The Immunology of Cancer: A Primer on Immunotherapy for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

Cancer immunotherapy has revolutionized oncological care over the past decade, transforming previously untreatable malignancies into manageable chronic diseases. As immunotherapy becomes increasingly prevalent, internists and critical care physicians encounter patients with immune-related complications that demand prompt recognition and management. This comprehensive review elucidates the mechanisms underlying modern immunotherapeutic approaches, details the spectrum of immune-related adverse events (irAEs), and provides practical guidance for managing these complex patients. We discuss immune checkpoint inhibitors, CAR-T cell therapy, the paradox of hyperprogressive disease, and predictive biomarkers—equipping the intensivist with essential knowledge to optimize outcomes in this evolving therapeutic landscape.

Keywords: Cancer immunotherapy, immune checkpoint inhibitors, CAR-T cells, cytokine release syndrome, immune-related adverse events, PD-1, PD-L1, CTLA-4

Introduction

The concept of harnessing the immune system to combat cancer dates back over a century to William Coley's bacterial toxin experiments. However, only in recent decades has our understanding of tumor immunology matured sufficiently to develop effective immunotherapies. The 2018 Nobel Prize in Physiology or Medicine, awarded to James Allison and Tasuku Honjo for their work on CTLA-4 and PD-1 respectively, underscored the paradigm shift in cancer treatment.

Unlike conventional cytotoxic chemotherapy that directly targets malignant cells, immunotherapy reactivates and augments the patient's own immune system to recognize and eliminate cancer. This fundamental difference in mechanism accounts for both the remarkable durability of responses—some lasting years beyond treatment cessation—and the unique toxicity profile characterized by immune-related adverse events (irAEs).

For the internist and intensivist, understanding cancer immunology is no longer optional. Patients receiving immunotherapy may present acutely with life-threatening complications such as fulminant colitis, severe pneumonitis, or cytokine release syndrome. Recognition of these syndromes and prompt intervention can be lifesaving. This review provides a comprehensive yet practical guide to the immunology of cancer and its therapeutic implications.

Immune Checkpoint Inhibitors (ICI): How Anti-PD-1/PD-L1 and Anti-CTLA-4 Drugs Work

The Cancer-Immunity Cycle and Immune Evasion

To understand checkpoint inhibitors, one must first appreciate the cancer-immunity cycle. This process involves tumor antigen release, antigen presentation by dendritic cells, T-cell priming and activation, trafficking to the tumor microenvironment, tumor infiltration, and cancer cell recognition and killing. At each stage, regulatory mechanisms exist to prevent excessive immune activation and autoimmunity.

Cancer cells exploit these regulatory checkpoints to evade immune surveillance—a phenomenon termed "immune escape." The two most clinically relevant checkpoints are CTLA-4 (Cytotoxic T-Lymphocyte Antigen-4) and the PD-1/PD-L1 (Programmed Death-1/Programmed Death Ligand-1) axis.

CTLA-4: The Brake on T-Cell Priming

CTLA-4 functions primarily in lymphoid organs during the initial phase of T-cell activation. When naive T cells encounter antigen-presenting cells (APCs), they require two signals: TCR engagement with MHC-peptide complexes (Signal 1) and costimulation via CD28-B7 interaction (Signal 2). CTLA-4, constitutively expressed on regulatory T cells (Tregs) and upregulated on activated effector T cells, competes with CD28 for B7 binding but delivers an inhibitory signal instead.

CTLA-4 has approximately 20-fold higher affinity for B7 molecules than CD28, effectively outcompeting the activating signal. Additionally, CTLA-4 can trans-endocytose B7 molecules from APCs, depleting them from the cell surface and further dampening T-cell activation.

Ipilimumab (Yervoy), the first FDA-approved checkpoint inhibitor (2011), blocks CTLA-4. By preventing CTLA-4 engagement, ipilimumab amplifies T-cell priming and promotes anti-tumor immunity. However, this mechanism is relatively non-specific, affecting both tumor-reactive and self-reactive T cells, which explains the higher incidence of irAEs with anti-CTLA-4 therapy compared to PD-1 inhibitors.

PD-1/PD-L1: The Peripheral Checkpoint

The PD-1/PD-L1 axis operates primarily in peripheral tissues, including the tumor microenvironment, functioning as an "off switch" for T cells that have already been activated and have infiltrated tissues. PD-1 is expressed on activated T cells, B cells, and natural killer cells. Its ligands, PD-L1 (B7-H1) and PD-L2, are expressed on various cell types including tumor cells, immune cells, and stromal cells.

When PD-1 binds to PD-L1 or PD-L2, it recruits phosphatases (SHP-1 and SHP-2) that dephosphorylate key signaling molecules downstream of the T-cell receptor, effectively inhibiting T-cell activation, proliferation, and cytokine production. Many tumors upregulate PD-L1 expression as an adaptive immune resistance mechanism—a process often driven by interferon-gamma (IFN-γ) secreted by tumor-infiltrating lymphocytes.

Anti-PD-1 antibodies include:

Pembrolizumab (Keytruda) - approved 2014
Nivolumab (Opdivo) - approved 2014
Cemiplimab (Libtayo) - approved 2018

Anti-PD-L1 antibodies include:

Atezolizumab (Tecentriq) - approved 2016
Durvalumab (Imfinzi) - approved 2017
Avelumab (Bavencio) - approved 2017

Blocking this interaction reinvigorates exhausted T cells within the tumor microenvironment, restoring their ability to recognize and kill cancer cells. The more targeted peripheral mechanism of PD-1/PD-L1 blockade generally results in a lower incidence of severe irAEs compared to CTLA-4 inhibition.

Combination Therapy: Synergistic but Toxic

The CheckMate 067 trial demonstrated that combining ipilimumab with nivolumab in metastatic melanoma significantly improved overall survival compared to either agent alone (median OS: 72.1 months vs 36.9 months for nivolumab and 19.9 months for ipilimumab). However, grade 3-4 irAEs occurred in 59% of combination patients versus 21% with nivolumab alone.

This synergy reflects the complementary mechanisms: CTLA-4 blockade enhances initial T-cell activation in lymph nodes, while PD-1 blockade sustains T-cell function in the tumor microenvironment. The combination effectively removes both central and peripheral brakes on anti-tumor immunity.

Clinical Pearl: Not All Responses Are Rapid

Unlike chemotherapy, where response is typically assessed within 6-8 weeks, immunotherapy responses may be delayed. Pseudoprogression—initial radiographic tumor enlargement followed by subsequent shrinkage—occurs in 5-10% of patients due to immune cell infiltration. The iRECIST criteria were developed to account for these unique response patterns. Clinicians must resist premature discontinuation in clinically stable patients with apparent radiographic progression.

Oyster: Duration of Therapy Remains Uncertain

Most trials limited checkpoint inhibitor therapy to 2 years, yet the optimal duration remains undefined. Some patients maintain durable responses after discontinuation, while others relapse. The KEYNOTE-024 trial showed that pembrolizumab for 2 years in NSCLC resulted in 5-year survival of 32% versus 16% with chemotherapy. Retreatment after progression can be effective, but rechallenge increases irAE risk.

Managing Immune-Related Adverse Events (irAEs): Colitis, Pneumonitis, Dermatitis, and Endocrinopathies

General Principles of irAE Management

Immune-related adverse events represent on-target, off-tumor toxicity—the immune system attacking normal tissues. Unlike traditional chemotherapy toxicities that are dose-dependent and predictable, irAEs can affect virtually any organ system, occur at any time (even months after treatment cessation), and vary widely in severity.

