CAR-T cell therapy [Neurosurgery Wiki]

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====== CAR-T cell therapy ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/161WTD0KV8_7VMEicxbMlG3kHyny78TXZwbiXYBy_AekXS8IsW/?limit=15&utm_campaign=pubmed-2&fc=20231004040912}}
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[[Chimeric antigen receptor]] T cells are [[T cell]]s 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.

===== Mechanism of action =====


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 [[antigen]]s, attack specific [[cancer cell]]s, 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 tumor]]s is not ideal.

{{::cart_therapyprocess.jpeg?600|}}
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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
((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.)).

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 tumor]]s. 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
((Kochenderfer JN, Wilson WH, Janik JE, et al.
Eradication of B-lineage cells and regression of
lymphoma in a patient treated with autologous
T cells genetically engineered to recognize CD19.
Blood. 2010;116(20):4099-4102.)).

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

===== Side effects =====

[[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
((Vinnakota JM, Biavasco F, Schwabenland M, Chhatbar C, Adams RC, Erny D, Duquesne S, El Khawanky N, Schmidt D, Fetsch V, Zähringer A, Salié H, Athanassopoulos D, Braun LM, Javorniczky NR, Ho JNHG, Kierdorf K, Marks R, Wäsch R, Simonetta F, Andrieux G, Pfeifer D, Monaco G, Capitini C, Fry TJ, Blank T, Blazar BR, Wagner E, Theobald M, Sommer C, Stelljes M, Reicherts C, Jeibmann A, Schittenhelm J, Monoranu CM, Rosenwald A, Kortüm M, Rasche L, Einsele H, Meyer PT, Brumberg J, Völkl S, Mackensen A, Coras R, von Bergwelt-Baildon M, Albert NL, Bartos LM, Brendel M, Holzgreve A, Mack M, Boerries M, Mackall CL, Duyster J, Henneke P, Priller J, Köhler N, Strübing F, Bengsch B, Ruella M, Subklewe M, von Baumgarten L, Gill S, Prinz M, Zeiser R. Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome. Nat Cancer. 2024 May 13. doi: 10.1038/s43018-024-00764-7. Epub ahead of print. PMID: 38741011.))
===== CAR-T cell therapy in Neurosurgery =====

[[CAR-T cell therapy in Neurosurgery]].
===== Solid tumor CAR-T cell therapy =====

[[Solid tumor CAR-T cell therapy]].

===== Case reports =====
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
((Gudera JA, Baehring JM, Karschnia P. Parkinsonism Following [[Chimeric Antigen Receptor]] [[T Cell]] [[Therapy]]. JAMA Neurol. 2024 Aug 12. doi: 10.1001/jamaneurol.2024.2506. Epub ahead of print. PMID: 39133506.))