Immunotherapy and targeted cancer therapy

• Checkpoint inhibitors and targeted drugs have turned many cancers into long, treated illnesses, but they work by jobs that normal tissues depend on.
• Checkpoint inhibitors free T cells to attack cancer; the same unleashed immunity produces immune-related adverse events in almost every organ.
• Tyrosine kinase inhibitors block a growth signal inside a cancer cell; they are oral, selective, and need careful watch for organ toxicity and drug interactions.
• Monoclonal antibodies bind a tumour antigen or a receptor, often needing an infusion and, for some, heart monitoring.
• CAR-T cells are the patient's own T cells re-engineered to recognise cancer; they can produce durable remission, but cytokine release and neurological toxicity are potentially life-threatening.
• The practical skill for a student is to name the drug family, link it to its target, anticipate its characteristic toxicity, and know when to stop the drug and escalate care.

By the end of this page you should be able to:

1. Place a cancer drug into one of four groups: immune checkpoint inhibitor, monoclonal antibody, tyrosine kinase inhibitor, or CAR-T cell therapy, and state its molecular target.
2. Explain how checkpoint inhibitors produce anti-tumour immunity and why this same mechanism produces inflammation in normal organs.
3. State the standard adult intravenous doses for pembrolizumab and the oral doses for imatinib in chronic myeloid leukaemia.
4. List the immune-related adverse events of checkpoint inhibitors by organ system, with their typical frequencies, and outline how a grade 2 or 3/4 event is managed. ^[1]
5. Describe tyrosine kinase and monoclonal antibody adverse effects that require monitoring, including cardiac and renal cautions.
6. Recognise cytokine release syndrome after CAR-T therapy and state the roles of tocilizumab and high-dose methylprednisolone.
7. Compare the four groups on route, speed, durability of benefit, and characteristic toxicity.
8. Apply the grading concepts of steroid-unresponsive and steroid-dependent immune-related adverse events to a clinical vignette.

Immunotherapy and targeted cancer therapy are now core treatments for many cancers. The two words cover several quite different machines. An immune checkpoint inhibitor blocks the off signals that protect healthy tissue, letting T cells attack cancer. A targeted small molecule, usually a tyrosine kinase inhibitor, jams a signalling enzyme that drives a particular cancer. A monoclonal antibody is a laboratory-made antibody that binds a tumour antigen or a growth-factor receptor. CAR-T cell therapy means removing a patient's own T cells, inserting a gene for a cancer-recognition receptor, multiplying the cells, and returning them as a living drug.

These agents differ from conventional cytotoxic chemotherapy. Cytotoxic drugs poison dividing cells broadly. The drugs in this topic hit a specific molecule or a specific immune pathway. That precision changes three things: which cancers respond, how responses present, and which side effects appear. A checkpoint inhibitor can produce long, treatment-free remission in melanoma, lung cancer, renal cell cancer and others, but a quarter of a typical treated population experiences a serious or severe immune-related adverse event. A tyrosine kinase inhibitor can keep chronic myeloid leukaemia in remission for decades, but only while it is taken and while the leukaemia cell clone remains sensitive. A monoclonal antibody against HER2 turns an aggressive breast cancer subtype into a treatable disease, but it can injure the heart. CAR-T cells can clear refractory lymphoma in a quarter to a half of patients, yet can trigger fever, shock and brain dysfunction within days.

The page is written for a first-time student. It defines terms as they appear, builds mechanisms before complications, and points out the red flags a junior doctor must not miss. Doses are typical adult doses from current prescribing information; routes, frequencies and regional differences are stated where sources give them. Renal, hepatic and age-related adjustments always need the local formulary and the specialist team.

Table 1 groups the main families, their representative members and their targets.

A quick naming lesson helps. Many drugs share a stem that reveals the class. The stem "-mab" denotes a monoclonal antibody, "-tinib" a tyrosine kinase inhibitor, "-ciclib" a cyclin-dependent kinase inhibitor, "-mumab" a monoclonal antibody targeting CTLA-4. CAR-T products are cells, not tablets or vials of drug in the usual sense, and are made individually for each patient.

