Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells’ responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.
Highlights
Since the 20th century, cancer therapy has been characterized by ups and downs that are due to the ineffectiveness of therapies and side effects, and conditioned by hope and the fact that in many cases, there has been complete remission [1]
The Food and Drug Administration (FDA) approved the positive results of ipilimumab in combination with nivolumab for metastatic melanoma, metastatic colorectal cancer, and advanced renal cell carcinoma [36,37,38]
The recommended dose of combination therapy for renal cell carcinoma and colorectal cancer is IV administration of 1 mg/kg ipilimumab over 30 min, following nivolumab administered on the same day, every three weeks with up to four doses or until intolerable toxicity or disease progression [40]
Summary
Since the 20th century, cancer therapy has been characterized by ups and downs that are due to the ineffectiveness of therapies and side effects, and conditioned by hope and the fact that in many cases, there has been complete remission [1]. Monoclonal antibodies targeting PD-1 (including pembrolizumab and nivolumab) as well as PD-L1 (including avelumab, atezolizumab, and durvalumab,) and those targeting CTLA-4 (including ipilimumab and tremelimumab) [12], have been approved by the FDA for several cancers, such as melanoma, renal cell cancer, lung cancer, and colorectal cancer [13]. A fully human immunoglobulin G4 anti-PD-1 monoclonal antibody that was created from Chinese hamster ovary cells, is approved for multiple advanced tumors, including melanoma, non-small cell lung cancer (NSCLC), renal cell cancer, Hodgkin’s lymphoma, squamous head and neck cancer, and urothelial carcinoma [14]. Durvalumab is a human immunoglobulin G1, an anti-PD-L1 monoclonal antibody that is approved for the treatment of advanced bladder cancer and NSCLC [22,23]. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers
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