II. Mechanism

  1. Extraction of WBCs via Leukapheresis
    1. White Blood Cells (including T Cells) extracted from patient's blood and T Cells are concentrated
  2. Reprogramming
    1. Synthesis of Gene encoding for chimeric Antigen receptor (CAR) that targets specific Antigen (along with cosignals)
    2. Manufacturing introduces into the T Cells, a CAR-encoded gene via viral vector
  3. Multiplication
    1. Engineered CAR T Cells are multiplied in a bioreactor
  4. Preparation with lymphodepletion
    1. Patient is administered Chemotherapy to suppress their own White Blood Cells
  5. Treatment
    1. Engineered CAR T Cells are infused into the patient
    2. T Cells recognize target Antigens and destroy cancer cells
      1. Sensitization to additional cancer cell components (cross-prime), providing additional cancer destruction

III. Preparations: CD19 Cell Surface Targets

  1. Tisagenlecleucel
    1. B Cell Acute Lymphoblastic Leukemia
  2. Axicabtagene ciloleucel
    1. B Cell Lymphoma subtypes

IV. Adverse Effects

  1. Cytokine Release Syndrome (CRS)
    1. Onset within the first week of Engineered CAR T Cell infusion, and peaks within the first 2 weeks
      1. CAR T Cells stimulate release of inflammatory Cytokines (e.g. Interleukin 6, Interferon gamma)
      2. Inflammatory Cytokines induce a Sepsis-like severe inflammatory cascade
    2. Signs
      1. Presents with initial Fatigue, malaise and low grade fever
      2. Later, severe findings include capillary leak, Tachycardia, Hypotension, high fever
      3. May result in multisystem organ failure and severe shock
      4. Severity of reaction is higher with greater tumor burden
    3. Management
      1. Stabilization and Supportive Care (often Critical Care)
      2. Cover with culture and broad spectrum antibiotics to cover Neutropenic Fever until infection is excluded
      3. Consider Tumor Lysis Syndrome
      4. Antipyretics
      5. Intravenous Fluids
      6. Vasopressors as needed
      7. Mechanical Ventilation as needed
      8. Tocilizumab (IL-6 receptor antagonist) 8 mg/kg (up to 800 mg) or for <30 kg, use 12 mg/kg
        1. Siltuimab is being studied as alternative agent in 2020
      9. Corticosteroids
        1. Indicated in Tocilizumab-resistant CRS or CRES
        2. Dexamethasone 10-20 mg IV every 6 hours
        3. Corticosteroids decrease CAR T Cell efficacy (avoid in mild to moderate cases)
  2. Neurotoxicity
    1. Signs
      1. Headache
      2. Expressive Aphasia
      3. Confusion to Delirium
      4. Seziures (including nonconvulsive Status Epilepticus in 10% of cases)
      5. Cerebral edema
      6. Encephalopathy (CAR T Cell-related encephalopathy or CRES)
    2. Management
      1. Seizure Prophylaxis
      2. Corticosteroids may be more effective than Tocilizumab (see dosing under CRS as above)
  3. On-Target/Off Tumor Recognition
    1. T Cell attacks noncancerous cells displaying target Antigen

V. References

  1. Jansson and Pallin (2020) Crit Dec Emerg Med 34(4): 19-28
  2. Santomasso (2019) Am Soc Clin Oncol Educ Book 39:433-444

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