One other distinction matters for the student. Targeted therapy is only useful when the target is actually present or activated. Philadelphia-chromosome positive chronic myeloid leukaemia depends on BCR-ABL, so imatinib works. In chronic myeloid leukaemia without BCR-ABL, imatinib has no place. EGFR tyrosine kinase inhibitors help only when the tumour has a sensitising EGFR mutation; giving gefitinib to an EFGR-wild-type tumour adds toxicity without benefit. Similarly, HER2-directed therapy needs HER2 overexpression or amplification, and checkpoint inhibitors work best, though not exclusively, in tumours with high tumour mutational burden or PD-L1 expression. Testing the tumour is therefore part of treatment.

A T cell does not activate simply because it meets an antigen. It needs a second, co-stimulatory signal, and then its response has to be switched off so it does not attack the body's own cells. Two proteins are the main brakes. CTLA-4 is expressed on activated T cells and on regulatory T cells, and it competes with the activating receptor CD28 for the B7 ligands (CD80 and CD86) on antigen-presenting cells; it down-regulates the response in lymphoid tissue, especially during the priming phase. PD-1 is expressed on activated T cells and, on engagement with PD-L1 or PD-L2 in peripheral tissues, shuts down T-cell cytotoxicity. Cancers exploit both. PD-L1 is up-regulated in many tumours and in the tumour microenvironment, and PD-1 or CTLA-4 blockade restores T-cell killing of tumour cells.

The same mechanism explains the toxicities. Removing a brake does not make the immune system specific again. Autoreactive T cells that were held in check can attack normal tissue. Activated B cells can make autoantibodies. Epitope spreading can draw in new targets after the first tissue is damaged. The result is immune-related adverse events that can affect skin, gut, liver, lung, endocrine glands, kidney, heart, nerves, joints, eyes and, rarely, multiple organs at once.

The two brakes behave differently. CTLA-4 is active earlier and more broadly, in lymphoid organs, and anti-CTLA-4 agents produce more frequent and more severe immune-related adverse events than anti-PD-1 or anti-PD-L1 agents. Combining the two, as with nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks in melanoma, increases both response and toxicity.^[5] Because organ involvement depends on which self-antigens are presented and on checkpoint expression in that organ, anti-PD-1 therapy can cause thyroiditis or nephritis even though the tumour is in the lung. ^[1]

A second protective idea is the test of tolerance: many immune-related adverse events settle when the drug is stopped and inflammation is controlled, but a minority persist for months and become chronic, active or inactive, or reappear after rechallenge. ^[3]

A therapeutic monoclonal antibody binds a cell-surface antigen or soluble molecule. Its actions are of three kinds. It can block signalling, as trastuzumab binding the HER2 receptor and stopping dimerisation and downstream growth signals. It can direct immune killing, through antibody-dependent cellular cytotoxicity and complement activation, which is relevant for anti-CD20 therapy in lymphoma. It can carry a payload, as in the antibody-drug conjugates used in breast cancer and myeloma, where the antibody delivers a cytotoxic drug to cells that express the target antigen.

Because they are large proteins, these drugs are not absorbed by the gut and are given intravenously or subcutaneously. Trastuzumab is a humanised IgG1 monoclonal antibody. It is not cleared by the kidney or liver in the conventional sense, and it does not participate in cytochrome P450 interactions. Its signature danger is cardiac dysfunction: HER2 signalling is involved in cardiomyocyte survival, and blocking it can reduce left ventricular ejection fraction, most often when an anthracycline has also been given.