The cornerstone of irAE management rests on three principles:

Early recognition and grading using the Common Terminology Criteria for Adverse Events (CTCAE)
Prompt immunosuppression with corticosteroids as first-line therapy
Multidisciplinary collaboration with oncology, gastroenterology, pulmonology, endocrinology, and rheumatology

Immune-Related Colitis

Gastrointestinal irAEs are among the most common, particularly with anti-CTLA-4 therapy. Immune-related colitis occurs in 8-27% of patients receiving ipilimumab and 1-3% with PD-1 inhibitors. Combination therapy increases risk to 10-13%.

Clinical Presentation:

Diarrhea (>6 stools/day above baseline)
Abdominal pain and cramping
Hematochezia or melena
Fever (in severe cases)
Symptoms typically develop 6-8 weeks after initiation but can occur throughout treatment

Diagnostic Approach:

Stool studies: C. difficile, ova and parasites, culture, fecal calprotectin (usually elevated >250 μg/g)
Laboratory tests: CBC, CMP, CRP, albumin
CT abdomen/pelvis: colonic wall thickening, pericolonic fat stranding
Colonoscopy with biopsies: required for grade 2 or higher; reveals diffuse colitis with histologic patterns similar to inflammatory bowel disease

Grading and Management:

Grade 1 (Increase of <4 stools/day):

Continue immunotherapy with monitoring
Symptomatic treatment: loperamide, hydration
Dietary modification: low-residue diet

Grade 2 (4-6 stools/day, moderate abdominal pain):

Hold immunotherapy
Prednisone 0.5-1 mg/kg/day PO
If no improvement in 3-5 days, escalate to Grade 3 management
Resume immunotherapy after symptoms resolve to grade 1 and steroids tapered to ≤10 mg/day

Grade 3 (≥7 stools/day, severe abdominal pain, peritoneal signs):

Permanently discontinue immunotherapy
Hospitalize for close monitoring
Methylprednisolone 1-2 mg/kg/day IV
If refractory to steroids after 3-5 days, add:
- Infliximab 5 mg/kg IV (avoid if perforation suspected)
- OR vedolizumab 300 mg IV (gut-selective, preferred if infection concern)
Colonoscopy to assess severity and rule out CMV colitis
Surgical consultation for signs of perforation

Grade 4 (Life-threatening, perforation, toxic megacolon):

ICU admission
High-dose methylprednisolone 2 mg/kg/day IV
Infliximab 5 mg/kg IV
Immediate surgical consultation
Broad-spectrum antibiotics if perforation suspected

Clinical Hack: The "Infliximab vs Vedolizumab" Decision

While infliximab is the traditional second-line agent, vedolizumab offers gut-specific immunosuppression with potentially lower infection risk. In patients with suspected concurrent infection or those who are severely immunocompromised, vedolizumab may be preferable. The AVOID trial is currently comparing these agents head-to-head.

Pearl: CMV Reactivation

Corticosteroid-refractory colitis should prompt CMV testing via immunohistochemistry on colonic biopsies or serum CMV PCR. CMV reactivation occurs in up to 20% of steroid-refractory cases. Treatment requires ganciclovir or foscarnet in addition to immunosuppression tapering.

Immune-Related Pneumonitis

Pneumonitis represents one of the most serious irAEs, with mortality rates of 10-17% in severe cases. Incidence is 3-5% with PD-1/PD-L1 inhibitors and <1% with CTLA-4 inhibitors. Combination therapy increases risk to 7-10%. Pneumonitis typically develops 2-6 months after initiation but can occur at any time.

Clinical Presentation:

Dyspnea (most common)
Non-productive cough
Fever (variably present)
Hypoxemia
Often insidious onset, easily mistaken for disease progression or infection

Radiographic Patterns:

Cryptogenic organizing pneumonia (COP): patchy consolidations
Non-specific interstitial pneumonia (NSIP): ground-glass opacities
Hypersensitivity pneumonitis: ground-glass and centrilobular nodules
Acute interstitial pneumonia/ARDS: diffuse alveolar damage

Diagnostic Workup:

Chest CT (high-resolution if available): essential for diagnosis
Oxygen saturation and ABG
Infectious workup: sputum cultures, respiratory viral panel, blood cultures
Consider bronchoscopy with BAL if diagnosis uncertain:
- Lymphocytic predominance (typically CD4+ or CD8+)
- Rule out infection, malignancy, hemorrhage
- Transbronchial biopsy rarely necessary

Grading and Management:

Grade 1 (Asymptomatic, radiographic only):

Hold immunotherapy
Close monitoring with weekly assessment
Repeat imaging in 3-4 weeks
If resolved, consider rechallenge with careful surveillance

Grade 2 (Symptomatic, not limiting ADLs):

Hold immunotherapy
Prednisone 1 mg/kg/day PO (or IV equivalent)
Broad empiric antibiotics until infection excluded
Hospitalize if borderline or high clinical suspicion for rapid deterioration
Improvement expected in 48-72 hours; if not, treat as Grade 3

Grade 3 (Severe symptoms, limiting ADLs, oxygen required):

Permanently discontinue immunotherapy
Hospitalize (ICU if hypoxemic despite supplemental oxygen)
Methylprednisolone 2-4 mg/kg/day IV divided q6-8h
Broad-spectrum antibiotics until infection definitively ruled out
Bronchoscopy strongly recommended
If no improvement in 48-72 hours, add:
- Infliximab 5 mg/kg IV, OR
- Mycophenolate mofetil 1000 mg PO BID, OR
- Cyclophosphamide 500-1000 mg/m² IV, OR
- IVIG 2 g/kg divided over 2-5 days

Grade 4 (Life-threatening, mechanical ventilation):

ICU admission with mechanical ventilation
High-dose methylprednisolone 1000 mg IV daily x 3 days, then 2-4 mg/kg/day
Early addition of second immunosuppressant (infliximab, mycophenolate, or IVIG)
Lung-protective ventilation strategies
Consider plasmapheresis in refractory cases (limited evidence)

Steroid Taper: Pneumonitis requires prolonged immunosuppression. After clinical and radiographic improvement, taper steroids slowly over 4-8 weeks (or longer). Rapid tapers frequently result in rebound inflammation. Maintain at least 10-20 mg prednisone daily for minimum 4 weeks before further reduction.

Oyster: Sarcoid-Like Reactions

A subset of patients develops sarcoid-like granulomatous inflammation with hilar lymphadenopathy, which can be mistaken for disease progression. Unlike typical pneumonitis, sarcoid reactions may not require treatment if asymptomatic. PET avidity in lymph nodes may persist despite clinical response.

Clinical Hack: The "Steroid Response Test"

If diagnostic uncertainty exists between pneumonitis and disease progression, a trial of high-dose steroids (1-2 mg/kg/day) for 48-72 hours can be diagnostic. Pneumonitis typically shows rapid clinical improvement, while progression does not respond. However, this approach should not delay bronchoscopy in appropriate candidates.

Immune-Related Dermatitis

Cutaneous irAEs are the most common toxicity, occurring in 30-40% of patients, though usually mild. Severe reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) are rare (<1%) but life-threatening.

