Nivolumab helps your immune system to fight cancers, by blocking tumor’s ability to evade immune response.
Main target of Nivolumab (brand name is Opdivo) is the Program Death protein (PD-1).
PD-1 receptor is normally present on different immune cells, such as B cells, T cells, and Natural killers (NK). One particular subtype of T-cells, which scientists call Tumor Infiltrating lymphocytes (TIL) express a lot of PD-1 receptors. TILs are quite good in recognizing different types of cancers and subjecting them to death. TILs have a pretty important role of “cancer killers”.
By binding to the PD-1 receptor of cancer killing cells, Nivolumab blocks one of the most important ways for tumor cells to escape the immune radar and get off.
Another prominent PD-1 inhibitor is Pembrolizumab, better known under the brand name keytruda
Algorithm of the Killers of a Cancer
Immune system works around the clock to find abnormal cells. Each day at least 20 cancer cells are elminated from our bodies. TILs monitor billions of cells to check if they have any suspicious features – special proteins, expressed on their surfaces.
There are also proteins, that make cells less suspicios, signalling to immune system about “perfectly normal cells“.
Imagine every second TILs conduct a risk-survey, analyzing both positive and negative evidence, before making a decision.
If an evidence is overwhelmignly positive, the cells would be destroyed. One of those whistle blowers is TCR (T-cell receptor), alerting immune system of potential abnormality such as cancerous major histocompatibility complex (MHC).
On the other side of the scale, is a PD-1, which works as cell’s best advocate. In case of melanoma it is advocate of a devil.
How Does PD-1 Work
PD-1 has 288 amino acids, which are arranged across the whole membrane (transmembraine protein ) of B-cells, T-cells and natural killer (NK) cells. For latter two, it limits their ability to kill other cells.
The PD-1 always present on some immune cells, but not in an active form. When it’s activated, the policemen can tick: “Not guilty. It is probably a benign, useful for our body cell“.
PD-1 plays crucial role for normal cells preventing autoimmune reactions. In one study, mice, who’s PD-1 system was completely shutdown, developed serius autoimmune inflammation of her kidneys and heart.
Scientists call PD-1 and other proteins, advocating for a cell, “negative checkpoints”. Hence the prosecutors are “positive one”, that enchance the immune response.
PD-1 and cancer cells
Cancers have few tricks to slip from the radar of immune system.
Activating of PD-1 is crucial for survival of many cancers, like melanoma, renal cell carcinoma, astrocytoma, or colorectal cancer.
To activate a “negative checkpoint” they all express two types of Program Death Ligands – PDL-1 and PDL-2 – to trick immune monitoring and evade the attack.
Once immune cell comes into vicinity of the cancer one for an inspection, they will check for positive and negative signs of a malignancy. They will PD-1 as one of their inspection tool. If the tumor cell has a PDL-1 or PDL-2, it will pass the test and get away.
PD-L1 in tumors
According to the research, only one in three cancers express PD-L1. Particularly, some solid tumors are pretty good in producing the ligand on the surfaces of their cells:
- an ovarian cancer,
- a melanoma,
- a lung cancer.
PD-L2 in tumors
PD-L2, having a similar structure to PD-L1, creates a better and stronger bond with PD-1. Studies estimate the binding affinity of PD-L2 is two to sixfold higher.
PD-L2 is found in many epithelial cancers and B-cell lymphomas.
How does Nivolumab bind the PD-1?
Paul Gauigin, a famous painter, once told his friend Bernard: “Do not copy a nature. Art is an abstraction”. Although much of the art’s history of the XXth century proved it was a worthy advice, modern scientists still consider imitation is one of the greatest tools in their arsenal.
Nivolumab is a mere antibody. Our immune system produce billions of them each day to eliminate unwanted and hurmful agents. There are few things that make Nivolumab special:
- It is monoclonal (mAb) – all copies of it have the same structure and represent the same class and a serotype of IgG.
- It is fully human – the structure is identical to a normal human antibody, which helps to stay longer in our bodies without eliciting our immune reaction.
- It belongs to the family of immune checkpoints inhibitors.
- It binds to a Program Death protein 1 with affinity and specificity. A single dose of nivolumab can link up around 85% of all PD-1 receptors, and after 24 hours, around 70%.
When Nivolumab connects to the PD-1 receptor on a T-cell or NK-cell it blocks PD-1’s ability to couple with PD-L1 or PD-L2, preventing a cancer cell from abusing this evasion route and getting off the immune radar.
What Cancers Can Nivolumab Treat?
Nivolumab was developed by Bristol-Myers Squibb and received FDA approval in 2014, initially for treating metastatic melanoma.
Over time, its applications expanded to cover multiple cancers:
1. Melanoma
Nivolumab was first approved for unresectable or metastatic melanoma. It demonstrated high efficacy, particularly in cases where other treatments failed.
2. Non-Small Cell Lung Cancer (NSCLC)
A significant milestone in the treatment of NSCLC, Nivolumab has shown effectiveness in patients with advanced or metastatic disease, especially after the failure of chemotherapy.
3. Renal Cell Carcinoma (RCC)
For advanced kidney cancers, Nivolumab improved overall survival rates compared to previously established treatments like everolimus.
4. Head and Neck Squamous Cell Carcinoma (HNSCC)
Nivolumab is particularly beneficial for recurrent or metastatic HNSCC with progression on or after platinum-based therapy.
5. Classical Hodgkin Lymphoma (cHL)
The ability of Nivolumab to respond to immune-evasive hematological cancers, such as cHL, has expanded its utility in hematological oncology.
6. Colorectal Cancer (CRC)
Certain CRC cases with mismatched repair deficiency (dMMR) respond well to Nivolumab due to high mutational burden, making the tumors more “visible” to the immune system.
What Are the Side Effects of Nivolumab?
Like all therapies, Nivolumab carries potential risks. Its immune system activation can lead to immune-related adverse events (irAEs), affecting both efficacy and tolerability. Below are some common and rare side effects:
Common Side Effects:
- Fatigue
- Rash and skin reactions such as pruritus
- Diarrhea or colitis
- Musculoskeletal pain
- General fever or flu-like symptoms
Immune-Related Adverse Events (irAEs):
These occur due to heightened immune activity and may involve any organ system. Examples include:
- Lungs (Pneumonitis). If you are short on breathe or have a persistent caugh, please let your doctor know, as Nivolumab might increase the risks of your lung tissues being damaged.
- Liver (Hepatitis): your doctor will check your liver function tests to ensure the enzymes are not elevated
- Endocrine Disorders: Some normal endocrine cells express small quintities of PDL-1 and can be targeted by immune system. Although recent studies haven’t found a link between PDL-1 expression and endocrine complications of nivolumab treatment, the doctor might check the levels of thyroid or pituitary hormones and request ultrasound or MRI to check up on your glands.
- Gut (Colitis): in rare cases, severe inflammation of the digestive tract may develop, prompting your doctor to check your stoll for potential inflammatory signs or request colonoscopy.
While these side effects are typically manageable, it’s essential to let your doctor ASAP if you expirience any problems and do your prescribe routine tests on time.
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