Tyrosine kinases are enzymes that transfer phosphate groups to tyrosine residues on proteins, propagating growth and survival signals. Many cancers are driven by abnormal kinase activity, either because a translocation creates a fusion kinase or because a receptor tyrosine kinase is mutated or overexpressed. A tyrosine kinase inhibitor is usually a small molecule that competes with adenosine triphosphate at the kinase active site, or binds an allosteric site, and stops phosphorylation. Imatinib binds the adenosine triphosphate pocket of BCR-ABL, the fusion kinase of chronic myeloid leukaemia and Philadelphia-chromosome positive acute lymphoblastic leukaemia, and also inhibits KIT and the platelet-derived growth factor receptor, which is why it works in gastrointestinal stromal tumours. Later drugs are more selective or more potent, but the principle is the same: pick the kinase, occupy it, and turn the growth signal off.

These drugs are oral, have variable food and acid effects, are metabolised largely by cytochrome P450 3A4, and interact with many other medicines. Some are substrates, inhibitors or inducers of transporters such as P-glycoprotein. Hepatic and renal impairment, diarrhoea, vomiting and concurrent enzyme modifiers all matter for exposure.

A chimeric antigen receptor is a synthetic receptor that combines an antibody-derived extracellular antigen-recognition domain with T-cell signalling domains. The usual design uses a single-chain variable fragment to recognise the tumour antigen, a hinge and transmembrane region, a co-stimulatory domain such as 4-1BB, and the CD3-zeta signalling chain. The chain is delivered by a lentiviral vector into the patient's own T cells. The cells are expanded in culture, undergo lymphodepleting chemotherapy, and are infused. Once inside the patient, the receptor drives T-cell proliferation, cytokine release and cytotoxic killing of cells bearing the target antigen. The same mechanisms produce the characteristic toxicities. Massive T-cell activation releases interleukin-6, interferon-gamma and other cytokines that cause fever, vasodilation, capillary leak and hypotension: cytokine release syndrome. The same cytokines and activated T cells inflame the endothelium and the blood-brain barrier, producing immune effector cell-associated neurotoxicity. The genetically modified cells can persist for years, giving long responses, but also prolonged cytopenias and hypogammaglobulinaemia.

Pharmacokinetics differ by family.

• Checkpoint inhibitors and other monoclonal antibodies are given intravenously or subcutaneously, are distributed in plasma and the extracellular space, and have half-lives measured in weeks. They are cleared by the reticuloendothelial system and by target-mediated mechanisms rather than hepatic enzymes. Renal and hepatic dose adjustments are usually unnecessary, and these drugs do not have cytochrome P450 interactions.
• Pembrolizumab is given as 200 mg intravenously every 3 weeks or 400 mg intravenously every 6 weeks, infused over 30 minutes. In children it is 2 mg/kg, up to 200 mg, every 3 weeks. Nivolumab is commonly combined with ipilimumab at 1 mg/kg nivolumab with 3 mg/kg ipilimumab every 3 weeks in melanoma, alongside single-agent schedules that vary by indication. These are adult doses from current prescribing information; children's dosing and regional practice may differ. ^[4]
• Tyrosine kinase inhibitors are oral, often once daily. Imatinib is typically 400 mg/day in the chronic phase of chronic myeloid leukaemia and 600 mg/day in accelerated phase or blast crisis, with doses of 400 mg or 600 mg given once daily and 800 mg as 400 mg twice daily. Absorption, drug interactions and renal caution matter: with moderate renal impairment, doses greater than 400 mg are not recommended. Hepatic metabolism and enzyme inducers or inhibitors are a bigger issue than renal clearance for most agents. Blood concentrations vary with food, acidity and adherence, and sub-therapeutic exposure from missed doses is a real cause of treatment failure. ^[6]
• CAR-T cells are living therapy. Their pharmacokinetics is described as cellular expansion, trafficking, persistence and contraction rather than absorption and clearance. Tisagenlecleucel is a CD19-directed genetically modified autologous T cell immunotherapy made from the patient's own mononuclear cells transduced with a lentiviral vector carrying an anti-CD19 chimeric antigen receptor with a 4-1BB co-stimulatory domain and a CD3-zeta signalling domain. Dosing is by body weight or body surface area, into millions of viable CAR-positive T cells per kilogram or per dose, and is product-specific. The cells proliferate in vivo after lymphodepletion; their peak expansion and persistence relate to response and to toxicity. ^[8]

