What is the approach to Tumor-Infiltrating Lymphocyte (TIL) therapy?

Approach to Tumor-Infiltrating Lymphocyte (TIL) Therapy

TIL therapy requires a structured approach including patient selection, tumor resection, lymphodepletion, TIL infusion, and IL-2 administration, with careful management of potential toxicities throughout the process. 1

Patient Selection and Preparation

Eligibility Criteria

• Patients with advanced disease that has progressed on prior treatments (including anti-PD-1 therapy)
• Must have at least one tumor lesion amenable to resection for TIL manufacturing
• Adequate organ function:
  • Renal: Creatinine clearance >60 mL/min (caution with CrCl 40-60 mL/min)
  • Cardiac: Left ventricular ejection fraction >45%
  • Pulmonary: No continuous oxygen requirement; FEV/FVC >70% or FEV >50% of predicted

Brain Metastases Considerations

• Untreated brain metastases should be treated with surgery or radiation prior to TIL therapy
• Brain metastases must be stable for ≥14 days before lymphodepletion
• Patients requiring steroids for symptomatic brain metastases are not candidates 1

Treatment Process

1. Tumor Resection

• Soft-tissue resection preferred over visceral resection
• Minimally invasive approach favored for visceral resections
• Small bowel resection preferred over large bowel if necessary
• For patients with both lung and liver targets, lung resection generally preferred 1

2. Non-Myeloablative Lymphodepletion

• Requires central venous catheter placement
• Standard regimen:
  • Cyclophosphamide 60 mg/kg IV daily (×2 doses)
  • Followed by fludarabine 25 mg/m² IV daily (×5 doses)
• Dose adjustments for renal impairment:
  • CrCl 50-79 mL/min: Reduce fludarabine to 20 mg/m²
  • CrCl 40-49 mL/min: Reduce fludarabine to 15 mg/m² 1

3. TIL Infusion

• Premedication:
  • Acetaminophen
  • Diphenhydramine or other H1-histamine antagonist
• No concurrent medications during infusion
• Vital sign monitoring every 30 minutes during infusion, then hourly for 4 hours
• Emergency medications (epinephrine, diphenhydramine) should be available 1

4. IL-2 Administration

• Diuresis to achieve near-euvolemia before IL-2 administration
• Discontinue antihypertensive medications 24 hours prior to IL-2
• Premedication with acetaminophen and NSAIDs (avoid NSAIDs if renal function compromised)
• Monitor serum creatinine twice daily during administration
• Avoid intravenous contrast and other nephrotoxins 1

Supportive Care

Management of Cytopenias

• G-CSF (filgrastim) 5 μg/kg/day SC starting the day after TIL infusion until ANC >500/mm³
• Transfuse platelets to maintain >30,000/mm³ (higher if on anticoagulants)
• Maintain hemoglobin ≥7.0 g/dL
• Use only irradiated blood products 1

Infection Prophylaxis

• Antibacterial: Levofloxacin or ciprofloxacin 500 mg daily until ANC >500/mm³
• Pneumocystis: Trimethoprim-sulfamethoxazole three times weekly
• Antiviral: Acyclovir 400 mg or valacyclovir 500 mg twice daily
• Antifungal: Fluconazole 400 mg daily until ANC >1000/mm³
• Continue antipneumocystis and antiviral prophylaxis for 6 months (at least 3 months) or until CD4 counts >200 cells/mm³ 1

Management of Infections

• For fever ≥38.0°C: Blood cultures, urine cultures, chest X-ray if pulmonary symptoms
• Initiate broad-spectrum antibiotics for neutropenic fever
• Do not administer TIL or IL-2 to patients with neutropenic sepsis 1

Discharge Considerations

• Criteria for discharge:
  • ANC >500 cells/mm³
  • Afebrile for 24 hours after stopping IV antibiotics
  • Platelet count >20,000/mm³ independent of transfusion
  • Return to near baseline pulmonary status if oxygen was required
  • Ability to safely perform activities of daily living
• Patients should remain within 30-50 miles (or <1 hour) of the treatment center for 30 days after infusion 1

Toxicity Management

Common Toxicities

• Myelosuppression from lymphodepletion (managed with transfusions and G-CSF)
• IL-2 related toxicities (fever, hypotension, capillary leak syndrome)
• Renal toxicity (monitor creatinine, maintain hydration)
• Gastrointestinal toxicity (nausea, vomiting, diarrhea)

Important Distinctions

• TIL therapy rarely causes cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) unlike CAR-T therapy
• Tocilizumab is not typically used for TIL therapy adverse events
• High-dose steroids should be avoided as they may diminish TIL antitumor activity 1

Clinical Outcomes

TIL therapy has shown promising results in several solid tumors:

• In advanced melanoma, TIL therapy demonstrated significantly longer progression-free survival (7.2 months vs 3.1 months) compared to ipilimumab, with 49% objective response rate 2
• Favorable outcomes have been reported in metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer 3
• TIL therapy may be effective even in patients who have failed conventional immunotherapies 3

Pitfalls and Caveats

• Patient Selection: Careful selection is critical; patients must be well enough to wait for TIL manufacturing (22-60 days) and tolerate all components of the regimen 1
• Renal Function: IL-2 is cleared renally; impaired renal function increases toxicity risk and may require modification of the regimen 1
• Steroid Use: Avoid systemic corticosteroids as they may diminish TIL efficacy; use only for immediate life-threatening conditions 1
• Brain Metastases: Exercise caution with hemorrhagic complications in patients with treated brain metastases 1
• Resource Intensive: TIL therapy requires significant institutional capacity, infrastructure, and multidisciplinary coordination 1

TIL therapy represents a promising personalized immunotherapy approach for patients with refractory solid tumors, but requires careful patient selection and management by experienced multidisciplinary teams at specialized centers.