CTLA-4 Monoclonal Antibody

Aka: CTLA-4 Monoclonal Antibody, Cytotoxic T-Lymphocyte Antigen-4-Directed Antibody, CTLA-4 inhibitor, Ipilimumab, Yervoy

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II. Indications

  1. Melanoma (unresectable of metastatic)
    1. Ipilimumab
  2. Renal Cell Carcinoma (advanced)
    1. Ipilimumab
  3. Colorectal Cancer (metastatic)
    1. Ipilimumab
  4. Hepatocellular Carcinoma (refractory)
    1. Ipilimumab
  5. Non Small Cell Lung Cancer (metastatic)
    1. Ipilimumab
  6. Malignant pleural Mesothelioma (unresectable)
    1. Ipilimumab
  7. Esophageal Squamous Cell Carcinoma (metastatic, advanced, unresectable)
    1. Ipilimumab

III. Mechanism

  1. See Immune Checkpoint Inhibitor
  2. Immune Checkpoint Inhibitors are a subtype of Monoclonal Antibody-Mediated Chemotherapy
  3. Antigen Presenting Cells (APC) can inhibit T Cells via several "Checkpoints"
    1. In healthy patients, this T-Cell suppression prevents Autoimmune Disease
    2. However, cancer cells may exploit this mechanism to allow for their own propagation
  4. Cytotoxic Lymphocyte Associated Protein 4 (CTLA-4) is one of these mechanisms
    1. Expressed on T Cell surface and APC-B7 Binding to CTLA-4 inhibits the T Cell
    2. Many cancer cells force overexpression of CTLA-4, down regulating T Cell response to the cancer
    3. Iplimumab (Yervoy) targets CTLA-4, and inhibits the inhibition (or checkpoint)

IV. Medications

  1. Ipilimumab (Yervoy)

V. Dosing

  1. See other references for disease specific dosing protocols

VI. Adverse Effects: CTLA-4 Monoclonal Antibody Specific Reported Effects

  1. General
    1. Ipilimumab (CTLA-4 inhibitor) is associated with up to 65% adverse effect rate
    2. Increased adverse effects with combination of Ipilimumab (CTLA-4 agent) and PD-1 or PDL-1 agents
      1. Adverse effects with combination therapy occur in nearly all patients and tend to be more severe
    3. Neurologic
    4. Encephalitis
    5. Hyperacusis
    6. Myositis, Polymositis or Ocular Myositis
  2. Rheumatologic
    1. Sarcoidosis

