Checkpoint Inhibitors and Hormonal Oncology

Mechanisms, irAE management, biomarkers, and CAR-T toxicity

ICI = immune checkpoint inhibitor  ·  irAE = immune-related adverse event  ·  CTLA-4 = cytotoxic T-lymphocyte antigen 4  ·  PD-1 = programmed death 1  ·  PD-L1 = programmed death ligand 1  ·  TMB = tumor mutational burden  ·  MSI-H = microsatellite instability-high  ·  dMMR = mismatch repair deficiency  ·  CRS = cytokine release syndrome  ·  ICANS = immune effector cell-associated neurotoxicity syndrome  ·  ADT = androgen deprivation therapy  ·  AR = androgen receptor  ·  SERM = selective estrogen receptor modulator  ·  AI = aromatase inhibitor

Checkpoint Inhibitor Biology

CTLA-4 Inhibition — Ipilimumab
  • Site: T-cell priming in lymph nodes
  • Mechanism: blocks CTLA-4/B7 interaction → amplifies T-cell priming; depletes Tregs via ADCC
  • Result: broad immune activation across many T-cell clones
  • Consequence: wider irAE spectrum than PD-1/PD-L1
  • Antibody class: fully human IgG1
PD-1/PD-L1 Inhibition
  • Site: effector phase in tumor microenvironment
  • PD-1 inhibitors: nivolumab, pembrolizumab, cemiplimab (IgG4)
  • PD-L1 inhibitors: atezolizumab, durvalumab, avelumab
  • More tumor-localized immune activation → narrower irAE spectrum
  • All ICIs: no CYP metabolism; no hepatic/renal dose adjustment

irAE Management by Organ

Organ Grade 2 Grade 3–4 Steroid-Refractory Agent Permanent DC?
Colitis Hold ICI; prednisone 1 mg/kg/day IV methylprednisolone Infliximab (anti-TNF) Grade 4: yes
Hepatitis Hold ICI; prednisone 0.5–1 mg/kg/day IV methylprednisolone Mycophenolate mofetil (NOT infliximab) Grade 3+: likely
Pneumonitis Hold ICI; prednisone 1–2 mg/kg/day; bronchoscopy to exclude infection IV methylprednisolone; mycophenolate or IVIG if refractory Mycophenolate, IVIG Grade 3–4: yes
Endocrine Continue ICI; initiate hormone replacement Acute adrenal crisis: IV hydrocortisone immediately N/A — steroids do not restore gland Usually no — continue ICI

Predictive Biomarkers & Hormonal Therapy Drug Interactions

ICI Predictive Biomarkers
  • PD-L1 TPS: tumor cells only; used in NSCLC (pembrolizumab monotherapy: TPS ≥ 50%)
  • PD-L1 CPS: tumor + immune cells; used in GI, head and neck, urothelial cancers
  • TMB-high: tumor-agnostic pembrolizumab approval (≥ 10 mutations/megabase)
  • dMMR/MSI-H: tumor-agnostic pembrolizumab approval; highest prevalence in colorectal and endometrial cancers
  • Universal dMMR/MSI-H testing recommended for all solid tumors
Hormonal Therapy Interactions
  • Enzalutamide: strong CYP3A4 inducer → reduces warfarin, DOACs, docetaxel levels
  • Tamoxifen + paroxetine/fluoxetine: CYP2D6 inhibition → reduces endoxifen → use venlafaxine instead
  • Abiraterone: prednisone mandatory (mineralocorticoid excess); empty stomach required
  • GnRH agonist + bulky metastases: antiandrogen first to prevent testosterone flare

CAR-T Cell Toxicity — CRS vs. ICANS

CRS (Cytokine Release Syndrome)
  • Mechanism: massive IL-6 release as CAR-T cells lyse tumor
  • Hallmark: fever; severity defined by hypotension and hypoxia
  • Biomarkers: elevated ferritin, CRP, IL-6
  • Treatment: tocilizumab (anti-IL-6 receptor) first-line
  • Add dexamethasone for grade 3–4 or tocilizumab-refractory
ICANS (Neurotoxicity)
  • Mechanism: CNS CAR-T trafficking, blood-brain barrier disruption, cytokine injury
  • Presents as: confusion, aphasia, tremor, seizure, cerebral edema
  • Treatment: dexamethasone exclusively
  • Tocilizumab NOT effective for ICANS — may worsen CNS toxicity
  • Levetiracetam for seizure prophylaxis

Non-Negotiable Rules

irAE steroids: taper slowly over at least 4–6 weeks — premature taper causes relapse. Hepatitis steroid-refractory: mycophenolate mofetil — NEVER infliximab (hepatotoxic). Adrenal crisis: IV hydrocortisone immediately — do not wait for lab results. All endocrine irAEs require lifelong hormone replacement. CRS → tocilizumab. ICANS → dexamethasone. Do not give tocilizumab for ICANS.