Common Presentations:

Maculopapular Rash (most common):

Erythematous, pruritic rash
Trunk and extremities
Usually develops within 3-6 weeks
Grade 1-2: topical corticosteroids and antihistamines
Grade 3: systemic corticosteroids 0.5-1 mg/kg/day

Pruritus without Rash:

Can be severe and debilitating
Treatment: antihistamines (hydroxyzine, cetirizine), menthol creams
Consider systemic steroids if refractory
Aprepitant 80 mg daily (off-label) may help refractory cases

Vitiligo:

Occurs in 3-5% of melanoma patients
Paradoxically associated with better outcomes
No treatment required; cosmetically bothersome to some patients

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN):

Medical emergency
Mucosal involvement, skin detachment >10% BSA (TEN)
Permanently discontinue immunotherapy
High-dose IV methylprednisolone 1-2 mg/kg/day
Consider IVIG 2-3 g/kg over 3-5 days
Burn unit consultation
Supportive care: fluid resuscitation, wound care, infection prevention

Pearl: Lichenoid Reactions

Oral lichenoid reactions can mimic oral lichen planus with painful oral ulcerations. Unlike typical drug reactions, these may persist for months. Treatment includes topical clobetasol, dexamethasone oral rinses, and systemic steroids for severe cases.

Immune-Related Endocrinopathies

Endocrine irAEs are common (10-15% with PD-1 inhibitors) and often permanent, requiring lifelong hormone replacement. Unlike other irAEs, they rarely respond to immunosuppression once established.

Hypothyroidism:

Most common endocrinopathy (6-10%)
Often preceded by transient thyroiditis with hyperthyroidism
Symptoms: fatigue, weight gain, cold intolerance, constipation
Diagnosis: elevated TSH, low free T4
Treatment: levothyroxine replacement (start 25-50 mcg daily, titrate)
Immunotherapy may continue with thyroid replacement

Hyperthyroidism/Thyroiditis:

Transient thyrotoxicosis (2-4% of patients)
Symptoms: tachycardia, tremor, weight loss, anxiety
Labs: suppressed TSH, elevated T3/T4
Treatment: beta-blockers (propranolol 10-40 mg TID), symptom management
Typically resolves in 4-8 weeks, often followed by hypothyroidism
Anti-thyroid drugs (methimazole) generally NOT helpful

Hypophysitis:

More common with CTLA-4 inhibitors (8-10% with ipilimumab vs 1% with PD-1)
Symptoms: headache, fatigue, visual changes, nausea
MRI: pituitary enlargement, stalk thickening (though may be normal)
Diagnosis: low morning cortisol (<5 μg/dL), low ACTH, variable TSH/T4
Test for adrenal insufficiency immediately
Treatment:
- Hydrocortisone 15-25 mg daily in divided doses (stress dosing if acute)
- Levothyroxine if secondary hypothyroidism (only AFTER cortisol replacement)
- High-dose steroids (prednisone 1 mg/kg) may preserve pituitary function if caught early
Immunotherapy may continue with hormone replacement

Type 1 Diabetes Mellitus:

Rare (<1%) but abrupt onset with DKA
More common with PD-1 inhibitors
Diagnosis: hyperglycemia, ketones, low/absent C-peptide, positive GAD/IA-2 antibodies
Treatment: insulin therapy, standard DKA management
Permanent; requires lifelong insulin

Primary Adrenal Insufficiency:

Rare; can be life-threatening
Symptoms: fatigue, nausea, hypotension, hyponatremia, hyperkalemia
Diagnosis: low cortisol, elevated ACTH (distinguishes from hypophysitis)
Treatment: hydrocortisone replacement, fludrocortisone
Adrenal crisis requires immediate hydrocortisone 100 mg IV

Clinical Hack: Screen Early, Screen Often

Obtain baseline TSH, free T4, and morning cortisol before starting immunotherapy. Repeat TSH every 6-12 weeks during treatment. For patients with vague symptoms (fatigue, headache), check cortisol FIRST before assuming progression or other causes. A low morning cortisol (<10 μg/dL) warrants endocrinology consultation; <5 μg/dL is diagnostic of insufficiency.

Oyster: The ACTH Conundrum

In secondary adrenal insufficiency from hypophysitis, ACTH may be low, normal, or even mildly elevated despite inadequate cortisol stimulation. Do not rely on ACTH alone—if morning cortisol is <10 μg/dL in a symptomatic patient, perform a cosyntropin stimulation test or empirically treat.

Other Notable irAEs

Myocarditis:

Rare (1-2%) but highest case fatality rate (25-50%)
Presents with dyspnea, chest pain, arrhythmias, heart failure
Troponin elevation (often dramatic), ECG changes, reduced ejection fraction
Diagnosis: cardiac MRI (edema, late gadolinium enhancement), endomyocardial biopsy
Treatment:
- Permanently discontinue immunotherapy
- High-dose methylprednisolone 1000 mg IV daily x 3-5 days
- Infliximab if refractory (caution with heart failure)
- Mycophenolate or abatacept may be added
- IVIG in severe cases
- Standard heart failure management
- Temporary pacing if high-grade AV block

Neurological irAEs:

Diverse presentations: peripheral neuropathy, myasthenia gravis, Guillain-Barré syndrome, encephalitis, aseptic meningitis
Often severe and refractory to treatment
Workup: MRI brain/spine, LP, nerve conduction studies, acetylcholine receptor antibodies
Treatment: high-dose steroids, IVIG, plasmapheresis
Neurology consultation essential

Nephritis:

Usually asymptomatic; detected by creatinine elevation
Acute interstitial nephritis most common
Diagnosis: urinalysis (proteinuria, hematuria, sterile pyuria), kidney biopsy if diagnosis uncertain
Treatment: hold immunotherapy, prednisone 0.5-1 mg/kg/day

CAR-T Cell Therapy: Mechanism and the Dangers of Cytokine Release Syndrome (CRS)

CAR-T Cell Therapy: Engineering Immunity

Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a paradigm shift in cancer treatment—a "living drug" that replicates and persists within the patient. Unlike checkpoint inhibitors that release existing brakes on immunity, CAR-T therapy involves ex vivo genetic modification of autologous T cells to recognize tumor-specific antigens.

The CAR Structure:

A typical CAR consists of four components:

Extracellular antigen-recognition domain: Usually derived from a monoclonal antibody's single-chain variable fragment (scFv), recognizes tumor surface antigens (e.g., CD19, BCMA)
Hinge/spacer region: Provides flexibility and optimal target engagement
Transmembrane domain: Anchors the CAR to T-cell surface
Intracellular signaling domains:
- CD3ζ chain (Signal 1): activates T cell
- Costimulatory domains (Signal 2): CD28 and/or 4-1BB enhance T-cell proliferation, cytokine production, and persistence

FDA-Approved CAR-T Products:

CD19-Targeted (B-cell malignancies):

Tisagenlecleucel (Kymriah): ALL, DLBCL
Axicabtagene ciloleucel (Yescarta): DLBCL, follicular lymphoma, mantle cell lymphoma
Brexucabtagene autoleucel (Tecartus): mantle cell lymphoma, ALL
Lisocabtagene maraleucel (Breyanzi): DLBCL

BCMA-Targeted (Multiple Myeloma):

Idecabtagene vicleucel (Abecma)
Ciltacabtagene autoleucel (Carvykti)

The CAR-T Process:

Leukapheresis: T cells collected from patient
Manufacturing: T cells genetically modified (viral transduction or CRISPR-based methods) to express CAR
Expansion: Modified T cells cultured and expanded (typically 2-4 weeks)
Lymphodepleting chemotherapy: Fludarabine and cyclophosphamide given days -5 to -3 to "make space" for CAR-T cells and enhance their expansion
CAR-T infusion: Single infusion of CAR-T cells (day 0)
Monitoring: Close observation for CRS and neurotoxicity, typically weeks 1-4 post-infusion

Cytokine Release Syndrome (CRS)

CRS is the most common serious toxicity of CAR-T therapy, occurring in 50-90% of patients (severe in 10-30%). It results from massive immune activation and cytokine release following CAR-T cell engagement with tumor cells.

