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Gene & Protein in Disease Genetically engineered T cells in cancer immunotherapy

study of 33 R/R multiple myeloma patients who were signaling pathways, thus further activating T cells in
treated by bb2121 CAR-T cells, with a total OR rate of 85%, a “positive feedback” manner. It can act on other cells
15 (45%) of patients achieved CR, with a median disease- such as endothelial cells to cause systemic inflammatory
free progression survival of 11.8 months . At present, reactions, mainly involving monocyte Chemoattractant
[24]
approved CAR-T cell products are all indicated for R/R Protein (MCP)-1, IL-8, and IL-6, increased secretion
hematological malignancies targeting CD19 or BCMA. of endothelial permeability factors such as vascular
hemophilia factor, and reduced levels of endothelial
4. Issues of CAR-T cell therapy in stabilizer angiotensin 1, which causes loss of vascular
hematological malignancies integrity, hemodynamic instability, capillary leakage
[32]
Although CAR-T cells produced a high ORR in syndrome, and coagulation dysfunction . Moreover,
hematological malignancies, it has certain limitations, nitric oxide produced by macrophage-derived nitric oxide
including related toxicity in the treatment process, high synthase can further enhance hemodynamic instability
demand for individualization, long production cycle, and vasodilation; therefore, macrophage activation plays a
[33]
expensive production cost, no response and relapse after key role in CRS development . The risk factors of CD19
remission in some patients. Cytokine release syndrome CAR-T cell therapy induced-CRS mainly include high
(CRS) and on target, off-tumor toxicity are specific side tumor burden, high-doses of CAR-T cells, expansion of
reactions of CAR-T cell therapy . In addition to toxicity, CAR-T cell in vivo, thrombocytopenia and endothelial
[25]
resistance occurs during CAR-T cell therapy. With an cell activation, the status of myelosuppression after
increase in the number of patients receiving CD19 CAR-T pretreatment, and costimulatory molecules of CD28 [15,34,35] .
cells and long-term follow-up data, 30 – 50% of B-ALL At present, scientists have found that IL-1, catecholamine
patients receiving CD19 CAR-T cells who achieved a CR activation, and pyroptosis of target cells can activate
would relapse within 1 year . Moreover, 10 – 20% of macrophages and participate in the pathogenesis of CRS
[26]
patients still show no response after treatment with CD19 related to CAR-T cell therapy [36-38] . Thus, a dissection of
CAR-T cells . Relapse in patients with multiple myeloma the mechanisms of CRS production caused by CAR-T
[27]
receiving BCMA CAR-T cell infusion is frequent as well . cell therapy will be beneficial for exploring therapeutic
[28]
Thus, resistance after CAR-T cell therapy is a major problem strategies to control CRS and elevate the safety during
in the field of cancer immunotherapy, and understanding CAR-T cell therapy. The cytokines closely related to CRS
[20]
the mechanism of resistance and non-responsiveness is mainly include IL-6, IL-1, IL-10, TNF-α, and IFN-γ .
critical for enhancing the anti-tumor effect of CAR-T cell The IL-6 receptor blocker tocilizumab has been approved
therapies. Existing studies have confirmed that functional for the treatment of CRS produced by CAR-T cell therapy.
defects in CAR-T cells, the tumor cell mutations, and Glucocorticoids (dexamethasone or methylprednisolone)
tumor microenvironment are implicated in the primary or can be used to treat suboptimal CRS after treatment with
[25]
secondary resistance of B cell malignant disease to CAR-T tocilizumab injection . In addition, plasma purification
[29]
cells . The following sections describe these problems (hemofiltration or plasmapheresis) is an effective
and their existing and potential solutions. therapeutic method for handling CAR-T cell infused-
related cytokine storm [39,40] . JAK and IL-1 pathway
5. Strategies to overcome issues in CAR-T inhibitors have also been shown to control CRS [36,41] .
cells for hematological malignancies Activation of the catecholamine system participates in the
CRS process, and whether β-receptor blockers can control
5.1. Toxic reactions of CAR-T cell therapy CRS or reduce grades should be further explored . One of
[37]
CRS is considered a specific side effect related to CAR-T the means to improve safety is altering the CAR structure
cell infusion, which mainly manifests as fever, hypotension, expressing suicide gene , which can selectively remove
[42]
hypoxia, organ dysfunction, hemocytopenia, coagulation CAR-T cells, but increase the risk of disease recurrence.
dysfunction, and hemophagocytic lymphohistiocytosis . Altering the affinities of the ScFv structure of CAR
[30]
CRS is an inflammatory syndrome caused by a variety of did not affect its efficacy, but the associated side effects
cytokines produced by activated CAR-T cells and other were reduced . Twenty patients with B-cell lymphoma
[43]
immune cells. If CAR-T cells recognized target cells, who were treated with Hu19-CD828Z T cells had lower
they secrete large amounts of the cytokines IFN- and cytokine levels compared to those treated with FMC63-
tumor necrosis factor alpha (TNF-α), which activate 28Z T cells, and the severe neurotoxicity incidence rate
monocytes and macrophages to produce large amounts was only 5% . In short, the control of CRS should follow
[44]
of pro-inflammatory cytokines, predominantly IL-6 [25,31] . the principles of prediction, close monitoring, timely
IL-6 can activate other immune cells through classical intervention, and prevention (Figure 1).

Volume 1 Issue 1 (2022) 3 https://doi.org/10.36922/gpd.v1i1.114