PharmacologyTier 1Medical Sciences concept

Immune checkpoint inhibitor mechanism (PD-1/PD-L1, CTLA-4)

Core concept

Checkpoints are physiological brakes on T cells preventing autoimmunity; tumours co-opt them
- Blocking the brake does not target the tumour - it releases pre-existing antitumour T cells

CTLA-4 - the priming brake

Upregulated on T cells ~48 h after activation; acts in the lymph node
Binds CD80/86 (B7) with ~500x the affinity of CD28
- Outcompetes CD28 -> loss of signal 2 -> T cell shut down
Ipilimumab blocks CTLA-4 -> B7 free to engage CD28 -> sustained priming, inc clonal expansion
- Also depletes intratumoural Tregs (which constitutively express CTLA-4)

PD-1/PD-L1 - the effector brake

PD-1 on activated T cells, B cells, NK cells; acts in the tumour, at the effector phase
PD-L1/PD-L2 on tumour cells and myeloid cells in the microenvironment
- IFN-gamma from infiltrating T cells induces PD-L1 - adaptive immune resistance
Ligation -> SHP-2 recruited to ITSM -> dephosphorylates TCR proximal signalling -> exhaustion
Blockade reverses exhaustion, restores cytotoxic activity

LAG-3 - the third checkpoint

LAG-3 (CD223) binds MHC II; relatlimab + nivolumab is the first approved LAG-3 combination (melanoma)

Target	Agents	Site of action
CTLA-4	ipilimumab, tremelimumab	Lymph node, priming
PD-1	nivolumab, pembrolizumab, cemiplimab, dostarlimab	Tumour, effector
PD-L1	atezolizumab, durvalumab, avelumab	Tumour
LAG-3	relatlimab (with nivolumab)	Tumour

Immune-related adverse events are the mechanism turned on self
- CTLA-4 blockade: more frequent and more severe, earlier onset - colitis, hypophysitis, rash
- PD-1/PD-L1 blockade: thyroiditis (most common), pneumonitis, hepatitis, colitis
- Combination ipilimumab + nivolumab: grade 3-4 irAE in ~55%
Hypophysitis is near-specific to CTLA-4; thyroid dysfunction to PD-1
irAE management by grade: continue + monitor (G1) -> prednisolone 1-2 mg/kg (G2-3) -> add infliximab or MMF if steroid-refractory
- Endocrinopathies are replaced, not steroid-reversed - drug can usually continue
Pseudoprogression - inc lesion size from immune infiltrate; iRECIST requires confirmatory imaging
Predictors of response: PD-L1 expression (TPS/CPS), MSI-high/dMMR, high tumour mutational burden

Melanoma, NSCLC, renal cell, urothelial, head and neck, Hodgkin lymphoma, MSI-high tumours of any site
Any new symptom in a patient on a checkpoint inhibitor is an irAE until proven otherwise
- Diarrhoea -> colitis, not gastroenteritis; dyspnoea -> pneumonitis, not infection
- Fatigue -> check TSH, 9am cortisol, ACTH
Checkpoint-inhibitor myocarditis - rare (~1%) but ~50% mortality; troponin rise, often with myositis and myasthenia-like overlap
Autoimmune disease and prior solid organ transplant are relative contraindications - flare and graft rejection
Steroids for irAE do not abolish antitumour efficacy; baseline prednisolone >10 mg/day does reduce it
Rapid-onset autoimmune (fulminant) type 1 diabetes with DKA and near-normal HbA1c

Immunosuppressant mechanisms - the same axis pushed the other way
Predictive biomarkers for targeted therapy - MSI, TMB, PD-L1
Monoclonal antibody target identification; CAR-T cell therapy
MHC/HLA in antigen presentation; T-cell costimulation (abatacept in RA)
Immune-related endocrinopathy - hypophysitis, thyroiditis, adrenal insufficiency

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