When is immunotherapy appropriate and what are the recommended agents, dosing regimens, and eligibility criteria for solid tumors, hematologic malignancies, and autoimmune diseases?

Immunotherapy: Appropriate Use, Agents, and Eligibility Criteria

Solid Tumors

Advanced Renal Cell Carcinoma (RCC)

Every patient with advanced RCC should receive anti-PD-1-based therapy as initial treatment unless a specific contraindication exists. 1

• First-line therapy selection:

  • Anti-PD-1 monotherapy or combination with CTLA-4 inhibitors (nivolumab/ipilimumab) or VEGFR TKIs are standard options 1
  • Patients with sarcomatoid histology derive particularly strong benefit from immunotherapy relative to VEGF TKI therapy 1
  • Papillary and unclassified RCC should also receive IO-based therapy in the first-line setting 1

• Eligibility criteria for RCC immunotherapy:

  • Patients must NOT have active autoimmune conditions requiring immunosuppressive therapy 1
  • Patients must NOT have a history of potentially life-threatening autoimmune conditions 1
  • Patients must NOT require corticosteroids for other conditions (e.g., brain metastases, spinal cord compression, lymphangitic tumor spread) 1
  • Baseline CNS imaging is recommended for all patients; bone imaging should be considered for symptomatic patients 1

Cutaneous Melanoma

For stage IIB or IIC melanoma, clinical trial enrollment is the preferred recommendation, with interferon-α2b as an alternative only in highly selected patients. 1

• Adjuvant therapy for high-risk stage II melanoma (>4mm depth or >2-4mm with ulceration):

  • Clinical trial participation is preferred (45% panel recommendation) 1
  • Interferon-α2b may be considered (10% panel recommendation) only in patients with good performance status, no significant depression, no psychiatric history, and no underlying autoimmune disease 1
  • Observation is acceptable for lower-risk patients (20% panel recommendation) 1

• Critical limitation: No survival benefit has been demonstrated for interferon-α2b in stage II melanoma across multiple randomized trials, despite some showing relapse-free survival improvements 1

Special Populations

HIV-Infected Patients

HIV-infected individuals with undetectable viral load on cART should be considered for immunotherapy without restriction. 1

• Eligibility requirements:

  • Plasma viral load (pVL) must be undetectable before starting immunotherapy 1
  • Patients must continue cART throughout immunotherapy 1
  • CD4+ T cell counts should preferably be above 200 cells/mm³ 1
  • CD4+ counts below 100 cells/mm³ are not an absolute contraindication but require careful risk-benefit assessment 1

• Preferred agents:

  • Pembrolizumab is the preferred anti-PD-1 antibody based on concordant prospective and retrospective safety data 1
  • Durvalumab is the preferred anti-PD-L1 antibody based on clinical trial safety data 1
  • Nivolumab has been used with good tolerance but has less robust prospective data 1

• Monitoring: HIV screening is not mandatory before immunotherapy except for AIDS-defining cancers or high-risk populations (sex workers, men who have sex with men, intravenous drug users) 1

Solid Organ Transplant Recipients

Previous allogeneic bone marrow transplantation is not an absolute contraindication to anti-PD-1 therapy, though graft-versus-host disease risk is substantially elevated. 1

• Anti-PD-1 therapy after allogeneic bone marrow transplantation carries high risk of graft-versus-host disease and immune-related toxicities but may be considered when no other treatment options exist 1

Pregnancy

Pregnancy during immunotherapy must be avoided, but if cancer develops during pregnancy, checkpoint inhibitors are not absolutely contraindicated. 1

• Three case reports document treatment with nivolumab or nivolumab plus ipilimumab during pregnancy without major obstetric complications 1
• The risk of abortion and premature delivery is theoretically increased due to disruption of maternal-fetal immune tolerance 1
• Data on teratogenic potential in humans are lacking 1

Pre-existing Autoimmune Disease

Autoimmune disorders are not an absolute contraindication to immunotherapy, but individual risk-benefit assessment is mandatory. 1

• Flare-ups of pre-existing autoimmune disease occur in 27-50% of cases, with 10-25% being high grade 1
• Additional immune-related adverse events occur in 25-30% of cases 1
• Response rates appear favorable in this population despite increased toxicity 1

Contraindications and Precautions

Absolute Contraindications

• Active autoimmune conditions requiring immunosuppressive therapy 1
• History of potentially life-threatening autoimmune conditions 1
• Concurrent need for corticosteroids (for brain metastases, spinal cord compression, etc.) 1
• Severe immunodeficiency (for live vaccines in immunotherapy patients) 2

Relative Contraindications Requiring Careful Assessment

• CD4+ T cell counts below 100 cells/mm³ in HIV patients 1
• Pregnancy (not absolute, but requires careful consideration) 1
• Pre-existing autoimmune disease (requires individual evaluation) 1
• Recent allogeneic bone marrow transplantation (high GVHD risk) 1

Monitoring and Response Evaluation

Response evaluation should use RECIST v1.1 for reporting endpoints, but immune-related response criteria (irRC or iRECIST) better capture immunotherapy-specific response patterns. 1

• Pseudo-progression (initial tumor size increase followed by reduction) is uncommon but possible 1
• Most progression is real and requires treatment change 1
• Patients tolerating immunotherapy with asymptomatic disease progression or mixed response should be considered for treatment beyond RECIST-defined progression 1

Critical Management Considerations

Immune-Related Adverse Events with Bulbar Involvement

Any bulbar symptoms from immune checkpoint inhibitor-induced myositis require immediate high-dose corticosteroids plus IVIG and/or plasma exchange. 3

• ICI-induced myositis occurs in approximately 1% of patients, with median onset at 4 weeks 3
• Bulbar involvement carries approximately 20% mortality rate (compared to <10% for idiopathic inflammatory myositis) 3
• Immunotherapy must be withdrawn for grade 2 or higher symptoms 3
• Cardiac evaluation is mandatory as myocarditis is part of the myositis spectrum 3

Patient Education

• Patients should receive written literature or online resources about immunotherapy mechanisms, available treatments, and expected toxicities 1
• Clear guidance on when to contact providers is essential given the unpredictable toxicity profile 1
• Early symptom reporting helps prevent grade 3 adverse events 1

Common Pitfalls to Avoid

• Do not assume all progression on imaging represents treatment failure—consider immune-related response patterns 1
• Do not withhold immunotherapy from HIV patients with well-controlled disease and adequate CD4+ counts 1
• Do not delay cardiac evaluation in patients with suspected myositis, as myocarditis can be fatal 3
• Do not use interferon-α2b for stage II melanoma expecting survival benefit—clinical trials are preferred 1
• Do not assume autoimmune disease is an absolute contraindication—individual assessment is required 1