Indications for immunotherapy are now defined by cancer type, stage and biomarker together. Checkpoint inhibitors are used in advanced and, increasingly, adjuvant and neoadjuvant settings for melanoma, non-small cell lung cancer, renal cell cancer, urothelial cancer, head and neck squamous cancer, cervical cancer, gastric and oesophageal cancer, hepatocellular cancer, biliary cancer, Merkel cell cancer, colorectal cancer that is microsatellite instability-high or mismatch-repair deficient, triple-negative breast cancer, and several others. The approved list has grown since the first ipilimumab benefit in melanoma. Selection is often based on PD-L1 expression measured on tumour or immune cells, tumour mutational burden, microsatellite instability status, or companion diagnostics, and on whether the cancer is potentially resectable. Pembrolizumab plus chemotherapy, antiangiogenic therapy, or lenvatinib is common in the advanced setting. Combination anti-CTLA-4 and anti-PD-1 therapy is used where a high response is needed and the toxicity cost is acceptable. ^[1]

Tyrosine kinase inhibitors are used only when the target is present. Imatinib is indicated for Philadelphia-chromosome positive chronic myeloid leukaemia in chronic phase, and accelerated phase or blast crisis, and for Kit-positive gastrointestinal stromal tumours and several rarer conditions. Epidermal growth factor receptor tyrosine kinase inhibitors are used in EGFR-mutated non-small cell lung cancer; ALK or ROS1 inhibitors in driver-positive lung cancer; cyclin-dependent kinase inhibitors with endocrine therapy in breast cancer; and vascular endothelial growth factor receptor inhibitors in renal cell and hepatocellular cancer.

Monoclonal antibodies include trastuzumab and its biosimilars for HER2-positive breast and gastric cancer, anti-CD20 antibodies for B-cell lymphoma, cetuximab and panitumumab for selected colorectal and head and neck cancers, and many others including antibody-drug conjugates, bispecific antibodies and T-cell engagers. Monoclonal antibodies may be used alone, with chemotherapy or with immunotherapy, as in trastuzumab with pembrolizumab and chemotherapy in gastric cancer.

CAR-T therapy is approved for relapsed or refractory haematological malignancies: paediatric and young adult B-cell precursor acute lymphoblastic leukaemia, large B-cell lymphoma after two or more lines of therapy, and follicular, mantle cell and other B-cell malignancies depending on the product. Tisagenlecleucel is indicated for young patients with refractory or second or later relapse B-cell precursor acute lymphoblastic leukaemia, and for relapsed or refractory large B-cell lymphoma and adult follicular lymphoma after two lines, as specified on the label.

Checkpoint inhibitors are given intravenously, usually every 3 or 6 weeks. Reconstitution and infusion times are product-specific: pembrolizumab is infused over 30 minutes. The one constant is that the dose is fixed or weight-capped by the label, rather than titrated to a blood level. Pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks for adults, and 2 mg/kg, capped at 200 mg, every 3 weeks for children.^[4]

Tyrosine kinase inhibitors are taken orally, usually with food and a full glass of water, once daily or twice daily depending on the drug. Imatinib is 400 mg daily in chronic-phase disease and 600 mg daily in accelerated or blast phase, with splitting of 800 mg doses. Renal impairment matters: do not give imatinib doses greater than 400 mg in moderate renal impairment, and use caution in severe impairment. Hepatic impairment, cardiac dysfunction and myelosuppression need individual adjustment. Blood monitoring is part of the dose, not an afterthought.

Monoclonal antibody dose schedules are chosen from the label. Trastuzumab is given intravenously with a loading followed by maintenance, or subcutaneously every 3 weeks in some settings, and always with cardiac monitoring. Antibody-drug conjugates carry cytotoxic payloads and have their own schedules and dose reductions for toxicities.

CAR-T therapy is not a milligram dose. The product is a fixed cell dose based on weight or body surface area, given once after lymphodepletion. Lymphodepleting chemotherapy is part of the treatment, and its timing and intensity influence expansion and toxicity. Infusion is usually in an accredited centre with inpatient monitoring.

