is therefore of vital importance to increase response rates and long-term survival benefit in melanoma patients. Both preclinical and retrospective clinical data support the hypothesis that radiotherapy increases the response rates to anti-PD-1 treatment by stimulating the accumulation and activation of CD8+ T cells in the tumour microenvironment. Combining radiotherapy with a PD-1 blocking antibody might therefore increase response rates and even induce long-term survival. The current phase II study will be testing these hypotheses and aims to improve local and distant tumour responses by exploiting the pro-immunogenic effects of radiotherapy in addition to anti-PD-1 treatment.MethodsThe trial will be conducted in patients with metastatic melanoma. Nivolumab or pembrolizumab, both antibodies that target PD-1, will be administrated according to the recommended dosing schedule. Prior to the 2nd cycle, radiotherapy will be delivered in three fractions of 8 Gy to the largest FDG-avid metastatic lesion. The primary endpoint is the proportion of patients with a partial or complete response in non-irradiated metastases according to RECIST v1.1. Secondary endpoints include response rate according to immune related response criteria, metabolic response, local control and survival. To identify peripheral blood biomarkers, peripheral blood mononuclear cells and serum samples will be collected prospectively before, during and after treatment and subjected to flow cytometry and cytokine measurement.DiscussionThe current phase II trial aims at exploring the suggested benefits of combining anti-PD-1 treatment and radiotherapy. The translational focus on immunologic markers might be suitable for predicting efficacy and monitoring the effect so to improve patient selection for future clinical applications.ClinicalTrials.gov Identifier NCT02821182
Highlights
Antibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma
The Gross Target Volume (GTV) will be expanded with 2–5 mm to the Planning Target Volume (PTV) to account for organ motion and setup error
A Planning Organ at Risk Volume (PRV) expansion of 2–5 mm will be added for organs at risk (OAR) and dose constraints apply to this PRV
Summary
Antibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma. Patients with metastatic melanoma had a median overall survival of only 6–9 months [1] until a breakthrough was achieved with novel immunomodulatory agents blocking specific immune checkpoints Immune checkpoints, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4), PD-1 and programmed cell death 1 ligand (PD-L1), are negative regulators of the immune system, that play critical roles in maintaining self-tolerance and modulating immune responses to protect normal tissue from immune collateral damage. Inhibition of these immune checkpoints by CTLA-4 blocking agents and anti PD-L1 antibodies is able to reactivate T cells and restore anti-tumour immunity, resulting in impressive efficacy in patients with metastatic melanoma [2].
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