Pathophysiology:

CAR-T cells recognize and engage target antigen → T-cell activation and proliferation → release of inflammatory cytokines (IL-6, IL-1, IL-2, IL-8, IFN-γ, TNF-α) → activation of monocytes/macrophages and endothelial cells → amplification cascade → systemic inflammatory response syndrome (SIRS).

IL-6 is the key driver of CRS severity. Elevated IL-6 correlates with fever, hypotension, and organ dysfunction. Importantly, CRS is mediated primarily by monocytes/macrophages (responding to CAR-T cytokines) rather than CAR-T cells themselves.

Clinical Presentation:

Onset: Typically 1-14 days post-infusion (median 3-5 days). Earlier onset often correlates with higher tumor burden and more severe CRS.

Symptoms/Signs:

Fever (defining feature, often high-grade)
Tachycardia, hypotension (may progress to shock requiring vasopressors)
Hypoxia (capillary leak, ARDS)
End-organ dysfunction: acute kidney injury, transaminitis, coagulopathy (elevated D-dimer, hypofibrinogenemia)
Constitutional symptoms: fatigue, myalgias, nausea

Grading CRS (ASTCT Consensus Grading 2019):

Grade 1:

Fever ≥38°C
No hypotension, no hypoxia requiring intervention

Grade 2:

Fever ≥38°C
Hypotension responsive to fluids OR
Hypoxia requiring low-flow oxygen (≤6 L/min or FiO₂ <40%)

Grade 3:

Fever ≥38°C
Hypotension requiring vasopressor (with or without vasopressin) OR
Hypoxia requiring high-flow oxygen (>6 L/min or FiO₂ ≥40%)

Grade 4:

Fever ≥38°C
Hypotension requiring multiple vasopressors (excluding vasopressin) OR
Hypoxia requiring positive pressure ventilation

Laboratory Findings:

Elevated CRP (often >20 mg/dL), ferritin (>10,000 ng/mL in severe cases)
IL-6 levels elevated (correlate with severity)
Elevated D-dimer, prolonged PT/PTT
Transaminitis, hyperbilirubinemia
Acute kidney injury (elevated creatinine)
Cytopenias (especially if bone marrow involvement)

Management of CRS:

Supportive Care (All Grades):

Aggressive IV hydration (caution in severe CRS with capillary leak)
Antipyretics: acetaminophen (avoid NSAIDs due to renal concerns)
Broad-spectrum antibiotics if infection suspected (fever may mask sepsis)
Monitor vital signs frequently; ICU transfer threshold should be low

Grade 1:

Observation, supportive care
Hold CAR-T-related prophylactic antimicrobials if possible
Monitor for progression

Grade 2:

Tocilizumab (IL-6 receptor antagonist):
- Dose: 8 mg/kg IV over 1 hour (max 800 mg)
- Repeat every 8 hours if no improvement (max 3-4 doses)
- Onset: fever defervescence typically within 12-24 hours
If no improvement within 24 hours, consider low-dose steroids:
- Dexamethasone 10 mg IV q6h

Grade 3:

Tocilizumab 8 mg/kg IV immediately
Dexamethasone 10 mg IV q6h (or methylprednisolone 1-2 mg/kg IV q12h)
Aggressive hemodynamic support:
- Vasopressors: norepinephrine first-line
- Invasive monitoring if multiple vasopressors required
Respiratory support as needed

Grade 4:

Tocilizumab 8 mg/kg IV immediately
High-dose methylprednisolone 1000 mg IV daily OR dexamethasone 20 mg IV q6h
ICU-level care:
- Multiple vasopressors, invasive hemodynamic monitoring
- Mechanical ventilation with lung-protective strategies
- Renal replacement therapy if indicated
Consider additional agents if refractory:
- Siltuximab (IL-6 antagonist) 11 mg/kg IV if tocilizumab unavailable
- Anakinra (IL-1 receptor antagonist) 100 mg SC q6-8h
- Ruxolitinib (JAK1/2 inhibitor) emerging data for refractory CRS

Pearl: The "Tocilizumab Window"

Tocilizumab blocks IL-6 signaling but does not deplete CAR-T cells, allowing therapeutic efficacy to continue. However, tocilizumab blocks fever (via central IL-6 inhibition), which can mask infection. Any patient receiving tocilizumab must be on broad-spectrum antibiotics. Additionally, tocilizumab has a narrow effect—it won't treat concurrent neurotoxicity, which requires steroids.

Hack: Early Intervention Is Key

Don't wait for grade 3 CRS to administer tocilizumab. Studies show early tocilizumab (at grade 2) reduces severe CRS without compromising CAR-T efficacy. The ELIANA trial initially showed tocilizumab use in 77% of patients, but with earlier intervention protocols, severe CRS rates have dropped from 30% to <10%.

Oyster: The Steroid Conundrum

While steroids effectively treat CRS, there's theoretical concern about impairing CAR-T expansion and long-term efficacy. However, real-world data suggests that early, brief steroid courses (3-5 days) don't significantly compromise responses. The key is using the minimal effective dose and tapering rapidly once CRS resolves. Prolonged high-dose steroids (>7 days) should be avoided when possible.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS, previously termed CAR-T-related encephalopathy syndrome (CRES), occurs in 30-60% of CAR-T recipients, with severe cases in 10-30%. Unlike CRS, ICANS pathophysiology is incompletely understood but involves blood-brain barrier disruption, cytokine penetration into CSF, and endothelial activation.

Clinical Features:

Onset: typically 5-10 days post-infusion (median 7 days), often after or concurrent with CRS
Encephalopathy: confusion, disorientation, decreased level of consciousness
Aphasia: expressive more common than receptive; word-finding difficulty
Impaired attention and concentration
Seizures (10-20% of cases)
Motor findings: tremor, myoclonus, ataxia (rare)
Cerebral edema with herniation (rare but fatal)

ICE Score (Immune Effector Cell-Associated Encephalopathy):

A bedside 10-point assessment tool:

Orientation (0-4 points): year, month, city, hospital
Naming (0-3 points): three objects shown
Following commands (0-1 point): "Show me two fingers"
Writing (0-1 point): ability to write a sentence
Attention (0-1 point): count backwards from 100 by 10

ASTCT ICANS Grading:

Grade 1:

ICE score 7-9
OR awakens spontaneously

Grade 2:

ICE score 3-6
OR awakens to voice

Grade 3:

ICE score 0-2
OR awakens only to tactile stimulus
OR seizure (any, with rapid resolution)
OR focal motor weakness

Grade 4:

Any of:
- Unresponsive or requires vigorous/painful stimuli to arouse
- Seizures: status epilepticus or repetitive clinical/electrical seizures
- Motor findings: deep focal weakness (e.g., hemiparesis)
- Elevated ICP/cerebral edema
- Depressed level of arousal with inability to perform ICE assessment

