What is the role and safe usage of Interleukins (IL), specifically Interleukin-2 (aldesleukin), in cancer treatment?

Interleukins in Cancer Treatment: Role and Safe Usage

High-Dose IL-2 (Aldesleukin) Overview

High-dose interleukin-2 (HD IL-2, aldesleukin/Proleukin) is FDA-approved for metastatic renal cell carcinoma and metastatic melanoma, offering the potential for durable complete responses lasting decades in a small subset of carefully selected patients (7-9% complete response rate), but requires administration at experienced centers with intensive monitoring due to significant multi-organ toxicity. 1, 2

Mechanism and Clinical Activity

• IL-2 is a cytokine originally called "T cell growth factor" that activates both effector and regulatory T cells, demonstrating clinical antitumor activity in preclinical models and clinical trials 1
• FDA approval for HD IL-2 in metastatic RCC (1992) was based on 255 patients showing 15% overall response rate (ORR), with 17 complete responses (CR) and 20 partial responses (PR) 1
• The median duration of response was 54 months, with 60% of CR patients remaining in complete remission at 10-year follow-up 1
• In metastatic melanoma, HD IL-2 produces ORR of 15-20% with durable complete responses in a small proportion of patients 3, 4

Patient Selection Criteria

Strict patient selection is mandatory and based primarily on safety criteria, as biomarkers predictive of response remain elusive. 1

Eligible Patients:

• ECOG performance status 0 preferred (patients with ECOG PS 0 respond better with higher response rates and lower toxicity) 2
• Good organ reserve (adequate cardiac, pulmonary, hepatic, and renal function) 1
• Predominantly clear cell histology for RCC (non-clear cell RCC much less likely to respond) 1
• Favorable or intermediate MSKCC risk features 1

Contraindications:

• Inadequate organ reserve 1
• Poor performance status (ECOG PS >1) - experience extremely limited and associated with higher treatment-related mortality 2
• Untreated or active brain metastases 1
• Serious underlying autoimmune disorders 1

Special Considerations:

• Patients with small brain metastases without significant peritumoral edema may be considered after local treatment (surgery or stereotactic radiotherapy), though this is individualized (Category 2B) 1
• 40% of experts would treat CNS lesions first with surgery or stereotactic RT, then proceed with HD IL-2 if other criteria are met 1

Dosing and Administration

The standard FDA-approved regimen is 600,000-720,000 IU/kg IV every 8 hours for a maximum of 14-15 doses per cycle, repeated after 9-14 days rest for a second cycle. 2, 5

• Higher-dose regimens with more frequent dosing produce higher-grade toxicity but deliver the most durable and complete responses 5
• Administration must be restricted to institutions with medical staff experienced in managing HD IL-2 and its toxicities 1
• Most adverse reactions are self-limiting and reverse within 2-3 days of discontinuation 2

Toxicity Profile and Management

Common Grade 3-4 Toxicities:

• Cardiovascular: Hypotension (15%), supraventricular tachycardia (3%), myocardial infarction (1%) 2
• Renal: Oliguria (33%), anuria (25%) 2
• Gastrointestinal: Diarrhea (10%), vomiting (7%) 2
• Metabolic: Bilirubinemia (13%), creatinine increase (5%) 2
• Respiratory: Respiratory disorder/ARDS (14%), dyspnea (5%) 2
• Neurologic: Coma (8%), psychosis (7%), confusion (5%) 2
• Hematologic: Thrombocytopenia (5%) 2

Fatal Events (<1% each):

• Cardiac arrest, myocardial infarction, pulmonary emboli, stroke, intestinal perforation, liver or renal failure, severe depression leading to suicide, pulmonary edema, respiratory arrest 2

Supportive Care Measures:

• Antipyretics (NSAIDs) started immediately prior to IL-2 to reduce fever (monitor renal function for synergistic nephrotoxicity) 2
• Meperidine for rigors associated with fever 2
• H2 antagonists for prophylaxis of GI irritation and bleeding 2
• Antiemetics and antidiarrheals as needed 2
• Antibiotic prophylaxis (oxacillin, nafcillin, ciprofloxacin, or vancomycin) to reduce staphylococcal infections in patients with indwelling central lines 2
• Hydroxyzine or diphenhydramine for pruritic rashes 2
• Generally discontinue supportive medications 12 hours after last IL-2 dose 2

Role in Modern Treatment Algorithms

Metastatic RCC:

• Nephrectomy prior to HD IL-2 confers benefit (Level A evidence) 1
• Many IL-2 treatment centers screen for HD IL-2 candidates prior to considering other agents as initial treatment 1
• For poor risk patients, 53% would proceed with anti-VEGFR TKI, 20% with temsirolimus, and 27% with clinical trials rather than HD IL-2 1

Metastatic Melanoma:

• HD IL-2 remains an option for select patients with excellent performance status 1
• Therapy should be restricted to institutions with experienced medical staff 1
• Combination biochemotherapy regimens (dacarbazine or temozolomide-based with cisplatin, vinblastine, IL-2, interferon alfa) are Category 2B alternatives 1

Contemporary Context: IL-2 in Cellular Therapy

In 2024, the role of IL-2 has evolved with FDA approval of lifileucel (TIL therapy), where HD IL-2 is given after TIL infusion to promote T cell survival and proliferation. 1, 6

• In the TIL context, fewer IL-2 doses are administered with more conservative holding parameters compared to HD IL-2 monotherapy 1, 6
• The lower number of doses and effects of preparative lymphodepletion result in much less cytokine-related toxicity than historical HD IL-2 monotherapy 1, 6
• TIL therapy with IL-2 support showed 31.4% ORR with median duration of response not reached at 36.5 months follow-up in heavily pretreated melanoma patients 1
• A phase 3 study demonstrated significant improvement in progression-free survival (7.2 vs 3.1 months) with TIL therapy compared to ipilimumab 1

Key Clinical Pitfalls

• Do not use HD IL-2 in patients with ECOG PS >1 - extremely limited experience and higher treatment-related mortality 2
• Avoid topical steroid preparations (e.g., hydrocortisone) for skin manifestations 2
• Monitor for delayed adverse reactions to iodinated contrast media and hypersensitivity to antineoplastic agents when IL-2 is combined with other drugs 2
• Recognize that non-clear cell RCC is much less likely to respond to IL-2 therapy 1
• Permanent sequelae can occur including myocardial infarction, bowel perforation/infarction, and gangrene 2

Evidence Quality Assessment

The recommendations are based on:

• Level A evidence: Long-term follow-up data for nephrectomy benefit and durable responses 1
• FDA drug label: Specific safety and efficacy data for aldesleukin 2
• Consensus guidelines: SITC 2016 for RCC 1, NCCN 2013-2014 for melanoma 1
• Recent expert consensus: 2024 TIL Working Group guidelines for contemporary IL-2 use 1