Immune checkpoint inhibitors

What it is

Immune checkpoint inhibitors are cancer drugs that block PD-1, PD-L1, or CTLA-4 to help T cells attack tumours. The most important practical fact is that these medicines can produce long-lasting responses in some cancers, but they can also cause immune-related side effects in almost any organ because they release normal brakes on the immune system.

These medicines are a type of immunotherapy, not chemotherapy. Instead of directly killing cancer cells, they change how the immune system responds to cancer. They are used in several cancers, including melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, some liver cancers, Hodgkin lymphoma, and some tumours with biomarkers such as high microsatellite instability or mismatch repair deficiency. In India, access depends on the cancer type, biomarker testing, hospital expertise, and cost, and treatment is usually given in medical oncology centres that can monitor immune-related toxicity.

Common checkpoint inhibitor groups include:

Target	What it blocks	Examples
PD-1	PD-1 receptor on T cells	nivolumab, pembrolizumab, cemiplimab
PD-L1	PD-L1 on tumour or immune cells	atezolizumab, durvalumab, avelumab
CTLA-4	CTLA-4 checkpoint on T cells	ipilimumab, tremelimumab
Combination therapy	More than one checkpoint pathway	nivolumab + ipilimumab

How it works

Immune checkpoints are normal control systems that prevent the immune response from becoming too strong and damaging healthy tissue. Cancer cells can exploit these pathways to avoid immune attack. For example, when PD-L1 on a tumour cell binds PD-1 on a T cell, the T cell receives an inhibitory signal and becomes less effective at killing the tumour.

Checkpoint inhibitors are usually monoclonal antibodies. They block the interaction between checkpoint proteins and their partner proteins, which reduces the inhibitory signal and allows T cells to stay active. CTLA-4 blockade mainly affects early T-cell activation, while PD-1 or PD-L1 blockade mainly acts in the tumour microenvironment, although this is a simplification.

This mechanism explains both benefit and harm. If the immune system becomes more active against cancer, it may also become more active against normal organs. That is why these drugs can cause inflammation of the skin, colon, lungs, liver, thyroid, pituitary gland, pancreas, kidneys, nerves, heart, and other tissues.

Evidence and uses

Checkpoint inhibitors have changed treatment for multiple advanced cancers and are now also used in some earlier-stage settings, often after surgery or with chemotherapy or radiation. In some diseases they improve overall survival, and in a subset of patients responses can last much longer than with older treatments. However, they do not work for everyone, and benefit varies by cancer type, stage, line of treatment, and biomarkers.

Examples of where they may be used include:

1. Metastatic disease: melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial cancer, and others.
2. Adjuvant or neoadjuvant treatment: in selected cancers before or after surgery.
3. Biomarker-driven treatment: tumours with MSI-H or dMMR, and in some settings tumours with high PD-L1 expression.
4. Combination regimens: with chemotherapy, targeted therapy, or another checkpoint inhibitor.

Biomarkers help but are imperfect. PD-L1 testing can guide treatment in some cancers, but a high PD-L1 result does not guarantee response and a low result does not always mean no benefit. Tumour mutational burden and MSI-H/dMMR can also matter in selected settings. Doctors also consider performance status, autoimmune disease history, organ function, infection risk, and prior transplant.

In India, checkpoint inhibitors are part of standard oncology practice in many tertiary centres, but the exact drug and schedule depend on approvals, availability, and affordability. Patients often need pathology review and biomarker testing before starting treatment.

Safety and interactions

The main safety issue is immune-related adverse events, often called irAEs. These are different from typical chemotherapy side effects. They can happen during treatment, after treatment, or occasionally months later. Some are mild, but some can be severe or life-threatening.

Important immune-related toxicities include:

Organ/system	Possible problem	Warning signs
Skin	rash, itching	widespread rash, blistering
Gut	colitis	diarrhoea, blood in stool, severe abdominal pain
Lungs	pneumonitis	new cough, breathlessness, low oxygen
Liver	hepatitis	jaundice, dark urine, abnormal liver tests
Endocrine glands	thyroiditis, hypophysitis, adrenal insufficiency, diabetes	fatigue, dizziness, headache, weight change, excessive thirst
Kidneys	nephritis	reduced urine, swelling, rising creatinine
Nervous system/heart	neuropathy, myocarditis, myositis	weakness, chest pain, palpitations

Combination therapy, such as nivolumab plus ipilimumab, generally causes more toxicity than single-agent PD-1 or PD-L1 treatment. Management may include pausing treatment, blood tests, scans, hormone replacement, or corticosteroids. Some severe toxicities need hospital admission and specialist care.

Drug interactions are less about classic liver-enzyme interactions and more about immune effects and overlapping toxicity. People with autoimmune disease, prior organ transplant, chronic viral hepatitis, or interstitial lung disease need careful assessment before treatment. Live clinical decisions should be made by an oncologist familiar with immunotherapy. Patients should tell their team about all medicines, including steroids, tuberculosis treatment, herbal products, and supplements.

When to see a clinician

Anyone receiving checkpoint inhibitor therapy should contact their oncology team promptly for new symptoms, even if they seem minor. Early treatment of immune-related toxicity can prevent serious complications.

Seek urgent medical care for:

• shortness of breath or chest pain
• severe diarrhoea or dehydration
• confusion, severe headache, or fainting
• jaundice or very dark urine
• marked weakness, severe muscle pain, or palpitations
• fever or signs of infection

It is useful to carry a treatment card or note stating that you are on immunotherapy, because emergency clinicians may otherwise mistake immune toxicity for infection or routine chemotherapy effects.

Limitations and open questions

Checkpoint inhibitors are important but not universal cancer treatments. Many patients do not respond, some develop resistance after an initial response, and some cannot safely receive them because of autoimmune disease, transplant history, or poor general condition. Biomarkers such as PD-L1 and MSI-H/dMMR improve selection but are still incomplete.

Evidence is strong for several approved uses, but questions remain about the best duration of therapy, how to predict who will benefit most, how to manage long-term endocrine and neurologic toxicity, and how to combine these drugs with chemotherapy, radiation, targeted therapy, or newer immunotherapies. Long-term follow-up is especially important because some immune side effects can persist even after the cancer treatment stops.