Immunotherapy and Biologics

Mechanistic groupings of immunotherapy-related disease

• Loss of peripheral self-tolerance (checkpoint inhibitors): removing PD-1/CTLA-4 inhibitory signaling permits expansion of autoreactive T-cell clones that were previously held in check, producing organ-specific autoimmunity (thyroiditis, hypophysitis, colitis, myocarditis)
• Supraphysiologic cytokine release (CAR-T, bispecific T-cell engagers, high-dose IL-2): massive T-cell activation floods the circulation with IL-6, IFN-γ, and TNF-α, causing capillary leak, vasodilatory shock, and blood–brain barrier disruption
• Iatrogenic immunosuppression (TNF-α inhibitors, anti-CD20, anti-integrin): blocking granuloma maintenance (TNF-α) or humoral/cell-mediated surveillance permits reactivation of latent organisms
• IgE-mediated hypersensitivity (allergen immunotherapy): introducing intact allergen to a patient with pre-formed specific IgE on mast cells can trigger systemic mast-cell degranulation; the therapeutic goal is the opposite — a shift toward Th1/Treg responses with IgG4 blocking antibodies
• Immunogenicity: chimeric constructs (infliximab, rituximab) elicit anti-drug antibodies causing infusion reactions and loss of response

Modifiable risk factors examiners plant in the stem

• Uncontrolled or severe asthma: the strongest identified risk factor for fatal systemic reactions to subcutaneous immunotherapy; the AAAAI/ACAAI Joint Task Force practice parameters advise assessing asthma control (and deferring injection if the patient is wheezing)
• Beta blockers and ACE inhibitors: beta blockade blunts the response to epinephrine; both are flagged as cautions before allergen immunotherapy
• Dosing/administration error or injection during peak pollen season, and skipping the post-injection observation period
• Unscreened latent infection: absent IGRA/tuberculin testing and hepatitis B serologies before TNF inhibitors or rituximab
• Live vaccines given during biologic therapy (contraindicated per ACIP)

Non-modifiable risk factors

• Pre-existing autoimmune disease (e.g., psoriasis, thyroiditis) predisposes to flare with checkpoint blockade
• Combination CTLA-4 plus PD-1 blockade carries higher irAE frequency and severity than either alone
• High tumor burden and rapid lymphodepletion before CAR-T infusion predict severe CRS/ICANS
• Prior systemic reaction to an allergen extract or biologic; mast cell disorders

Immune Checkpoint Inhibitors (ICIs)

• Blockade of PD-1/PD-L1 and CTLA-4 pathways removes "brakes" on T cells, allowing exhausted T cells to recognize and attack tumor-associated antigens
• Normal checkpoint proteins serve as negative regulators to prevent autoimmunity; their blockade paradoxically increases anti-tumor immunity but risks breaking self-tolerance
• PD-1 expressed on T cells binds PD-L1 on tumor cells and antigen-presenting cells, delivering inhibitory signals; antibodies prevent this interaction
• CTLA-4 expressed on T cells competes with CD28 for B7 ligands; blockade enhances T cell priming in lymph nodes

Monoclonal Antibodies (mAbs)

• IgG-based proteins engineered to bind specific cellular targets with high affinity and specificity
• Binding mechanisms include direct neutralization (anti-cytokine), opsonization (marking cells for destruction), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC)
• Enable precision targeting: anti-TNF-α mAbs prevent inflammatory signaling; anti-CD20 depletes B cells in lymphoma and autoimmune disease
• Humanized and fully human antibodies reduce immunogenicity compared to chimeric constructs

CAR-T Cell Therapy

• Ex vivo genetic engineering of patient T cells to express chimeric antigen receptors that recognize tumor-specific antigens (e.g., CD19 in B-cell malignancies)
• CAR structure includes extracellular antigen-binding domain, transmembrane domain, and intracellular signaling domains (CD3ζ and costimulatory molecules like CD28/4-1BB)
• Engineered T cells expand dramatically in vivo, achieving sustained tumor cell killing and long-term persistence
• Risk of cytokine release syndrome (CRS) due to massive T cell activation and inflammatory mediator production

Cytokine-Based Immunotherapy

• Type I interferons (IFN-α, IFN-β) enhance MHC expression, NK cell activation, and antiviral/antiproliferative effects
• IL-2 promotes T cell and NK cell proliferation; high-dose IL-2 previously standard for melanoma and RCC but largely replaced due to toxicity
• GM-CSF mobilizes myeloid progenitors and enhances antigen presentation