Diagnostic Workup:

Brain MRI: typically normal, but may show PRES, white matter signal changes, or edema
Lumbar puncture (if safe): typically shows elevated protein and pleocytosis
EEG: if seizure suspected; may show diffuse slowing or epileptiform discharges
Rule out infection, metabolic derangements, intracranial hemorrhage

Management of ICANS:

Prophylaxis:

Levetiracetam 500-1000 mg BID starting day of CAR-T infusion and continuing for 30 days (standard at most centers)

Grade 1:

Close neurological monitoring (q2-4h)
ICE score assessments q8-12h
Levetiracetam if not already on prophylaxis
Consider dexamethasone 10 mg IV if symptoms persist >72 hours

Grade 2:

Dexamethasone 10 mg IV q6h
ICE score q4-6h
Levetiracetam continuation
MRI brain if not already obtained
Consider ICU transfer if trending toward grade 3

Grade 3:

ICU admission
Dexamethasone 10-20 mg IV q6h (or methylprednisolone 1-2 mg/kg IV q12h)
Continuous EEG monitoring
Seizure management: benzodiazepines, additional AEDs as needed
Consider methylprednisolone 1000 mg IV daily x 3 days if refractory

Grade 4:

ICU with intensive monitoring
High-dose methylprednisolone 1000-2000 mg IV daily
Aggressive seizure management
Intubation for airway protection if GCS ≤8
ICP monitoring if cerebral edema present
Consider:
- Anakinra 100 mg SC q6h (emerging evidence)
- Siltuximab if refractory
- Hyperosmolar therapy (mannitol, hypertonic saline) for elevated ICP

Critical Distinction: CRS vs ICANS

CRS and ICANS frequently overlap but require different management. Tocilizumab treats CRS but does NOT treat ICANS (IL-6 antagonism may worsen neurotoxicity in some cases). Steroids treat both. Key distinguishing features:

Feature	CRS	ICANS
Fever	Always present	May or may not be present
Hypotension	Common	Uncommon
Hypoxia	Common	Uncommon
Encephalopathy	Rare	Defining feature
Treatment	Tocilizumab ± steroids	Steroids (NOT tocilizumab)

Clinical Hack: Don't Miss Concurrent ICANS

Altered mental status in a patient with CRS is ICANS until proven otherwise. If a patient with CRS develops confusion after tocilizumab, assume ICANS and add steroids immediately. Perform ICE score at every assessment—don't rely on "looks confused." Quantify it.

Pearl: ICANS Can Occur Without CRS

Approximately 10-15% of ICANS cases occur in the absence of CRS. Neurotoxicity is not simply a consequence of systemic inflammation—it has distinct pathophysiology. Always assess for ICANS independently of CRS status.

The "Hyperprogressive Disease" Paradox with Immunotherapy

Defining Hyperprogressive Disease (HPD)

While checkpoint inhibitors produce durable responses in some patients, a subset paradoxically experiences accelerated tumor growth compared to pre-treatment kinetics—a phenomenon termed hyperprogressive disease (HPD). This represents one of immunotherapy's most vexing challenges, occurring in approximately 9-29% of patients depending on definitions used.

Diagnostic Criteria:

Multiple definitions exist, creating controversy:

Tumor Growth Rate (TGR) Criteria:
- TGR ratio >2 (comparing pre- and post-treatment tumor growth velocity)
- Requires baseline imaging, pre-treatment imaging, and on-treatment imaging
RECIST-Based Criteria:
- 50% increase in tumor burden within 2-3 months of starting immunotherapy
- Compared to best response with previous therapy
Time to Treatment Failure (TTF):
- TTF <2 months with rapid clinical deterioration

Clinical Characteristics of HPD:

Rapid clinical decline: dramatic symptom worsening within weeks
New metastatic sites appearing quickly
Significant increase in tumor size (often >50% in <8 weeks)
Shorter overall survival compared to patients with standard progressive disease
Can occur with any checkpoint inhibitor (PD-1/PD-L1 or CTLA-4)

Potential Mechanisms

The mechanisms underlying HPD remain incompletely understood, with several hypotheses:

1. Aberrant Immune Cell Recruitment: Checkpoint blockade may recruit immunosuppressive cells (Tregs, myeloid-derived suppressor cells) to the tumor microenvironment in certain contexts, enhancing tumor growth rather than inhibiting it.

2. Fc-Mediated Depletion of Effector T Cells: PD-1 antibodies binding to PD-1+ T cells may trigger antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), inadvertently depleting effector T cells. This hypothesis suggests anti-PD-L1 antibodies might have lower HPD risk, though clinical data don't consistently support this.

3. Oncogenic Pathway Activation: Certain tumor genomic alterations correlate with HPD:

MDM2/MDM4 amplification (most strongly associated)
EGFR alterations (particularly in lung cancer)
Chromosome 11q13 amplification
DNMT3A mutations

These alterations may promote aggressive tumor behavior when combined with immune perturbation.

4. Compensatory Checkpoint Upregulation: Blocking one checkpoint may lead to compensatory upregulation of alternative inhibitory pathways (e.g., TIM-3, LAG-3, TIGIT), resulting in T-cell exhaustion and tumor escape.

5. Tumor Flare Reaction: Similar to hormonal flare in prostate cancer with LHRH agonists, initial immune activation might paradoxically stimulate tumor growth through cytokine release (IL-6, IL-8) promoting angiogenesis and proliferation.

Risk Factors for HPD

Clinical Factors:

Age >65 years (inconsistently associated)
Poor performance status (ECOG ≥2)
Multiple metastatic sites (≥3 organ systems)
Liver metastases (associated with immunosuppressive microenvironment)
Royal Marsden Hospital (RMH) prognostic score ≥2 (LDH elevated, albumin <35 g/L, liver mets)

Tumor Characteristics:

High tumor burden
Rapidly proliferative tumors (high Ki-67)
MDM2/MDM4 amplification (seen in 15-20% of HPD cases)
EGFR-mutant NSCLC (controversial; some series show increased risk)

Treatment Factors:

Combination checkpoint inhibitor therapy may have higher HPD rates than monotherapy (needs validation)
Prior therapies: heavily pre-treated patients may have higher risk

Clinical Recognition and Management

Early Warning Signs:

Rapid clinical deterioration within 4-8 weeks
New symptoms or significant worsening of existing symptoms
Dramatic pain increase requiring opioid escalation
Declining performance status
Rising tumor markers

Imaging Assessment:

Obtain first restaging scan at 6-8 weeks (earlier than typical 12-week interval if clinical concern)
Compare tumor measurements to baseline AND to pre-treatment imaging if available
Calculate tumor growth rate if serial imaging available
PET-CT may help distinguish pseudoprogression from true HPD (HPD shows markedly increased FDG uptake)

Management Strategies:

Immediate Discontinuation:
- Stop checkpoint inhibitor at first sign of HPD
- Don't wait for confirmatory imaging if clinical deterioration is dramatic
Pivot to Alternative Therapy:
- Chemotherapy (if chemotherapy-naive or long treatment-free interval)
- Targeted therapy if actionable mutation present
- Clinical trial with non-immunotherapy agent
- Combination approaches (chemotherapy + immunotherapy) may overcome HPD in selected cases
Corticosteroids:
- Some experts advocate for steroids (e.g., dexamethasone 4-8 mg daily) to dampen inflammatory tumor microenvironment
- Limited evidence; theoretical benefit in cytokine-driven HPD
Salvage Immunotherapy:
- Switching to alternative checkpoint inhibitor generally NOT recommended
- Combination with other agents (chemotherapy, targeted therapy) may be considered in clinical trial setting

