Anti-PD-1 and Novel Combinations in the Treatment of Melanoma—An Update

Abstract

Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).

DNA Strand Break Properties of Protoporphyrin IX by X-ray Irradiation against Melanoma

“…Preclinical and clinical data suggest that RT can cause disruption of the blood-brain barrier, enhancing drug delivery to the brain. Moreover, RT may increase the antitumor response by promoting antigen presentation and T-cell activation [45]. 5-ALA PDT can activate an otherwise quiescent local immune response under certain circumstances [46][47][48][49].…”

An update on the safety of nivolumab for the treatment of advanced melanoma

“…It was already reported that in NCT02983045 phase 1/2 trial of Nivolumab + BEMPEG (pegIL-2) 38 patients have been recruited and 53% ORR was achieved. In NCT01968109 phase 1/2 trial of Nivolumab with BMS-986,016 (anti-LAG-3) 43 anti-PD-1 refractory patients we recruited and obtained 16% ORR [110].…”

Moderne Aspekte der Immuntherapie mit Checkpoint-Inhibitoren bei Melanom

“…Tumore nutzen möglicherweise diese Immuncheckpoint-Moleküle, die eine Schlüsselrolle für die Aufrechterhaltung der Selbsttoleranz unter physiologischen Bedingungen spielen, um der Immunantwort zu entgehen. Daher könnte die Hemmung dieser Interaktionen antitumorale Immunreaktionen in Gang setzen [14]. Ferner hat sich gezeigt, dass die Kombination von Anti-CTLA-4- und Anti-PD-1-Antikörpern synergistisch wirkt, indem sie zu einer Expansion der aktivierten CD8-T-Effektorzellen führt [15, 16].…”