Over the last few years, technological advances in genetic engineering have resulted in the advent of the very promising chimeric antigen receptor (CAR) T-cell therapies. CAR T-cell therapies constitute a milestone in current cell and gene therapies and it seems that will revolutionize the fields of Hematology and Oncology. Since the first introduction of CAR T-cell technology in the late 1980s, major steps in the refinement of CAR T-cell production have been achieved leading to the first FDA approved commercial product in 2017 for the management of highly aggressive B-cell hematological malignancies. Both pivotal clinical trials and real world data have demonstrated unprecedented response rates in relapsed/refractory hematological patients, covering the unmet need of treatment of patients with no other therapeutic options while treatment indications for CAR T-cell therapy gradually expand.
However, despite the great success, CAR T-cell therapies can cause major toxicities hampering their broad application. The most frequently encountered toxicities include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which both can evolve in life-threatening conditions. Clinical manifestations of ICANS comprise a constellation of progressive neurological signs or symptoms which might overlap with other encephalopathies and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema.
Although many pre-clinical and clinical studies have investigated the pathogenesis of ICANS, the exact mechanisms driving CAR T-cell neurotoxicity remain elusive. ICANS is most frequently developed in the context of cytokine storm following CRS, however there are many cases where neurotoxicity presents as a sole entity. Previous data has shown that ICANS may be associated with increased permeability of the blood–brain barrier, endothelial activation in the central nervous system (CNS) and up-regulation of inflammatory molecules. This data derive mostly from the application of CAR T-cells in hematological malignancies; however, an explosion of studies are underway exploring the therapeutic potential and safety profile of CAR T-cells in solid tumors including those involving the CNS.
Therefore, there is a pressing need of better understanding the pathophysiological aspects of ICANS in order to effectively prevent, or even to implement therapeutic strategies, as currently there are no established factors predicting neurotoxicity and no agent is completely effective at mitigating ICANS.
To better tackle ICANS a multidisciplinary collaboration is needed between clinical researchers from different specialties including cell therapists, molecular engineers, hematologists, neurologists, oncologists, pediatricians and radiologists. Moreover, the contribution of scientists with a basic or translational background will substantially shed light in the field. A compilation of cutting edge knowledge on this Research Topic will significantly move the exciting field of CAR T-cell therapy one step closer to a safer treatment modality with broader application.
Areas of interest may include, but are not limited to the investigation of the pathogenesis, prediction, prevention, prognosis and treatment of ICANS in the following diseases:
• Hematological malignancies
• Primary or secondary CNS involvement in hematological malignancies
• Solid tumors
• CNS tumors
We welcome articles from both basic science and clinical research including Original Research, Systematic Review, Methods, Review, Mini Review, Hypothesis and Theory, Perspective, Clinical Trial and Opinion.
Over the last few years, technological advances in genetic engineering have resulted in the advent of the very promising chimeric antigen receptor (CAR) T-cell therapies. CAR T-cell therapies constitute a milestone in current cell and gene therapies and it seems that will revolutionize the fields of Hematology and Oncology. Since the first introduction of CAR T-cell technology in the late 1980s, major steps in the refinement of CAR T-cell production have been achieved leading to the first FDA approved commercial product in 2017 for the management of highly aggressive B-cell hematological malignancies. Both pivotal clinical trials and real world data have demonstrated unprecedented response rates in relapsed/refractory hematological patients, covering the unmet need of treatment of patients with no other therapeutic options while treatment indications for CAR T-cell therapy gradually expand.
However, despite the great success, CAR T-cell therapies can cause major toxicities hampering their broad application. The most frequently encountered toxicities include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which both can evolve in life-threatening conditions. Clinical manifestations of ICANS comprise a constellation of progressive neurological signs or symptoms which might overlap with other encephalopathies and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema.
Although many pre-clinical and clinical studies have investigated the pathogenesis of ICANS, the exact mechanisms driving CAR T-cell neurotoxicity remain elusive. ICANS is most frequently developed in the context of cytokine storm following CRS, however there are many cases where neurotoxicity presents as a sole entity. Previous data has shown that ICANS may be associated with increased permeability of the blood–brain barrier, endothelial activation in the central nervous system (CNS) and up-regulation of inflammatory molecules. This data derive mostly from the application of CAR T-cells in hematological malignancies; however, an explosion of studies are underway exploring the therapeutic potential and safety profile of CAR T-cells in solid tumors including those involving the CNS.
Therefore, there is a pressing need of better understanding the pathophysiological aspects of ICANS in order to effectively prevent, or even to implement therapeutic strategies, as currently there are no established factors predicting neurotoxicity and no agent is completely effective at mitigating ICANS.
To better tackle ICANS a multidisciplinary collaboration is needed between clinical researchers from different specialties including cell therapists, molecular engineers, hematologists, neurologists, oncologists, pediatricians and radiologists. Moreover, the contribution of scientists with a basic or translational background will substantially shed light in the field. A compilation of cutting edge knowledge on this Research Topic will significantly move the exciting field of CAR T-cell therapy one step closer to a safer treatment modality with broader application.
Areas of interest may include, but are not limited to the investigation of the pathogenesis, prediction, prevention, prognosis and treatment of ICANS in the following diseases:
• Hematological malignancies
• Primary or secondary CNS involvement in hematological malignancies
• Solid tumors
• CNS tumors
We welcome articles from both basic science and clinical research including Original Research, Systematic Review, Methods, Review, Mini Review, Hypothesis and Theory, Perspective, Clinical Trial and Opinion.
