On May 16, an article was published in the magazine Blood, entitled “CAR-T Cell Neurotoxicity: Hope is on the Horizon”. The focus is on the current unmet need to alleviate CAR-T-induced neurotoxicity (NT).

This article expands the results of a study led by researchers from Harvard Medical School, Yale School of Medicine, and Massachusetts General Hospital Cancer Center, entitled “Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. This study is led by Karschnia et al., also the research finding is also published in the same issue of Blood.

Toxic side effects limit the accessibility of CAR-T therapy

A key finding by Karschnia et al. is that severe NT and prolonged exposure to glucocorticoids (which are currently recommended treatment) as long as over 10 days are unfavorable prognostic factor sfor overall survival after CAR-T treatment (p=0.013 and p=, respectively) 0.030). Severe NT occurred in >50% of NT patients in this study.

In addition, NT is associated with Cytokine Release Syndrome (CRS). An anti-IL-6 receptor antagonist, tocilizumab (Actemra), is the only approved CRS treatment currently approved by the FDA. However, studies have shown that prophylactic use of tocilizumab can increase the overall incidence of NT and the incidence of severe NT.

Most patients receive CAR-T treatment as inpatients and sometimes need to enter the intensive care unit (ICU) to manage these side effects, which creates additional health and economic burdens and less favorable reimbursement for hospitals and institutions. Therefore, only limited access is available.

Therefore, it is pointed out that under the premise of not affecting the efficacy, it is necessary to develop a strategy to improve the safety of CAR-T in order to improve its benefit-risk characteristics, cost-effectiveness, and make CAR-T applicable to not only patients with relapsed/refractory disease, but also in the early treatment.

GM-CSF Neutralization Can Simultaneously improve the safety and effectiveness of CAR-T

The article also highlights the pathophysiology of CAR-T-induced NT and cytokine release syndrome (CRS) and identifies that neutrophil-macrophage colony-stimulating factor (GM-CSF) neutralization can possibly improve CAR -T’s safety and effectiveness simultaneously, given the dual mechanism of action of GM-CSF neutralization.

Neurotoxicity and pathophysiological mechanisms of CRS (Source: blood)

GM-CSF is produced by CAR-T cells after contact with tumors as a communication conduit between the CAR-T cell-specific immune response and the extra-target inflammatory cascade produced by myeloid lineage cells.

In one aspect, GM-CSF is a key upstream trigger factor that leads to an inflammatory cytokine cascade of NT and CRS. GM-CSF acts directly on myeloid cells, expanding, activating and promoting the production of other chemokines and cytokines, including MCP-1/CCL2, IP-10/CXCL10, and cytokines IL-6 and IL-1.

The increase in fever and MCP-1 levels after 36 hours of CAR-T cell administration has been shown to be the best predictor of severe NT and CRS with high levels of specificity and sensitivity. Furthermore, IL-6 is only released by antigen-presenting cells or tumor cells in a contact-free manner, which helps explain why prophylactic administration of tocilizumab does not effectively reduce the overall incidence of CRS or NT because of this cytokine located at downstream of the inflammatory cascade.

Once initiated, this inflammatory cascade may become a self-sustaining “storm”. The production of chemokines leads to further proliferation of myeloid cells and transport to tumor lesions. Positive feedback loops can lead to abnormally high levels of inflammatory cytokines, endothelial activation, vascular permeability, ultimately leads to CRS and NT.

On the other hand, GM-CSF also acts directly on myeloid cells, promoting the proliferation and trafficking of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which have been shown to inhibit T cell proliferation and effects. Therefore, neutralizing GM-CSF is a new approach that may break the efficacy/toxicity link of the new next generation CAR-T that are under development. According to Dr. Cameron Durrant, CEO of Humanigen, GM-CSF neutralization may be the next generation strategy to potentially increase the effectiveness, safety and cost-effectiveness of CAR-T therapy.

Other NT pathogenesis factors

In addition to the most obvious inflammatory cascade, disruption of the blood-brain barrier (BBB) ​​and infiltration of bone marrow cells and pro-inflammatory cytokines into the central nervous system (CNS) are other important factors in the pathogenesis of NT.

In a study led by Karschnia et al, low platelet counts were associated with severe NT prior to CAR-T cell infusion. The integrity of the BBB can be monitored non-invasively by magnetic resonance imaging (MRI). Conventional contrast agents containing strontium are used in conjunction with MRI to detect and quantify BBB leaks. Preclinical in vivo studies have shown that diffuse neuroinflammation and BBB injury after CAR-T cell therapy cause a large influx of pro-inflammatory cytokines into the CNS, which is thought to transmit neuroinflammation. This is consistent with data reported in clinical trials of CAR-T cells, where BBB destruction and a significant increase in proinflammatory cytokine and CD14+ bone marrow cell levels in cerebrospinal fluid were observed in patients with severe NT, suggesting a potential occurring of local CNS specificity.

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