Monitoring is planned before the first dose: complete blood count, liver and renal function, thyroid function, glucose, and an assessment of cardiac function where relevant. In centres that give CAR-T, a treatment plan and a trained team are required.

Immune-related adverse events are the price of releasing a powerful immune response. They differ from cytotoxic side effects: they can begin or worsen weeks after a dose, can affect almost any organ, and can be life-threatening even when the tumour is responding. Table 2 summarises the organ systems involved and the frequencies seen in a large pooled analysis.

These events affect between 45 and 83 percent of treated patients at any grade, and severe events occur in up to 28 percent. They most often appear in the first 3 to 4 months, but delayed and late-onset events after treatment has stopped are well recognised, and some persist for months. ^[1]

The nature of the agent matters. Anti-PD-1 and anti-PD-L1 toxicities are generally milder and less common than anti-CTLA-4 toxicities, and combination therapy raises the risk above either drug alone.

Common presentations are fatigue, rash, pruritus, diarrhoea, cough or dyspnoea, persistent headache, abdominal pain, visual changes, palpitations, and laboratory abnormalities. Red flags that warrant same-day assessment include dyspnoea at rest, new chest pain, confusion, severe headache, bloody diarrhoea, jaundice, urine output fall, severe rash with mucous membrane involvement, and any suspicion of adrenal crisis.

Endocrine events are common and manageable. Thyroid dysfunction occurs most often, usually hypothyroidism after transient thyrotoxicosis. Hypophysitis is the classic anti-CTLA-4 endocrinopathy and can cause adrenal insufficiency, hypothyroidism and diabetes insipidus. Primary adrenal insufficiency and insulin-dependent diabetes also occur. Unlike other immune-related adverse events, endocrine toxicities usually do not require stopping the checkpoint inhibitor and rarely need high-dose glucocorticoids: the management is hormone replacement.^[2] Cooperation between oncology and endocrinology is essential, and patients starting these drugs need a baseline and at least periodic thyroid function and a low threshold for morning cortisol testing when symptomatic.

Management is built on grading, usually by the Common Terminology Criteria for Adverse Events. For a grade 1 event, the drug is usually continued with close monitoring. For grade 2, the drug is withheld and oral prednisone at 0.5 to 1 mg/kg/day or an equivalent dose is started, with a taper of at least 4 weeks once symptoms resolve. For grade 3 or 4 events, the checkpoint inhibitor is withheld and often permanently discontinued, and systemic corticosteroids at 1 to 2 mg/kg/day prednisone equivalent are given. Infliximab, vedolizumab, mycophenolate mofetil or tocilizumab are used for steroid-refractory disease, and plasma exchange or other support may be needed for severe neurological or cardiac disease.^{[3] [1]}

Two management concepts from the consensus vocabulary help with practice. Steroid-unresponsive disease: life-threatening events that fail to improve after 1 to 3 days of correctly dosed steroid, or non-life-threatening events after 7 to 14 days. Steroid-dependent disease: symptoms improve on steroids but return on taper; if dependence reaches 12 weeks, it is termed chronic steroid dependence. Endocrinopathies and some neuropathies are often chronic and inactive, needing replacement rather than escalating immunosuppression; active inflammatory events such as colitis need ongoing immunosuppression. ^[3]

Rechallenge is possible for many grade 2 events after full resolution, but after a grade 3 or 4 event it is usually contraindicated except in exceptional circumstances and after multidisciplinary review. Concurrent immunosuppression, slow steroid tapers and careful long-term follow-up are used because re-emergent events are reported in 10 to 40 percent of rechallenged patients.^[3]

Kidney involvement is a useful teaching example. Checkpoint inhibitor-associated acute kidney injury is usually acute tubulointerstitial nephritis, often in a patient also receiving a proton pump inhibitor or non-steroidal anti-inflammatory drug. Creatinine rises, often with sterile pyuria. Guidelines agree on stopping the drug and starting corticosteroids, but differ on when to continue immunotherapy, on whether biopsy is needed before steroids, and on dose, ranging from 0.5-1 mg/kg/day at lower grades to 1-2 mg/kg/day at higher grades. In general, nephrologists favour biopsy to separate immune-related from unrelated injury. Another common practice is to keep low-dose prednisone 5 to 10 mg/day during rechallenge, although data are limited. ^[1]