Immune Tolerance Restoration

• CTLA-4-Ig (abatacept) and CD28 superagonists provide costimulation signals needed for T cell activation; used in autoimmune diseases to restore regulatory T cell (Treg) function
• TNF-α inhibitors (etanercept, infliximab, adalimumab) block major pro-inflammatory cytokine, reducing systemic inflammation in autoimmune disease but impairing anti-microbial immunity

Immune-Related Adverse Events (irAEs) from Checkpoint Inhibitors

• Colitis/diarrhea: most common GI irAE; ranges from mild diarrhea to fulminant colitis with bloody stools, abdominal pain, and fever
• Pneumonitis: dyspnea, cough, hypoxia; can progress rapidly to respiratory failure; manifests as interstitial lung disease on imaging
• Endocrinopathy: thyroiditis with hypothyroidism or hyperthyroidism (thyroid antibodies present); type 1 diabetes from pancreatic beta cell destruction; hypophysitis with central hormone deficiencies
• Dermatitis: pruritic rashes (often maculopapular), vitiligo; rarely Stevens-Johnson syndrome/toxic epidermal necrolysis
• Hepatitis: elevated transaminases and bilirubin; can progress to fulminant hepatic failure
• Myositis/myocarditis: muscle pain, weakness, elevated CK; myocarditis presents with chest pain, arrhythmias, cardiogenic shock (life-threatening)
• Neurologic: peripheral neuropathy, Guillain-Barré syndrome, encephalitis, meningitis

CAR-T Cell Toxicity

• Cytokine release syndrome (CRS): high fever, hypotension, tachycardia, respiratory distress; IL-6 and TNF-α markedly elevated; severity graded 1-4
• Immune effector cell-associated neurotoxicity syndrome (ICANS): confusion, delirium, seizures, cerebral edema; can occur with or without concurrent CRS
• Tumor lysis syndrome: hyperkalemia, hyperuricemia, acute kidney injury from massive tumor cell death

TNF Inhibitor and Biologic Therapy Effects

• Infections: reactivation of latent tuberculosis (TB), invasive fungal infections (histoplasmosis, coccidioidomycosis), atypical mycobacteria
• Autoimmunity: paradoxical development of anti-TNF antibodies, lupus-like syndrome, vasculitis
• Cytopenias: from direct bone marrow effects or immune mechanisms

Monoclonal Antibody Reactions

• Infusion reactions: fever, chills, rigors, dyspnea, hypotension (especially with first infusion of chimeric antibodies)
• Target-specific toxicity: anti-HER2 (trastuzumab) causes cardiotoxicity; anti-EGFR causes severe acneiform rash

Clinical Recognition of Immunotherapy Complications

• High index of suspicion: new or worsening symptoms during or shortly after checkpoint inhibitor initiation warrant immune-mediated etiology investigation
• Timeline: irAEs typically occur weeks to months into therapy but can emerge at any point, even after completion
• Exclude alternative diagnoses: differentiate infectious colitis from immune-mediated colitis; pneumonia from pneumonitis; viral gastroenteritis from anti-CTLA-4 colitis

Laboratory and Imaging Assessment

• Complete blood count, comprehensive metabolic panel: screen for cytopenias, electrolyte abnormalities, renal/hepatic dysfunction
• Inflammatory markers: elevated CRP, ESR, procalcitonin; elevated LDH suggests CAR-T-related cell lysis
• Cytokine levels: marked elevations in IL-6, TNF-α, IFN-γ diagnostic of CRS; serum ferritin elevation correlates with severity
• Organ-specific testing: high-sensitivity troponin, BNP (cardiac); lipase, transaminases (hepatic/pancreatic); TSH, free T4 (endocrine)
• Imaging: CT chest for pneumonitis (bilateral ground-glass opacities, interstitial pattern); colonoscopy with biopsy for colitis (inflammatory infiltrate, epithelial damage)
• EEG and lumbar puncture: for neurologic symptoms to exclude infection or primary CNS involvement

Diagnostic Criteria

• irAE grading (CTCAE v5.0): grade 1-5 severity; immune-mediated attribution based on temporal relationship, exclusion of alternatives, and histopathologic/serologic confirmation
• CRS grading: based on vital sign abnormalities (hypotension, hypoxia) and organ dysfunction; ICANS graded by neurologic exam findings
• Positive predictive antibodies: anti-thyroid peroxidase (anti-TPO), anti-tissue transglutaminase (for celiac-like enteropathy), GAD antibodies (type 1 diabetes)