VII. Adverse Effects: General Immune Checkpoint Inhibitors

  1. See Immune Checkpoint Inhibitor
  2. Precautions
    1. Immune Checkpoint Inhibitors counter mechanisms to prevent Autoimmunity (i.e. risking autoimmune reactions)
    2. Toxicity may be severe or even life threatening
    3. Reactions may be delayed for even a year after medication is discontinued
    4. Initially may be unclear that presentation is related to Immunotherapy adverse effects
      1. Keep a broad differential diagnosis with careful history and examination
      2. Consult the patient's oncologist
  3. General Immunotherapy related adverse effects
    1. Ipilimumab (CTLA-4 inhibitor) is associated with up to 65% adverse effect rate
    2. Increased adverse effects with combination of Ipilimumab (CTLA-4 agent) and PD-1 or PDL-1 agents
      1. Adverse effects with combination therapy occur in nearly all patients and tend to be more severe
    3. Reactions are classified on a 4 grade scale from low grade or high grade reactions (simplified into 2 groups below)
      1. Low grade Immunotherapy related adverse effects
        1. Supportive and symptomatic care
        2. Localized Corticosteroids (e.g. rash, colitis) or oral Prednisone (0.5 to 1 mg/kg/day)
      2. High grade Immunotherapy related adverse effects (severe or life threatening)
        1. Hospitalization
        2. High dose Corticosteroids (1 to 2 mg/kg up to 4 mg/kg/day)
        3. Infliximab (tnf-alpha agent) or Mycophenolate have been used in steroid refractory cases
          1. Consider if no Corticosteroid response in 2 to 3 days
        4. Corticosteroids tapering over 4 to 6 weeks is started after symptoms improve
          1. Start Pneumocystis jirovecii prophylaxis if longterm Corticosteroids are used
  4. Immune
    1. Graft Versus Host Disease
      1. Occurs in recipients of Hematopoietic Stem Cell Transplant
    2. Immune Mediated Reactions may affect any system
      1. Immune-Mediated Colitis
      2. Immune-Mediated Hepatitis
      3. Immune-Mediated Dermatitis
      4. Immune-Mediated Endocrinopathy (e.g. Thyroiditis)
      5. Immune-Mediated Pneumonitis
      6. Immune-Mediated Nephritis
  5. Skin reactions (34-62%)
    1. Pruritus
    2. CTLA-4 inhibitor (Ipilimumab) with onset of rash 3-6 weeks after treatment
      1. Morbilliform Rash
    3. PD-1 Inhibitor (e.g. Atezolizumab) with onset of rash at 4-10 months after treatment
      1. Lichenoid Dermatitis
      2. Eczematous Dermatitis
      3. Vitiligo
  6. Diarrhea or colitis (up to 44-46% of cases, esp. combination therapy)
    1. Exclude Clostridium difficile and CMV-Associated Diarrhea (and obtain CT Abdomen if significant Abdominal Pain)
    2. Onset typically 5-8 weeks after treatment
    3. Earlier onset and worse with CTLA-4 inhibitor than with PD-1 Inhibitors
    4. Treat symptomatically
      1. Loperamide may be used if infection has been excluded (e.g. Clostridium difficile, CMV-Associated Diarrhea)
  7. Hepatotoxicity
    1. Evaluate for Viral Hepatitis and Alcoholic Hepatitis
    2. Occurs in <2% of monotherapy but 17% of combination therapy (CTLA-4 inhibitor with PD-1 Inhibitor)
    3. Onset 6 weeks after starting CTLA-4 inhibitor and 12 weeks after starting PD-1 Inhibitor
    4. Mycophenolate Mofetil has been used in severe hepatotoxicity
  8. Endocrine Effects
    1. Autoimmune Thyroid Dysfunction resulting in Thyroiditis, Hypothyroidism or Hyperthyroidism (24%)
    2. Hypophysitis with anterior pituitary deficiency (esp. Hypothyroidism)
    3. Type I Diabetes Mellitus
    4. Adrenalitis and Adrenal Insufficiency
  9. Pneumonitis
    1. Life threatening condition, occurs in 3% of monotherapy but 10% of combination therapy (CTLA-4 with PD-1)
    2. Often treated initially as Pneumonia until able to distinguish from pneumonitis
    3. Presents as cough, fever, Hypoxemia and in some cases Respiratory Failure
    4. Start with Chest XRay, but best diagnosed on CT Chest
    5. Onset 2.5 months after starting treatment
  10. Myocarditis
    1. Presents with Chest Pain, Dysrhythmia and in some cases Cardiogenic Shock
    2. Obtain EKG, Troponin and ntBNP (MRI heart with biopsy may be needed for diagnosis)
  11. Hypersensitivity
    1. Older monoclonal antibodies were produced in mice and resulted in Hypersensitivity
    2. Newer drugs use a greater percentage of human antibodies (65-100%)
    3. Corticosteroids tapered over a 4-6 week course may be needed
  12. Other reactions
    1. Nephritis and Renal Insufficiency
    2. Neurologic adverse effects (e.g. Encephalitis)
    3. Ophthalmic adverse effects
    4. Vasculitis
    5. Myositis
    6. Arthritis
  13. References
    1. (2018) Presc Lett 25(10): 57
    2. Mazjoub (2019) Ann Emerg Med 73(1): 79-87 +PMID:29880440 [PubMed]
    3. Puzanov (2017) J Immunother Cancer 5(1): 95 +PMID:29162513 [PubMed]

VIII. Safety

  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, Pregnancy category X, crosses the placenta)
    1. Use reliable Contraception

IX. Drug Interactions

  1. Vitamin K Antagonists (Warfarin)
  2. Cardiac Glycosides (Digoxin)

X. Resources

  1. Ipilimumab (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2265ef30-253e-11df-8a39-0800200c9a66
  2. American Cancer Society
    1. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html

XI. References

  1. (2024) Presc Lett 31(3): 17
  2. Jansson and Pallin (2020) Crit Dec Emerg Med 34(4): 19-28
  3. Dine (2017) Asia Pac J Oncol Nurs 4(2): 127–135 [PubMed]
  4. Smith (2021) Am Fam Physician 103(3): 155-63 [PubMed]

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