Oyster: Pseudoprogression vs HPD

Distinguishing pseudoprogression (immune infiltration causing apparent tumor enlargement, followed by response) from HPD is critical but challenging. Key differences:

Feature	Pseudoprogression	HPD
Timing	Usually 8-12 weeks	4-8 weeks
Clinical status	Stable or improving	Rapidly declining
Tumor markers	Stable or decreasing	Rising
FDG-PET	Increased or stable	Markedly increased
Subsequent imaging	Tumor shrinkage	Continued growth
Incidence	5-10%	9-29%

Pearl: The "Wait and Watch" Dilemma

When faced with radiographic progression at first restaging in a clinically stable patient, the clinician faces a difficult decision: continue immunotherapy (risking HPD) or switch therapy (risking discontinuation of effective treatment with pseudoprogression). Multidisciplinary discussion, tumor markers, PET imaging, and close clinical follow-up guide this decision. Generally, if performance status is declining or symptoms worsening, don't wait—change therapy.

Clinical Hack: Baseline Tumor Growth Kinetics Matter

If available, obtain tumor measurements from scans 3-6 months prior to immunotherapy initiation. Calculating pre-treatment tumor growth velocity allows more accurate assessment of whether post-treatment progression represents acceleration (HPD) versus natural disease progression.

Biomarkers for Response: PD-L1 Expression, Tumor Mutational Burden, and MSI-H

The Quest for Predictive Biomarkers

Despite revolutionary efficacy in some patients, checkpoint inhibitors benefit only a minority—response rates typically range from 15-45% depending on tumor type. The inability to reliably predict responders results in substantial toxicity and cost burden for non-responders. Multiple biomarkers have emerged, each with strengths and limitations.

PD-L1 Expression

Rationale: Tumor PD-L1 expression represents adaptive immune resistance—upregulation in response to IFN-γ from tumor-infiltrating lymphocytes. Theoretically, PD-L1+ tumors should benefit more from PD-1/PD-L1 blockade.

Testing Methods:

Immunohistochemistry (IHC) on tumor tissue
Multiple companion diagnostic assays: 22C3, 28-8, SP142, SP263 (not interchangeable)
Scoring: Tumor Proportion Score (TPS) = % of viable tumor cells with membrane staining
Combined Positive Score (CPS) = (PD-L1+ tumor cells + immune cells) / total tumor cells × 100

Clinical Utility:

NSCLC:

Pembrolizumab monotherapy approved for PD-L1 TPS ≥50% (first-line)
KEYNOTE-024: TPS ≥50% had 45% ORR with pembrolizumab vs 28% with chemotherapy
TPS 1-49%: combination therapy preferred
TPS <1%: checkpoint inhibitor efficacy reduced but not absent (10-15% still respond)

Head and Neck Squamous Cell Carcinoma:

Pembrolizumab approved for CPS ≥1
Higher CPS correlates with better outcomes, but responses occur across all CPS levels

Gastric Cancer:

Pembrolizumab approved for CPS ≥1 (combined with chemotherapy)

Limitations of PD-L1 Testing:

Imperfect Correlation:
- 10-15% of PD-L1 negative patients still respond
- 40-50% of PD-L1 positive patients don't respond
- PD-L1 expression is dynamic, changing with therapy and over time
Spatial and Temporal Heterogeneity:
- PD-L1 expression varies within primary tumor, between metastases, and over time
- Single biopsy may not represent overall tumor PD-L1 status
Technical Variability:
- Different assays yield different results
- Subjective interpretation by pathologists
- Pre-analytical variables (fixation, processing) affect staining
Tumor Type Dependency:
- Strong predictive value in NSCLC, less so in melanoma and RCC
- Melanoma and RCC respond regardless of PD-L1 status

Pearl: PD-L1 Is Enrichment, Not Exclusion

PD-L1 should be viewed as an enrichment biomarker (identifying patients with higher response probability) rather than an exclusion biomarker (determining who should never receive immunotherapy). Clinical context, tumor type, and alternative therapies must be considered.

Tumor Mutational Burden (TMB)

Rationale: Higher somatic mutation burden generates more neoantigens—novel peptides resulting from tumor mutations. More neoantigens increase likelihood of immune recognition and response to checkpoint blockade.

Testing Methods:

Whole exome sequencing (WES): gold standard, expensive, ~50 million bases
Targeted panel sequencing: practical, ~1-2 million bases (e.g., FoundationOne CDx, MSK-IMPACT)
Reported as mutations per megabase (mut/Mb)

Threshold:

TMB-high (TMB-H) typically defined as ≥10 mut/Mb (panel-based) or ≥20 mut/Mb (WES)
Optimal threshold varies by tumor type and assay

Clinical Evidence:

FDA Approval:

Pembrolizumab approved (2020) for TMB-H (≥10 mut/Mb) tumors that have progressed on prior therapy and have no satisfactory alternative treatment options
Based on KEYNOTE-158 trial: 29% ORR in TMB-H tumors vs 6% in TMB-low

CheckMate-227:

First-line NSCLC: nivolumab + ipilimumab vs chemotherapy
TMB ≥10 mut/Mb: improved PFS with immunotherapy (7.2 vs 5.5 months)
TMB <10 mut/Mb: no PFS benefit

Tumor Types with High TMB:

Melanoma (median ~15 mut/Mb)
NSCLC (median ~8 mut/Mb, higher in smokers)
Small cell lung cancer (~10 mut/Mb)
Bladder cancer (~10 mut/Mb)
MSI-H tumors (often >20 mut/Mb)

Limitations of TMB:

Imperfect Correlation:
- Many TMB-H patients don't respond
- Some TMB-low patients respond well
- Correlation stronger for combination immunotherapy than monotherapy
Technical Challenges:
- Panel-based TMB less accurate than WES
- Variability between panels (different gene sets)
- Blood-based TMB (liquid biopsy) less validated
Neoantigen Quality Matters:
- Not all mutations generate immunogenic neoantigens
- Clonality (shared among all tumor cells) affects response
- TMB doesn't capture neoantigen presentation or T-cell repertoire
Cost and Accessibility:
- Comprehensive genomic profiling expensive ($3,000-5,000)
- Not universally available
- Turnaround time 2-3 weeks

Oyster: The Blood TMB Story

Blood-based TMB (bTMB) from circulating tumor DNA offered promise as a non-invasive biomarker. However, the B-F1RST trial in NSCLC failed to validate bTMB ≥16 as predictive of pembrolizumab benefit, leading to FDA withdrawal of the bTMB indication. Plasma-based TMB remains investigational.

Microsatellite Instability-High (MSI-H) / Mismatch Repair Deficiency (dMMR)

Biological Basis: DNA mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2) correct DNA replication errors. Deficiency in MMR (dMMR) leads to accumulation of mutations, particularly in microsatellites (repetitive DNA sequences), resulting in microsatellite instability (MSI).

