Table 2.

Chimeric antigen receptor T-Cell therapy: from molecular target to clinical manifestation of toxicity [1,4,5,6,9,12,13,14,15,16,17,18,19].

Mechanisms of Action	Toxicity–Molecular Target	Clinical Manifestation of CRS or Cytokines’ Direct Effects **
Autologous T cells are collected via leukapheresis. Lentiviral or retroviral vectors are used to transduce CD-19 specific CARs into T cells. Permanent modification of the genome for long-term gene expression, to recognize and bind specific antigens to the cancer cells. CAR-T cells are grown and multiplied in the bioreactor to create millions of copies. Patient underwent lymphodepletion chemotherapy (fludarabine 300 mg/mq daily for 3 days and cyclophosphamide 500 mg/mq daily for 3 days) to suppress the endogenous T-cell compartment. After a quality check, the modified cells are reinfused to the patient where they proliferate, detect, and destroy the tumor cells.	Activation of T cells upon engagement of the CAR by CD19. Release of IL-2, soluble IL-2Ra, IFN-g, and granulocyte–macrophage colony-stimulating factor by the activated T cells and other inflammatory cytokines and chemokines by surrounding immune cells. Increased levels of ang-2, which promotes capillary leakage, along with decreased ang-1, resulting an increased ang-2:ang-1 ratio. IFN-g stimulates macrophages to release IL-6, IL-10, and TNF-a IL-6, and other secreted inflammatory cytokines mediate myocardial dysfunction potentially affecting cardiac integrity. Microvascular dysfunction and increased permeability may further exacerbate cardiac stress and trigger a myocardial inflammatory response, and procoagulant factors, such as vWF, may cause microvascular obstruction. TNF-α has recently been associated with immune-related cardiac dysfunction. Cytokine release syndrome (CRS) is the most common treatment-related adverse event and is described in 85–93% of patients at any grade. 0–46% experience severe or fatal forms of CRS. Symptoms range from mild flu-like symptoms and fever to life-threatening complications, including capillary leakage, severe hypotension, shock, and multiorgan failure *.	Cardiotoxicity: tachycardia; hypotension; fluid refractory hypotension; pulmonary edema; depressed left ventricular function; cardiac failure; cardiac failure requiring inotropic support; elevated troponin; arrhythmia; ST changes; cardiac arrest; stress-induced cardiomyopathy, pericardial disease. Neurotoxicity: diminished attention, language disturbance; dysgraphia; confusion; disorientation; agitation; tremors; seizures; motor deficits; increased intracranial pressure; transverse myelitis. Renal toxicity: acute kidney injury; electrolyte disturbances. Hematologic toxicity: anemia; thrombocytopenia; neutropenia; lymphopenia; DIC; B-cell aplasia; VTE. Gastrointestinal toxicity: nausea, vomiting; diarrhea; transaminitis; hyperbilirubinemia.

Ang-1: Angiopoietin 1; 2Ang-2: Angiopoietin 2; CAR: chimeric antigen receptor; DIC: disseminated intravascular coagulation; IL: interleukin; IFN-g: interferon gamma; TNF-α: tumor necrosis factor- alpha; vWF: von Willebrand factor; VTE: venous thromboembolism. * In accordance with a recent consensus approach to grading the severity of cytokine release syndrome, which was released by the American Society for Transplantation and Cellular Therapy (ASTCT) in 2019 [22]. ** Some of the toxicities may in part be attributed to the lymphodepletion regimen used prior to CAR-T-cell infusion and to acute volume changes.