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Gene & Protein in Disease Review of CAR-T in ADs

3.8. Application of CAR-T cells in the treatment of cytokine IL-1 and IL-6 inhibitors. 84,85 These findings
MS set the foundation for improving the safety of CAR-T
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MS, a demyelinating disease of the CNS, results from treatment and developing new intervention therapies.
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the migration of self-reactive T cells into the CNS, where At present, the primary strategies to overcome the adverse
they become activated by APCs, leading to inflammatory reactions of cytokine storms include the administration of
demyelinating disease. At present, MS is mainly treated glucocorticoid drugs such as hydrocortisone, suppression
with non-specific immunosuppressive medications. 80 of cytokine secretion, utilization of drugs that target and
block cytokine signaling pathways (such as IL-6 receptor
Fransson et al. transferred myelin cell glycoprotein inhibitors), 87-89 introduction of controllable suicide genes
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(MOG)-CAR into CD4+ T cells along with the mouse Foxp3 (such as caspase 9 or HSV-TK) as safety switches that can
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gene, which drives Treg differentiation. These modified induce T cell apoptosis and reverse graft-versus-host disease
Treg cells inhibited T cell activation in vitro and were in cases of acute toxicity, and development of “on switch”
subsequently employed to treat experimental autoimmune CAR-T cells that are closed by default and only open under
encephalomyelitis (EAE) mice. Administering the modified the action of regulating drugs to control the timing and
Tregs through the intranasal route facilitated their entry dosage of CAR-T therapy and improve safety. In addition,
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into various brain regions, resulting in the alleviation of the severity of CRS is related to disease progression and
disease symptoms and a reduction in IL-12 and interferon- disease burden, with CRS being more severe in patients
gamma mRNA levels in brain tissue. Immunohistochemical with a higher disease burden. Therefore, administering
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analysis revealed restoration of myelin basic protein CAR-T cell therapy before disease deterioration can reduce
(MBP) and glial fibrillary acidic protein, which indicated the risk of CRS occurrence.
the restoration of myelin formation and reactive astrocyte
proliferation in mice treated with modified Tregs compared Furthermore, the development of non-invasive
with the control treatment group. On re-exposure to the imaging and monitoring platforms provides support for
EAE-inducing inoculum, symptom-free mice remained monitoring and evaluating CAR-T cell transport, toxicity,
mitigated, demonstrating the sustained therapeutic effects and expansion in real time. This technology facilitates the
of the modified Tregs. Furthermore, De Paula Pohl rapid implementation of techniques aimed at enhancing
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et al. 81,82 engineered Tregs expressing a TCR specific for CAR-T cell transport and minimizing toxicity, particularly
the MBP peptide, which decreased MBP-reactive T effector in Phase I clinical trials. Another typical adverse effect
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cell growth and alleviated MOG-induced EAE symptoms. associated with CAR-T cell treatment is neurotoxicity.
These findings suggest that CAR-Tregs hold promise for Following CAR-T therapy, transgenic T cells can be
cellular therapy in MS patients. 81,82 detected in the cerebrospinal fluid, accompanied by the
presence of cytokines in the brain. Elevated cytokine levels
4. Challenges associated with CAR-T cell in the brain can lead to brain CRS, leading to neurotoxicity
therapy and possible solutions characterized by symptoms such as expressive aphasia,

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While CAR-T cell therapy has demonstrated preliminary seizures, and syncope. To manage neurotoxicity resulting
efficacy in treating ADs, its widespread application in the from CAR-T therapy, corticosteroids are frequently
field of autoimmunity is hindered by several challenges. For employed due to their ability to penetrate the blood–
example, CAR-T cell treatment can easily trigger CRS, with brain barrier effectively, a feat often unattainable by many
severe CRS occurring in 27 – 53% of cases. This condition monoclonal antibodies. 95
typically manifests 6 – 20 days post-therapy, presenting The production and preparation of CAR-T cells pose
symptoms such as fever, weariness, muscle soreness, and even significant challenges due to their complexity and difficulty.
organ malfunction, sometimes progressing to life-threatening Mass production is hindered by these complexities,
complications. Therefore, to increase the safety of CAR-T cell rendering it both challenging and expensive. After infusion,
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treatment, we must better understand the pathophysiology ensuring the expansion and subsequent safety of CAR-T
of CRS and establish predictive and management strategies cells requires long-term monitoring and evaluation. This
for its side effects. Specifically, the mechanism underlying process is highly intensive in terms of human and financial
CRS involves the rapid clearance of immune cells and the resources, often surpassing the capacity of most patients.
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generation of numerous inflammatory factors, such as Furthermore, CAR-T cells are generally modified from
cytokines and chemokines, inducing inflammation, tissue autologous T cells, and those derived from allogeneic
damage, and potentially fatal outcomes. 83 sources are prone to immune rejection, posing challenges
CAR T cell-induced cytokine release syndrome is to their widespread adoption. However, these restrictions
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mediated by macrophages and can be blocked using on CAR-T cell treatment can be overcome by developing

Volume 3 Issue 2 (2024) 9 doi: 10.36922/gpd.2851