Tyrosine kinase inhibitors produce class-specific toxicities that are often predictable from their targets. Inhibition of the epidermal growth factor receptor produces an acneiform rash, diarrhoea and paronychia. Inhibition of vascular endothelial growth factor receptors produces hypertension, hand-foot skin reaction, proteinuria and bleeding. BCR-ABL and KIT inhibitors such as imatinib cause peripheral oedema, particularly periorbital oedema, pleural effusions, myelosuppression, nausea, muscle cramps and hepatotoxicity. Fluid retention can become clinically important, and cardiac disease requires caution. Myelosuppression may need dose holds or reductions according to blood counts. Skin reactions can be severe enough to stop the drug. Renal function should be evaluated before and during treatment, and with moderate renal impairment doses above 400 mg of imatinib are not recommended. Dose modifications during cytopenias are guided by the label. ^[6]

Hepatotoxicity is a class concern: transaminase rises may be asymptomatic, so liver function tests are checked regularly and the drug is held and then dose-reduced or stopped for severe injury. Many tyrosine kinase inhibitors prolong the QT interval and interact with drugs that affect cardiac conduction or cytochrome P450 activity. Photosensitivity, dysgeusia and fatigue are common but less dangerous. Second-generation and later tyrosine kinase inhibitors are generally more potent and more selective, and they bring their own issues such as vascular and pulmonary arterial hypertension, or interstitial lung disease.

Monoclonal antibody toxicities fall into three groups. Infusion-related reactions are fever, chills, rigors and hypotension, usually within hours and usually prevented by premedication and slow rates. Immune-mediated adverse events occur when the antibody itself modulates immunity, as with the anti-CTLA-4 and anti-PD-1 agents. Target-specific toxicities follow the biology of the target. Trastuzumab reduces HER2 signalling in cardiomyocytes and can cause cardiomyopathy, asymptomatic left ventricular ejection fraction decline and heart failure, especially after anthracyclines or with pre-existing cardiac disease.^[7] Anti-EGFR antibodies cause skin rash and magnesium wasting. Anti-CD20 antibodies cause infusion reactions, hepatitis B reactivation and hypogammaglobulinaemia. For trastuzumab, left ventricular ejection fraction is assessed at baseline and repeated, and the drug is permanently discontinued if the ejection fraction remains reduced for more than 8 weeks or the drug has to be held more than 3 times for cardiomyopathy. ^[1][3]

CAR-T toxicity is front-loaded, potentially catastrophic, and manageable if recognised early. Cytokine release syndrome begins within days of infusion with fever, tachycardia, hypotension, hypoxia and confusion. It is graded by fever, hypotension and hypoxia. Mild cases need supportive care and sometimes antipyretics. Severe cases are treated with tocilizumab, an interleukin-6 receptor antibody that often produces rapid improvement, together with corticosteroids. For life-threatening cytokine release syndrome, high-dose methylprednisolone 1,000 mg intravenously one to two times per day for 3 days is used, and if there is no improvement, further or longer high-dose steroid. Neurotoxicity, now called immune effector cell-associated neurotoxicity syndrome, produces tremor, dysphasia, confusion, impaired handwriting and, in severe cases, seizures and cerebral oedema. It is treated with corticosteroids; tocilizumab does not cross the blood-brain barrier well, so steroids carry the main role. Other late problems are cytopenias, infection, hypogammaglobulinaemia needing immunoglobulin replacement, and rare secondary malignancies of T-cell origin. Kymriah's label carries a boxed warning for cytokine release syndrome, neurological toxicities and secondary haematological malignancies, and advises staying near a treatment centre for at least 2 weeks. ^[8]

Pembrolizumab has no absolute contraindications in its current label, but caution is required with recent or planned allogeneic haematopoietic stem cell transplantation, with solid organ transplant recipients because of a high risk of rejection, with severe autoimmune disease, and in pregnancy because IgG4 antibodies cross the placenta. Opdivo's label notes the same general concerns. Combining anti-PD-1 blockade with a thalidomide analogue and dexamethasone in multiple myeloma is not recommended outside controlled trials.

