CAR-T cell therapy

• Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy
• Acute Symptomatic Seizures During CAR T-Cell Therapy for Hematologic Malignancies: Tri-Site Mayo Clinic Experience
• Neurotoxic complications of chimeric antigen receptor (CAR) T-cell therapy
• CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant
• Brain MRI changes in children and young adults with B-cell acute lymphoblastic leukemia following chimeric antigen receptor T-cell therapy
• CAR-NK cell therapy combined with checkpoint inhibition induces an NKT cell response in glioblastoma
• CAR T cell therapy for glioblastoma: A review of the first decade of clinical trials
• Prostaglandin F2 receptor negative regulator as a potential target for chimeric antigen receptor-T cell therapy for glioblastoma

Chimeric antigen receptor T cells are T cells with genetic engineering to produce an artificial T cell receptor for use in immunotherapy.

Understanding CAR-T Cell Therapy:

CAR-T cell therapy involves genetically modifying a patient's own T cells, a type of immune cell, to express a chimeric antigen receptor (CAR) on their surface. This CAR is designed to target a specific protein or antigen present on the surface of cancer cells.

Therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal.

Nowicki KW, D'Angelo MP, Sekula RF Jr. Engineering Chimeric Antigen Receptors Into Homing Missiles. Neurosurgery. 2018 Dec 27. doi: 10.1093/neuros/nyy629. [Epub ahead of print] PubMed PMID: 30590676 ¹⁾.

CAR T cells were originally developed by Kochenderfer et al. against leukemia and lymphoma but have been adapted and explored as immunotherapy against central nervous system tumors. CAR T cells are synthetically engineered from a patient’s autologous T-cells to recognize cancer-specific antigens and generate a strong anti-tumor immune response ²⁾.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable success as an immunotherapy for hematological malignancies, and its potential for treating solid tumors is an active area of research.

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1CreER:Tak1fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy ³⁾

CAR-T cell therapy in Neurosurgery.

Solid tumor CAR-T cell therapy.

A case report describes a 67-year-old woman who had received adoptive immunotherapy with chimeric antigen receptor T cells for multiple myeloma and was experiencing parkinsonism-like symptoms ⁴⁾