Management of Immune-Related Adverse Events

• Grade 1 irAEs: continue checkpoint inhibitor; supportive care (antihistam

Emergencies — recognize and treat before confirmatory testing

• Anaphylaxis to allergen immunotherapy or a biologic: IgE-mediated mast-cell degranulation; urticaria, throat tightness, wheeze, hypotension, usually within 30 minutes of a subcutaneous injection. Treat with epinephrine 0.3 mg IM into the anterolateral thigh — the AAAAI/ACAAI parameters require epinephrine, trained personnel, and a supervised observation period on site
• ICI myocarditis: lymphocytic infiltration of myocardium; chest pain, new conduction block or arrhythmia, rising high-sensitivity troponin. Disproportionately fatal despite low incidence; NCCN/ASCO advise permanent discontinuation and high-dose corticosteroids
• Hypophysitis with secondary adrenal insufficiency: headache, fatigue, hyponatremia, hypotension refractory to fluids; give stress-dose glucocorticoid before levothyroxine to avoid precipitating crisis
• Cytokine release syndrome: fever then vasodilatory shock and hypoxia after CAR-T; tocilizumab (anti-IL-6R) is the anchor drug, with corticosteroids added for refractory or concurrent neurotoxicity
• ICANS: expressive aphasia and inattention progressing to seizure or cerebral edema; corticosteroids are preferred because tocilizumab penetrates CNS poorly
• Immune-mediated pneumonitis or fulminant colitis with perforation

Infectious complications of immunosuppressive biologics

• Reactivation tuberculosis with TNF-α inhibitors: TNF-α maintains granuloma integrity, so reactivation is often extrapulmonary or disseminated — screen with IGRA/tuberculin before starting
• Hepatitis B reactivation with anti-CD20 therapy (rituximab); progressive multifocal leukoencephalopathy with natalizumab, presenting as subacute focal deficits with white-matter lesions
• Endemic mycoses (histoplasmosis, coccidioidomycosis) in the appropriate geography

Class-specific complications

• Omalizumab: delayed anaphylaxis, sometimes hours after dosing — carries a boxed warning; patients are prescribed an epinephrine autoinjector
• Dupilumab: conjunctivitis/blepharitis and transient blood eosinophilia; a rising eosinophil count with new neuropathy or infiltrates should raise concern for unmasked eosinophilic granulomatosis with polyangiitis as oral steroids are tapered
• Trastuzumab: reversible decline in LVEF (unlike anthracycline cardiotoxicity); anti-EGFR agents: acneiform rash on face and upper trunk

• Fever plus hypotension days after CAR-T infusion is CRS, not sepsis: IL-6 is the driver, so the single best next step after cultures and fluids is tocilizumab; add corticosteroids for refractory CRS or any significant ICANS. The classic distractor is escalating antibiotics alone.
• New diarrhea on ipilimumab = immune colitis: stool studies (including C. difficile) first to exclude infection, then systemic corticosteroids; infliximab for steroid-refractory colitis. Do not give antimotility agents as definitive therapy.
• Grade rules the drug decision: continue therapy with supportive care for mild irAEs, hold and give corticosteroids for moderate, and permanently discontinue for severe or life-threatening events — myocarditis and most neurologic irAEs mean permanent discontinuation per NCCN/ASCO.
• Endocrine irAEs are the exception: thyroiditis, type 1 diabetes, and hypophysitis usually require lifelong hormone replacement rather than immunosuppression, and the drug can often continue. Vitiligo on checkpoint blockade for melanoma is a benign finding.
• Before a TNF-α inhibitor, screen for latent TB and hepatitis B — this is the classic "one association examiners test." TNF-α maintains granulomas, so reactivation is frequently disseminated or extrapulmonary and the PPD/IGRA may be the only clue.
• Allergen immunotherapy is the only therapy that alters the natural history of allergic rhinitis and venom allergy — it induces IgG4 blocking antibodies and Treg-mediated tolerance. Per the AAAAI/ACAAI Joint Task Force, uncontrolled asthma is the setting in which fatal systemic reactions occur, and every patient waits on site after injection.
• Anaphylaxis answer is always epinephrine IM first (0.3 mg in adults), not antihistamines, not steroids, not albuterol. Omalizumab carries a boxed warning for delayed anaphylaxis.
• Match biologic to the phenotype: anti-IgE (omalizumab) for allergic asthma with elevated IgE, anti-IL-5 pathway agents for eosinophilic asthma, and anti-IL-4Rα (dupilumab) for type 2 asthma and moderate-to-severe atopic dermatitis. GINA reserves all of these for severe, uncontrolled disease on maximal inhaled therapy — never as a step-1 controller.