Tyrosine kinase inhibitors carry specific cautions. Imatinib is teratogenic in animal studies at exposures close to the human dose. People of reproductive potential need effective contraception during treatment. Hepatic impairment often needs reduced starting doses; severe renal impairment, cardiac failure and myelosuppression require caution; and QT prolongation interactions need review. Most tyrosine kinase inhibitors are substrates of cytochrome P450 3A4, so strong modulators of that enzyme raise or lower exposure. Many require gastric acid for absorption, which makes proton pump inhibitors a practical problem.

Trastuzumab is contraindicated in patients with hypersensitivity to it. Cardiac disease, previous anthracycline exposure and pregnancy are major cautions, and concomitant use with anthracyclines adds to heart failure risk.

CAR-T cells should not be given to patients with active infection or inflammatory disorders because of the risk of severe cytokine release. The product's boxed warning also covers neurological toxicities and secondary haematological malignancies, and accredited centres apply their own eligibility rules.

Checkpoint inhibitors do not have conventional pharmacokinetic drug interactions, but the immune system can be altered by medicines and by concurrent disease. High-dose corticosteroids or immunosuppressants may blunt the anti-tumour effect while they are used for toxicity, which is one reason clinicians use the lowest dose and shortest course consistent with control. Proton pump inhibitors are implicated in a higher risk of checkpoint inhibitor acute kidney injury. Live vaccines are avoided during checkpoint inhibitor therapy and for a period after it ends. For endocrine management, high-dose steroids have not shown benefit in most immune-related thyroid disease and can cause harm, so hormone replacement is preferred.

Tyrosine kinase inhibitors have the richest interaction list. Strong cytochrome P450 3A4 inhibitors such as clarithromycin, ketoconazole and some HIV protease inhibitors increase exposure; strong inducers such as rifampicin, carbamazepine and St John's wort reduce it. Acid-reducing agents can alter absorption of drugs that need low pH. Imatinib should be given with food and water, and doses of 800 mg split. Myelosuppressive chemotherapy or other kinase inhibitors add to haematological toxicity.

Monoclonal antibodies such as trastuzumab do not affect cytochrome P450 enzymes but can be combined with chemotherapy, so the toxicity profile of the combination reflects both. Antibody-drug conjugates are sensitive to hepatic metabolism of the payload and to prior neuropathy, which guides sequencing.

Baseline assessment before starting any of these drugs includes a full history, blood pressure, complete blood count, renal and liver function, thyroid function, glucose, and any organ-specific tests dictated by the drug. For checkpoint inhibitors, liver enzymes, creatinine and thyroid function are checked at baseline and periodically, and patients are taught to report early symptoms. Corticosteroid or infliximab needs for toxicity are accompanied by infection prophylaxis in the appropriate setting. ^[4]

For tyrosine kinase inhibitors, complete blood count, liver function, renal function, electrolytes and an electrocardiogram as appropriate are checked before treatment and at intervals. Cardiac function, blood pressure, proteinuria and thyroid function are added depending on the specific drug. Adherence counselling is monitoring as much as pill counts.

For trastuzumab and other potentially cardiotoxic monoclonal antibodies, left ventricular ejection fraction is measured at baseline and periodically. For CAR-T cells, monitoring after infusion includes daily observation in hospital for fever, hypotension, hypoxia and neurological change, then frequent outpatient checks with complete blood count, inflammatory markers and immunoglobulin levels for months.