MSI-H/dMMR tumors have:

Very high TMB (often >50 mut/Mb)
Abundant neoantigens
Dense lymphocytic infiltration
High PD-L1 expression

Testing Methods:

MSI Testing:

PCR-based: analyzes 5 microsatellite markers (Bethesda panel)
MSI-H: ≥2/5 markers unstable
MSI-L: 1/5 unstable
MSS: 0/5 unstable

MMR IHC:

Evaluates MLH1, MSH2, MSH6, PMS2 protein expression
dMMR: loss of ≥1 MMR protein
pMMR: intact expression of all four proteins

Next-Generation Sequencing:

Can detect MSI from panel sequencing data
Good concordance with PCR-based testing

Epidemiology:

Colorectal cancer: 15% of stage II-III, 4% of metastatic
Endometrial cancer: 20-30%
Gastric cancer: 10-20%
Rare in most other tumor types (<5%)
Germline MMR mutations (Lynch syndrome) account for 3% of MSI-H cancers

Clinical Efficacy:

Landmark FDA Approval (2017):

Pembrolizumab: first tissue/site-agnostic cancer approval based on MSI-H/dMMR status
KEYNOTE-016/164/012/158 pooled analysis: 39.6% ORR, 78% disease control rate
Responses remarkably durable (median not reached at 4+ years)

CheckMate-142:

Nivolumab in MSI-H/dMMR metastatic colorectal cancer: 31% ORR
Nivolumab + ipilimumab: 55% ORR, 71% disease control rate
Superior to historical chemotherapy controls

MSI-H as a Predictive Biomarker:

MSI-H/dMMR status is the strongest predictive biomarker for checkpoint inhibitor efficacy, showing benefit across tumor types:

Tumor Type	MSI-H Frequency	Checkpoint Inhibitor ORR
Colorectal	4% (metastatic)	40-55%
Endometrial	25-30%	45-50%
Gastric	10-20%	50-60%
Small bowel	10-15%	35-40%
Ovarian	<5%	40-50%

Clinical Hack: Test All Advanced Colorectal Cancers

Given the dramatic efficacy of immunotherapy in MSI-H/dMMR mCRC and poor prognosis with chemotherapy alone, NCCN guidelines recommend universal MSI/MMR testing in all stage IV colorectal cancers at diagnosis. Consider first-line immunotherapy for MSI-H/dMMR mCRC given superior outcomes and lower toxicity compared to chemotherapy.

Pearl: MSI-H Predicts LACK of Benefit from Fluoropyrimidine Adjuvant Therapy

In stage II colon cancer, MSI-H/dMMR tumors have better prognosis but don't benefit from 5-FU-based adjuvant chemotherapy (potentially harmful). However, in stage III, benefit is less clear. MSI-H status guides not only immunotherapy decisions but also chemotherapy selection.

Emerging and Investigational Biomarkers

Tumor-Infiltrating Lymphocytes (TILs):

"Hot" tumors (dense CD8+ T-cell infiltration) respond better than "cold" tumors
Challenges: quantification subjective, requires tumor tissue, no standardized scoring

Interferon-Gamma (IFN-γ) Gene Signature:

Elevated IFN-γ pathway gene expression predicts response
Composite scores (e.g., Tumor Inflammation Signature) under development
Requires RNA sequencing, not widely available

Gut Microbiome:

Emerging data suggest microbiome composition influences immunotherapy response
Firmicutes/Bacteroidetes ratio, Akkermansia muciniphila abundance associated with better outcomes
Fecal microbiota transplantation from responders to non-responders under investigation

Circulating Tumor DNA (ctDNA):

Early decreases in ctDNA levels correlate with response
May allow earlier assessment than radiographic imaging
Standardization and validation ongoing

Immune Contexture:

Spatial arrangement of immune cells relative to tumor (Immunoscore)
Quantifies CD3+ and CD8+ T cells in tumor center and invasive margin
Prognostic in colorectal cancer; predictive utility under investigation

Combining Biomarkers: The Future

Single biomarkers have limited predictive accuracy. Multiparameter approaches integrating PD-L1, TMB, MSI, gene expression signatures, and immune contexture may improve patient selection. Machine learning algorithms analyzing comprehensive genomic and transcriptomic data show promise but require validation.

The ideal biomarker strategy balances:

Predictive accuracy: sensitivity and specificity for response
Accessibility: cost, tissue requirements, turnaround time
Actionability: informing treatment decisions
Tumor type applicability: universal vs histology-specific

Oyster: Biomarker Combinations in Clinical Trials

Multiple trials are exploring biomarker-driven strategies:

SWOG S1800A: PD-L1/TMB-stratified treatment in NSCLC
TAPUR: TMB-guided basket trial across tumor types
POD1UM: PD-L1-stratified first-line therapy in NSCLC

Results will refine our understanding of optimal biomarker utilization.

Practical Considerations for the Internist and Intensivist

Pre-Treatment Assessment

Before initiating checkpoint inhibitors or CAR-T therapy, comprehensive baseline evaluation is essential:

Laboratory Testing:

CBC, CMP, LFTs
TSH, free T4
Morning cortisol, ACTH
Inflammatory markers (CRP, ESR) for baseline
Hepatitis B/C serology, HIV (CAR-T requirement)

Imaging:

Baseline CT chest/abdomen/pelvis
Brain MRI if indicated by tumor type
Consider PET-CT for response assessment planning

Functional Assessment:

ECOG performance status
Pulmonary function tests (if baseline lung disease)
Cardiac evaluation (echo/EKG) if CAR-T planned or cardiac risk factors

Patient Education:

irAE symptoms to watch for
Importance of early reporting
Steroid card if high-risk endocrinopathy
Emergency contact information

Monitoring During Therapy

Immune Checkpoint Inhibitors:

Clinical assessment before each infusion
Labs: CBC, CMP, LFTs, TSH q6-12 weeks
Imaging: typically q12 weeks (q6-8 weeks if clinical concern)
Symptoms: daily patient self-monitoring

CAR-T Therapy:

Inpatient monitoring ≥7 days post-infusion at experienced center
Vital signs q4-6h for first 14 days
Daily CRS/ICANS assessments
Labs: CBC, CMP, LFTs, CRP, ferritin daily x 14 days
Tocilizumab and dexamethasone immediately available

When to Consult Specialists

Oncology: Always involved; first call for any immune-related toxicity

Gastroenterology: Grade 2+ colitis, GI bleeding, steroid-refractory diarrhea

Pulmonology: Any pneumonitis, bronchoscopy for diagnosis

Endocrinology: Thyroid dysfunction, suspected hypophysitis, adrenal insufficiency, diabetes

Cardiology: Troponin elevation, arrhythmia, heart failure symptoms

Neurology: Any neurological symptoms (weakness, seizures, encephalopathy)

Dermatology: SJS/TEN, severe rash, bullous lesions

Rheumatology: Inflammatory arthritis, myositis, vasculitis

The Role of Corticosteroids: Principles

Early is better than late: Don't delay steroids hoping for spontaneous resolution in grade ≥2 irAEs
Dose matters: Under-dosing leads to prolonged toxicity; use adequate doses
Taper slowly: Rapid tapers risk rebound inflammation; taper over ≥4-6 weeks for serious irAEs
Don't fear steroids: Brief steroid courses (<1 week) don't significantly impair immunotherapy efficacy
Concurrent prophylaxis: PCP prophylaxis (TMP-SMX) and PPI for patients on prolonged high-dose steroids

Documentation and Communication

Steroid Card: All patients on chronic steroids should carry a card or wear medical alert jewelry indicating:

Steroid-dependent adrenal insufficiency
Stress dosing requirements
Emergency contact information

Transition of Care: When patients transfer between facilities or providers, critical information must be communicated:

Immunotherapy agent and dates
History of irAEs and treatments
Current immunosuppression regimen
Baseline organ function
Endocrine replacement needs

Conclusion

Cancer immunotherapy represents one of medicine's greatest advances, fundamentally altering the natural history of previously fatal malignancies. Yet this revolution demands that internists and critical care physicians develop expertise in immunology, novel toxicities, and complex management paradigms.

