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Immune Checkpoint Inhibitor
Aka: Immune Checkpoint Inhibitor, Cytotoxic T lymphocyte associated-4 Inhibitor, CTLA-4 inhibitor, Ipilimumab, Yervoy, Programmed Cell Death Protein 1 Inhibitor, PD-1 Inhibitor, Pembrolizumab, Keytruda, Nivolumab, Opdivo, Programmed death ligand-1 Inhibitor, PDL-1 Inhibitor, Atezolizumab, Tecentriq, Avelumab, Bavencio, Durvalumab, Imfinzi
- See Also
- Monoclonal Antibody-Mediated Chemotherapy
- Targeted Cancer Therapy
- CAR T-Cell Therapy
- Small Molecule Inhibitor-Mediated Chemotherapy
- Chemotherapy
- Mechanism
- Immune Checkpoint Inhibitor are a subtype of Monoclonal Antibody-Mediated Chemotherapy
- Tumor cells produce immunosuppressive agents
- Transforming growth factor beta
- Suppression of Tumor-specific T Cells
- Promotion of Immunosuppressive Regulatory T cells
- T Cells target infected and cancerous cells
- Antigen presenting cells (APC) present Antigens to T Cells via Major Histocompatibility Complex (MHC)
- T Cell activation on APC Antigen Presentation requires 2 steps (prevents Autoimmune Disease)
- Step 1: T Cell receptor (TCR) on surface of T Cell recognizes foreign Antigen presented by APC-MHC
- Step 2: Co-stimulation by B7 on APC binding to CD28 on T Cell
- Once activated by APC, T cells destroy tissues displaying the target Antigen
- T cells mature within the Thymus, recombining TCRs to maintain wide Antigenic recognition (but avoiding self-Antigen)
- Antigen presenting cells (APC) can also inhibit T Cells via several "Checkpoints" (prevents Autoimmune Disease)
- Cytotoxic Lymphocyte Associated Protein 4 (CTLA-4)
- Expressed on T Cell surface and APC-B7 Binding to CTLA-4 inhibits the T Cell
- Many cancer cells force overexpression of CTLA-4, down regulating T Cell response to the cancer
- Iplimumab (Yervoy) targets CTLA-4, and inhibits the inhibition (or checkpoint)
- Programmed Cell Death Receptor 1 (PD-1)
- Expressed on T Cell surface and APC-B7 Binding (PD Ligand 1) inhibits the T cells
- Several checkpoint inhibitors target PD-1 and PD-L1, and inhibit the inhibition
- References
- Zuazo (2017) Ann Transl Med 5(19):385 [PubMed]
- Adverse Effects: Immune Checkpoint Inhibitors
- Precautions
- Immune Checkpoint Inhibitors counter mechanisms to prevent Autoimmunity (i.e. risking autoimmune reactions)
- Toxicity may be severe or even life threatening
- Reactions may be delayed for even a year after medication is discontinued
- Initially may be unclear that presentation is related to Immunotherapy adverse effects
- Keep a broad differential diagnosis with careful history and examination
- Consult the patient's oncologist
- General Immunotherapy related adverse effects
- Ipilimumab (CTLA-4 inhibitor) is associated with up to 65% adverse effect rate
- Increased adverse effects with combination of Ipilimumab (CTLA-4 agent) and PD-1 or PDL-1 agents
- Adverse effects with combination therapy occur in nearly all patients and tend to be more severe
- Reactions are classified on a 4 grade scale from low grade or high grade reactions (simplified into 2 groups below)
- Low grade Immunotherapy related adverse effects
- Supportive and symptomatic care
- Localized Corticosteroids (e.g. rash, colitis) or oral Prednisone (0.5 to 1 mg/kg/day)
- High grade Immunotherapy related adverse effects (severe or life threatening)
- Hospitalization
- High dose Corticosteroids (1 to 2 mg/kg up to 4 mg/kg/day)
- Infliximab (tnf-alpha agent) has been used in steroid refractory cases