Pregnancy and breastfeeding. Checkpoint inhibitors can cause fetal harm and are not recommended during pregnancy or breastfeeding; contraception is advised during treatment and after the last dose. Tyrosine kinase inhibitors such as imatinib are teratogenic in animals at clinically relevant exposures and are contraindicated in pregnancy. Trastuzumab can cause fetal harm and oligohydramnios and is avoided in pregnancy.

Children and older adults. Pembrolizumab and other checkpoint inhibitors have weight-based dosing in children and adolescent indications. Imatinib has paediatric dosing for chronic myeloid leukaemia and gastrointestinal stromal tumour. Kymriah is approved for patients up to 25 years for B-cell acute lymphoblastic leukaemia and for adults with certain lymphomas. Older adults are more likely to have cardiac, renal and hepatic impairment and need dose adjustment and closer monitoring, but age alone is not a reason to withhold effective therapy.

Organ impairment. Hepatic impairment generally requires dose changes for small-molecule kinase inhibitors, while monoclonal antibodies are less affected. Renal impairment modifies imatinib dosing and is a risk factor for checkpoint inhibitor acute kidney injury. Immune checkpoint inhibitors can be used in dialysis patients, with close monitoring.

Autoimmune and transplant settings. Active severe autoimmune disease and solid organ transplantation require specialist input before checkpoint inhibitors, because flares and rejection are common. In renal transplantation, immune checkpoint inhibitor therapy is usually reserved for cancers with no good alternative, with close multidisciplinary follow-up.

Table 3 compares the families across practical dimensions.

• Checkpoint inhibitors free T cells by blocking CTLA-4 or the PD-1/PD-L1 axis; the same mechanism produces immune-related adverse events.
• Anti-CTLA-4 agents are more toxic than anti-PD-1/PD-L1 agents, and combination therapy is more toxic than either alone.
• Between 45 and 83 percent of treated patients develop some grade of immune-related adverse event, and up to 28 percent severe disease.^[1]
• Events usually begin in the first 3 to 4 months, but delayed, re-emergent and chronic events occur.
• First-line treatment of most non-life-threatening grade 2 events is prednisone 0.5 to 1 mg/kg/day with at least a 4-week taper; grade 3 or 4 events need 1 to 2 mg/kg/day and often permanent drug withdrawal.
• Endocrine events usually need hormone replacement rather than escalation of immunosuppression.
• Steroid-unresponsive events: no improvement after 1 to 3 days if life-threatening, or after 7 to 14 days if not. Steroid-dependent events recur on taper; dependence beyond 12 weeks is called chronic.
• Tyrosine kinase inhibitors are oral enzyme inhibitors with predictable target toxicities, renal and hepatic cautions, and many drug interactions.
• Imatinib is typically 400 mg/day in chronic-phase disease and 600 mg/day in accelerated or blast phase, with caution when renal function is impaired.^[6]
• Monoclonal antibodies such as trastuzumab carry target-specific risk: cardiac dysfunction that warrants baseline and periodic left ventricular ejection fraction checks.
• CAR-T cells are living, genetically modified autologous T cells; their key toxicities are cytokine release syndrome and neurotoxicity, treated with tocilizumab and corticosteroids.
• High-dose methylprednisolone 1,000 mg intravenously one to two times daily for 3 days is used for life-threatening cytokine release syndrome. ^[8]
• Patient monitoring, patient education, early recognition and a predefined escalation pathway matter as much as drug choice.

• Related verified topics in haematology-oncology and pharmacology will be linked here as they are published; topical cross-references include adverse drug reactions and pharmacovigilance, systemic anticancer therapy, acute leukaemia, lymphoma, melanoma, and renal cell cancer.
• Regional guidance differs: the SITC, ASCO, NCCN, ESMO and AIOM position on grade 1 to 4 kidney injury during immunotherapy disagree on whether to continue the drug, whether to biopsy before steroids, and the starting dose. State the range 0.5 to 2 mg/kg/day predicted on grade and local protocol.
• Low-resource note: where infusion facilities, telemetry, cytokine release grading or tocilizumab are unavailable, use written treatment algorithms, pre-negotiated referral pathways and pre-treatment counselling rather than improvised decisions.