II. Mechanism

  1. Immune Checkpoint Inhibitor are a subtype of Monoclonal Antibody-Mediated Chemotherapy
  2. Tumor cells produce immunosuppressive agents
    1. Transforming growth factor beta
    2. Suppression of Tumor-specific T Cells
    3. Promotion of Immunosuppressive Regulatory T cells
  3. T Cells target infected and cancerous cells
    1. Antigen presenting cells (APC) present antigens to T Cells via major histocompatibility complex (MHC)
    2. T Cell activation on APC antigen presentation requires 2 steps (prevents Autoimmune Disease)
      1. Step 1: T Cell receptor (TCR) on surface of T Cell recognizes foreign antigen presented by APC-MHC
      2. Step 2: Co-stimulation by B7 on APC binding to CD28 on T Cell
    3. Once activated by APC, T cells destroy tissues displaying the target antigen
    4. T cells mature within the Thymus, recombining TCRs to maintain wide antigenic recognition (but avoiding self-antigen)
    5. Antigen presenting cells (APC) can also inhibit T Cells via several "Checkpoints" (prevents Autoimmune Disease)
      1. Cytotoxic Lymphocyte Associated Protein 4 (CTLA-4)
        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)
      2. Programmed Cell Death Receptor 1 (PD-1)
        1. Expressed on T Cell surface and APC-B7 Binding (PD Ligand 1) inhibits the T cells
        2. Several checkpoint inhibitors target PD-1 and PD-L1, and inhibit the inhibition
  4. References
    1. Zuazo (2017) Ann Transl Med 5(19):385 [PubMed]

III. Adverse Effects: Immune Checkpoint Inhibitors

  1. 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
  2. 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) has been used in steroid refractory cases
        4. Corticosteroids tapering is started after symptoms improve
          1. Pneumocystis jirovecii prophylaxis if longterm Corticosteroids are used
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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)
  9. 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
  10. Other reactions
    1. Nephritis and Renal Insufficiency
    2. Neurologic adverse effects
    3. Ophthalmic adverse effects
    4. Vasculitis
    5. Myositis
    6. Arthritis
  11. 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]

IV. Preparations: Immune Checkpoint Inhibitors

  1. Target: Cytotoxic T Lymphocyte associated-4 (CTLA-4)
    1. Ipilimumab (Yervoy)
      1. Melanoma
  2. Target: Programmed Cell Death Protein 1 (PD-1)
    1. Pembrolizumab (Keytruda)
      1. Melanoma
      2. Non-Small Cell Lung Cancer
      3. Hodgkin Lymphoma
      4. Head and Neck Squamous Cell Carcinoma
      5. Urothelial Cancer
      6. Gastric Carcinoma
      7. Microsatellite Instability high or mismatch repair deficient solid tumors
    2. Nivolumab (Opdivo)
      1. Melanoma
      2. Non-Small Cell Lung Cancer
      3. Hepatocellular Carcinoma
      4. Hodgkin Lymphoma
      5. Head and Neck Squamous Cell Carcinoma
      6. Urothelial Cancer
      7. Microsatellite Instability high or mismatch repair deficient solid tumors
  3. Target: Programmed death Ligand-1 (PDL-1)
    1. Atezolizumab (Tecentriq)
      1. Non-Small Cell Lung Cancer
      2. Urothelial Cancer
    2. Avelumab (Bavencio)
      1. Urothelial Cancer
      2. Merkel Cell Carcinoma
    3. Durvalumab (Imfinzi)
      1. Urothelial Cancer

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