As a biologist, Christina loves exploring the sciences and applying them to everyday life.
Nivolumab's Usage and Mechanism
The drug optivo, also known as nivolumab, is used as an immunotherapy to treat cancer. Initially, it was used exclusively against advanced melanoma, in cases where tumors cannot be removed or chemotherapy wasn’t successful (US). However, Optivo is now used to treat various cancers, including non-small cell lung cancer and Hodgkin’s Lymphoma (Wishart). Nivolumab operates as a Programmed Death 1 (PD1) immune checkpoint inhibitor (Wishart). The immune system’s regulatory system for T cells utilize PD1 (Brahmer). PD-1 receptors are on the membrane of the T cells, and Programmed Death Ligand 1 (PD-L1), naturally found on other immune cells, bind to PD-1, inactivating the T cells (Brahmer). In addition to T cell activation, the PD-1 pathway also controls T cell proliferation, glucose metabolism, and cytokine signaling (Scott).
Programmed Death- Ligand 1 Expression: Cancer Cells vs Normal Cells
The expression of PD-L1 in normal cells is relatively low. In cancer cells, however, PD-L1 expression is much higher frequently (Scott), allowing the cancer to utilize the PD1 pathway to deactivate T cells (Shaheen). High PD-L1 expression is frequently associated with a worse prognosis, perhaps due to this pathway being the mechanism behind immune system escape. When PD-L1 binds to PD-1, Ras and PTEn are inhibited, resulting BCl-xL not being able to inhibit apoptosis (Bardhan, Anagnostou, & Boussiotis, 2016). By utilizing the PD-1 pathway, cancers cells can create an immunosuppressed microenviroment, which is perfect for cancer proliferation (Qin).
Patients should be counselled regarding the risk of immune-mediated adverse effects, infusion-related adverse effects, complications of allogenic hematopoietic stem cell transplants, [and] embryo-fetal toxicity.
Structure and Pharmacokinetics
Optivo is a fully human IgG4 immune checkpoint antibody (Wishart), and like most PD-1 inhibitors, is comprised of both a heavy chain and a light chain. Specifically, nivolumab has a Gamma 1 heavy chain and a Kappa light chain, and it has a half-life of 25 days (Wishart). Steady concentrations of nivolumab are reached by 12 weeks after a dosage of 3 mg/kg every 2 weeks administered intravenously (Scott). Notably, PD-L1 expression levels or tumor size don’t affect the drug’s clearance (Scott). Optivo uses the spleen as the main organ of distribution (Qin). Due to elimination of nivolumab occurring via reticuloendothelial enzymes, co-administration of nivolumab with other drugs doesn’t affect its pharmacokinetics (Scott).
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Brief History of Development
The first developed checkpoint inhibitor was ipilimumab, approved in 2011 for metastatic melanoma (Patel). Instead of targeting PD-1, ipilimumab targets the cytotoxic T-lymphocyte associated protein 4, a different checkpoint in the immune system (Selby). Developed around the same time as nivolumab was pembrolizumab, which also targets PD-1 and was first tested against advanced skin cancer (Shaheen). Pembrolizumab has a half-life of 26 days and proved useful as a treatment when ipilimumab failed to control the cancer (Dang). Like nivolumab, the usages then expanded, and it is now used to treat metastatic melanoma (Dang).
To test the effectiveness of the PD1 pathway on immune system, various studies were conducted. First, there was an in vitro study proving macrophages and T cells increase their PD-L1 expression levels after being treated with various interleukins (Selby). This was followed by in vivo mouse studies in which the PD-1 pathway was inhibited, resulting in an overexpression of T cells (Selby). Occasionally, autoimmune diseases developed due to the absence of the regulation of T cells (Selby).
Common Treatment Combinations with Nivolumab
Nivolumab can be used as a treatment by itself or as part of combination treatment. Frequently, nivolumab is used in combination with ipilimumab (Scott). Against previously untreated melanoma, the combination of ipilimumab and nivolumab had a response rate of 58% (Asher), compared to the 40% response rate from nivolumab alone (Amraee). This higher response rate is likely due to the combination treatment targeting two separate immune system checkpoints, and this is typically used in cases of metastatic advance state lunge cancers with tumors that are PD-L1 positive but lacking an abnormal epidermal growth factor receptor or an abnormal anaplastic lymphoma kinase (Asher). Nivolumab is also frequently combined with chemotherapy as well. For treating Hodgkin’s Lymphoma, nivolumab is typically a solo treatment, having a response rate of 69% (Amraee).
Possible Side Effects
Because nivolumab activates T cells, many common side effects are mild symptoms of T cell overactivation, which is typically an exaggerated immune response. These symptoms include inflammation, fatigue, low sodium, decreased appetite, and cough (Cuhna). Specifically, nivolumab can cause immune mediated inflammation in the lungs, colon, liver, and kidneys, in addition to autoimmune diabetes, like type 1 diabetes (Cuhna). Peripheral neuropathy can also occur. For patients with Hodgkin’s lymphoma that had replaced after allogenic hematopoietic cell transplantation, nivolumab could induce Graft vs Host Disease, in which graft cells recognize the host body as foreign and attacks it, but this side effect was only observed in patients were previously had a history of acute Graft vs Host Disease (Herbaux). The chances of developing serious side effects increased with nivolumab is used in a combination therapy.
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- Wishart, D. S. (2015). Nivolumab. Uses, Interactions, Mechanism of Action | DrugBank Online. Retrieved February 25, 2022, from https://go.drugbank.com/drugs/DB09035
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