Key principles for the practicing clinician:

Immunotherapy responses differ fundamentally from chemotherapy: delayed responses, pseudoprogression, and durable activity characterize checkpoint inhibitors.
irAEs can affect any organ system at any time: maintain high clinical suspicion, grade systematically, and intervene early with immunosuppression.
CRS and ICANS are distinct syndromes requiring different management: tocilizumab for CRS, steroids for ICANS—know the difference.
Hyperprogressive disease is real and devastating: recognize early warning signs and don't hesitate to discontinue immunotherapy in rapidly deteriorating patients.
Biomarkers inform but don't dictate: PD-L1, TMB, and MSI-H enrich for responders but shouldn't absolutely exclude patients from therapy.
Multidisciplinary collaboration is essential: no single specialist can manage these complex patients alone.

As immunotherapy expands to earlier disease stages, additional indications, and combination regimens, the internist's role becomes increasingly critical. Familiarity with these concepts—from checkpoint biology to cytokine storms—transforms academic knowledge into lifesaving clinical acumen.

The patient in your ICU with fulminant colitis, the emergency department patient with altered mental status post-CAR-T, the clinic patient with fatigue and hypotension—these scenarios demand prompt recognition, systematic evaluation, and evidence-based intervention. Master these principles, collaborate with specialists, and remain vigilant for novel toxicities. In doing so, you'll optimize outcomes for patients benefiting from this remarkable therapeutic revolution.

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Key Clinical Pearls Summary

Checkpoint Inhibitors:

Responses may be delayed; pseudoprogression occurs in 5-10% of patients
Consider continuing therapy through initial "progression" if patient clinically stable
Duration of therapy remains uncertain; some maintain responses after 2 years of treatment
Combination CTLA-4 + PD-1 increases efficacy but also toxicity (59% grade 3-4 irAEs)

irAE Management:

Grade ≥2 irAEs require immunosuppression; don't delay steroid initiation
Colitis: CMV reactivation occurs in 20% of steroid-refractory cases
Pneumonitis: requires slow steroid taper (4-8 weeks minimum) to prevent rebound
Endocrinopathies: screen early and often; most are permanent requiring lifelong replacement
Myocarditis: highest mortality (25-50%); check troponin if any cardiac symptoms
Always check morning cortisol in patients with vague symptoms before assuming progression

CAR-T Therapy:

CRS and ICANS are distinct: tocilizumab for CRS, steroids for ICANS
Early tocilizumab (at grade 2 CRS) reduces severe CRS without impairing efficacy
Perform ICE score at every assessment; quantify neurologic status objectively
ICANS can occur without CRS; always assess independently
Levetiracetam prophylaxis standard for 30 days post-CAR-T infusion

Hyperprogressive Disease:

Occurs in 9-29% of patients receiving checkpoint inhibitors
Warning signs: rapid clinical deterioration within 4-8 weeks, new metastatic sites
MDM2/MDM4 amplification strongest genomic association
First restaging at 6-8 weeks if clinical concern (don't wait for 12 weeks)
Discontinue immunotherapy immediately if HPD suspected

Biomarkers:

PD-L1 is enrichment biomarker, not exclusion marker (PD-L1 negative patients can respond)
TMB-H (≥10 mut/Mb) predicts better response, especially with combination therapy
MSI-H/dMMR strongest predictive biomarker (40-55% ORR across tumor types)
Test all metastatic colorectal cancers for MSI/MMR at diagnosis
Single biomarkers have limited accuracy; multiparameter approaches emerging

Critical Actions:

Educate patients about irAE symptoms before starting therapy
Maintain high index of suspicion for irAEs throughout and after treatment
When in doubt, check inflammatory markers and consider steroid trial
Early multidisciplinary consultation saves lives
Document steroid-dependent adrenal insufficiency clearly for all providers

Abbreviations

ACTH - Adrenocorticotropic hormone
ADL - Activities of daily living
APC - Antigen-presenting cell
ARDS - Acute respiratory distress syndrome
ASTCT - American Society for Transplantation and Cellular Therapy
BAL - Bronchoalveolar lavage
BCMA - B-cell maturation antigen
CAR - Chimeric antigen receptor
CMP - Comprehensive metabolic panel
COP - Cryptogenic organizing pneumonia
CPS - Combined positive score
CRP - C-reactive protein
CRS - Cytokine release syndrome
CTCAE - Common Terminology Criteria for Adverse Events
CTLA-4 - Cytotoxic T-lymphocyte antigen-4
ctDNA - Circulating tumor DNA
DKA - Diabetic ketoacidosis
DLBCL - Diffuse large B-cell lymphoma
dMMR - Mismatch repair deficient
ECOG - Eastern Cooperative Oncology Group
FDA - Food and Drug Administration
HPD - Hyperprogressive disease
ICANS - Immune effector cell-associated neurotoxicity syndrome
ICI - Immune checkpoint inhibitor
ICE - Immune effector cell-associated encephalopathy
ICU - Intensive care unit
IFN-γ - Interferon gamma
IHC - Immunohistochemistry
IL - Interleukin
irAE - Immune-related adverse event
IVIG - Intravenous immunoglobulin
LDH - Lactate dehydrogenase
MHC - Major histocompatibility complex
MMR - Mismatch repair
MRI - Magnetic resonance imaging
MSI - Microsatellite instability
MSI-H - Microsatellite instability-high
NCCN - National Comprehensive Cancer Network
NSCLC - Non-small cell lung cancer
NSIP - Non-specific interstitial pneumonia
ORR - Overall response rate
OS - Overall survival
PCR - Polymerase chain reaction
PD-1 - Programmed death-1
PD-L1 - Programmed death ligand-1
PET - Positron emission tomography
PFS - Progression-free survival
pMMR - Mismatch repair proficient
PRES - Posterior reversible encephalopathy syndrome
RCC - Renal cell carcinoma
RECIST - Response Evaluation Criteria in Solid Tumors
RMH - Royal Marsden Hospital
scFv - Single-chain variable fragment
SIRS - Systemic inflammatory response syndrome
SJS - Stevens-Johnson syndrome
TCR - T-cell receptor
TEN - Toxic epidermal necrolysis
TGR - Tumor growth rate
TIL - Tumor-infiltrating lymphocyte
TMB - Tumor mutational burden
TMB-H - Tumor mutational burden-high
TNF - Tumor necrosis factor
TPS - Tumor proportion score
Treg - Regulatory T cell
TSH - Thyroid-stimulating hormone
TTF - Time to treatment failure
WES - Whole exome sequencing

Author Contributions and Disclosures

This review article is intended for educational purposes for postgraduate trainees in internal medicine and critical care. The authors have no conflicts of interest to disclose. No funding was received for this work.

Correspondence

For questions or comments regarding this review, readers are encouraged to consult the referenced primary literature and updated clinical practice guidelines from ASCO, ESMO, NCCN, and SITC.

Published: 2025

Target Audience: Postgraduate trainees and practicing physicians in internal medicine, critical care, and hospital medicine

Sunday, October 19, 2025