- Corticosteroids tapering is started after symptoms improve
- Pneumocystis jirovecii prophylaxis if longterm Corticosteroids are used
- Skin reactions (34-62%)
- Pruritus
- CTLA-4 inhibitor (Ipilimumab) with onset of rash 3-6 weeks after treatment
- Morbilliform Rash
- PD-1 Inhibitor (e.g. Atezolizumab) with onset of rash at 4-10 months after treatment
- Lichenoid Dermatitis
- Eczematous Dermatitis
- Vitiligo
- Diarrhea or colitis (up to 44-46% of cases, esp. combination therapy)
- Exclude Clostridium difficile and CMV-Associated Diarrhea (and obtain CT Abdomen if significant Abdominal Pain)
- Onset typically 5-8 weeks after treatment
- Earlier onset and worse with CTLA-4 inhibitor than with PD-1 Inhibitors
- Treat symptomatically
- Hepatotoxicity
- Evaluate for Viral Hepatitis and Alcoholic Hepatitis
- Occurs in <2% of monotherapy but 17% of combination therapy (CTLA-4 inhibitor with PD-1 Inhibitor)
- Onset 6 weeks after starting CTLA-4 inhibitor and 12 weeks after starting PD-1 Inhibitor
- Mycophenolate mofetil has been used in severe hepatotoxicity
- Endocrine Effects
- Autoimmune Thyroid Dysfunction resulting in Thyroiditis, Hypothyroidism or Hyperthyroidism (24%)
- Hypophysitis with anterior pituitary deficiency (esp. Hypothyroidism)
- Type I Diabetes Mellitus
- Adrenalitis and Adrenal Insufficiency
- Pneumonitis
- Life threatening condition, occurs in 3% of monotherapy but 10% of combination therapy (CTLA-4 with PD-1)
- Often treated initially as Pneumonia until able to distinguish from pneumonitis
- Presents as cough, fever, Hypoxemia and in some cases Respiratory Failure
- Start with Chest XRay, but best diagnosed on CT Chest
- Onset 2.5 months after starting treatment
- Myocarditis
- Presents with Chest Pain, Dysrhythmia and in some cases Cardiogenic Shock
- Obtain EKG, Troponin and ntBNP (MRI heart with biopsy may be needed for diagnosis)
- Hypersensitivity
- Older monoclonal antibodies were produced in mice and resulted in Hypersensitivity
- Newer drugs use a greater percentage of human antibodies (65-100%)
- Corticosteroids tapered over a 4-6 week course may be needed
- Other reactions
- Nephritis and Renal Insufficiency
- Neurologic adverse effects
- Ophthalmic adverse effects
- Vasculitis
- Myositis
- Arthritis
- References
- (2018) Presc Lett 25(10): 57
- Mazjoub (2019) Ann Emerg Med 73(1): 79-87 +PMID:29880440 [PubMed]
- Puzanov (2017) J Immunother Cancer 5(1): 95 +PMID:29162513 [PubMed]
- Preparations: Immune Checkpoint Inhibitors
- Target: Cytotoxic T Lymphocyte associated-4 (CTLA-4)
- Ipilimumab (Yervoy)
- Melanoma
- Target: Programmed Cell Death Protein 1 (PD-1)
- Pembrolizumab (Keytruda)
- Melanoma
- Non-Small Cell Lung Cancer
- Hodgkin Lymphoma
- Head and Neck Squamous Cell Carcinoma
- Urothelial Cancer
- Gastric Carcinoma
- Microsatellite Instability high or mismatch repair deficient solid tumors
- Nivolumab (Opdivo)
- Melanoma
- Non-Small Cell Lung Cancer
- Hepatocellular Carcinoma
- Hodgkin Lymphoma
- Head and Neck Squamous Cell Carcinoma
- Urothelial Cancer
- Microsatellite Instability high or mismatch repair deficient solid tumors
- Target: Programmed death Ligand-1 (PDL-1)
- Atezolizumab (Tecentriq)
- Non-Small Cell Lung Cancer
- Urothelial Cancer
- Avelumab (Bavencio)
- Urothelial Cancer
- Merkel Cell Carcinoma
- Durvalumab (Imfinzi)
- Urothelial Cancer
- References
- Jansson and Pallin (2020) Crit Dec Emerg Med 34(4): 19-28
- Dine (2017) Asia Pac J Oncol Nurs 4(2): 127–135 [PubMed]
- American Cancer Society
- https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html