Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events

Abstract

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as ‘living drugs,’ their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

“…Whereas tocilizumab is very effective for the management of CRS, it has no effect in most cases of ICANS 14 , 16 , 17 , 84 . This may be because of the differences in pathophysiology between CRS and ICANS and/or poor penetration of tocilizumab across the BBB.…”

“…Low-grade CRS is managed by supportive care with antipyretics while ensuring that there is no concurrent cause for fever, such as infection. Moderate to severe CRS is treated with the IL-6R-blocking antibody tocilizumab with or without immunosuppression with corticosteroids, together with intensive supportive care including fluid resuscitation and vasopressors for hypotension and supplemental oxygen delivery as needed for hypoxia 9 , 14 , 82 – 84 . Low-grade ICANS is also typically managed by diagnostic work-up and supportive care, whereas severe ICANS is usually treated with corticosteroids at most centres 14 , 84 .…”

“…Moderate to severe CRS is treated with the IL-6R-blocking antibody tocilizumab with or without immunosuppression with corticosteroids, together with intensive supportive care including fluid resuscitation and vasopressors for hypotension and supplemental oxygen delivery as needed for hypoxia 9 , 14 , 82 – 84 . Low-grade ICANS is also typically managed by diagnostic work-up and supportive care, whereas severe ICANS is usually treated with corticosteroids at most centres 14 , 84 . The use of tocilizumab has markedly reduced the incidence of severe CRS, likely owing to the fact that levels of IL-6 peak early during CRS and it is a key mediator of the downstream inflammatory cascade 4 .…”

Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals

“…Adoptive immunotherapy using CAR-T cells have become an innovative treatment option for patients with refractory or recurrent B-cell malignancies [ 1 , 2 , 3 , 4 ]. Unfortunately, life-threatening side effects, such as cytokine release syndrome and injury to normal organs essential for life support, have been observed in clinical trials [ 5 , 6 , 7 ]. These side effects, not only threaten patient safety, but also limit the effectiveness of CAR-T cell therapy.…”

Neurological Immunotoxicity from Cancer Treatment

“…The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on IECrelated adverse events has recently advocated for the use of ASTCT criteria in monitoring for neurotoxicity [85]. In those patients who develop ICANS, recommendations include workup with CRP, complete metabolic panel, complete blood counts, fibrinogen, prothrombin time test, and international normalized ratio.…”