Immune Effector Cell Associated Neurotoxicity (ICANS) in Pediatric and Young Adult Patients Following Chimeric Antigen Receptor (CAR) T-Cell Therapy: Can We Optimize Early Diagnosis?

Abstract

The Cornell Assessment for Pediatric Delirium (CAPD) was first proposed by the Pediatric Acute Lung Injury and Sepsis Investigators Network-Stem Cell Transplantation and Cancer Immunotherapy Subgroup and MD Anderson CARTOX joint working committees, for detection of immune effector cell associated neurotoxicity (ICANS) in pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy. It was subsequently adopted by the American Society for Transplantation and Cellular Therapy. The utility of CAPD as a screening tool for early diagnosis of ICANS has not been fully characterized. We conducted a retrospective study of pediatric and young adult patients (n=15) receiving standard-of-care CAR T-cell products. Cytokine release syndrome (CRS) and ICANS occurred in 87% and 40% of patients, respectively. ICANS was associated with significantly higher peaks of serum ferritin. A change in CAPD from a prior baseline was noted in 60% of patients with ICANS, 24–72 h prior to diagnosis of ICANS. The median change from baseline to maximum CAPD score of patients who developed ICANS versus those who did not was 13 versus 3, respectively (p=0.0004). Changes in CAPD score from baseline may be the earliest indicator of ICANS among pediatric and young adult patients which may warrant closer monitoring, with more frequent CAPD assessments.

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

“…Importantly, clinical trials with autologous CAR-T cells produced after RV/LV transduction have established a clear toxicity profile, in particular cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity (ICANS) (97). With optimized clinical management standards, the rates of severe CRS and ICANS were markedly reduced and the results have been crucial to further expand the extended clinical application of CAR-T cells, e.g.…”

Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice

“…In summary, the incidence of CRS is reported to range from 25 to 80%, while for ICANS, from 50 to 70% [ 36 , 37 ]. These potentially life-threatening responses are associated, respectively, with targeted cell lysis and related electrolyte imbalance.…”

“…Our experience with vaccines to prevent SARS-CoV-2 infection at an international level shows that they have a highly favorable safety profile, with some rare fatal events, considering the vast number of people vaccinated worldwide in the post-marketing setting. It must be highlighted that the biopharmaceutical technology that led, in a very short time, to the development of COVID vaccines (i.e., mRNA vaccines) comes from cancer immunotherapy research [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Commonly detected toxic responses following cancer vaccine administration include myalgia, cough, chills, fever, pain at the injection site, asthenia, flu-like syndrome, and respiratory abnormalities [ 20 ,…”

“…Furthermore, each subclass of genetic therapy has inherent limitations. For example, oncolytic viruses can affect only viral antigens, limiting the effectiveness of OV therapy; the reaction and the immune response have significant individual variability, and a relevant problem is the rapid viral elimination of OVs from the organism [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. In addition, CAR-T therapy requires a very complex lymphodepletion process, implemented with chemotherapy before infusion; the consequent risk of serious adverse events such as cytokine release syndrome calls for immediate management and advanced clinical skills [ 72 ].…”

Cytokine Release Syndrome and Associated Acute Toxicities in Pediatric Patients Undergoing Immune Effector Cell Therapy or Hematopoietic Cell Transplantation

“…Initial management of a patient with ICANS should include close serial neurologic examination and bedside fundoscopy. Evolution of encephalopathy can be trended by ICE score in children > 12 years old, or by CAPD score in younger children and in patients who are developmentally unable to be evaluated using the ICE score ( Tables 4 , 5 ) ( 9 , 82 ). Lumbar puncture can be helpful to evaluate for infection and inflammation and should be considered in conjunction with cross-sectional imaging if there is concern for cerebral edema or hemorrhage.…”