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First, let's take a look at what is Armored CAR-T ?
Armored CAR-T: Armored is translated into armor, which gives the CAR-T cells a more powerful equipment. Specifically, it refers to the coexpression of some key cytokines or costimulatory ligands on the basis of the second/third generation CAR-T, namely the fourth generation CAR-T [1].
Significance: Whether it is hematoma or solid tumor, CAR-T cell activity is short, low proliferation, inhibition of tumor microenvironment will inhibit T cell activity, cytokine or co-stimulatory ligand can be added to immune regulation, significantly enhance T cells Amplification activity and longevity, icing on the cake. 
Example: IL-12 : Systemic injection of IL-12 cytokines can cause severe inflammation, but after the fourth generation of CAR-T cells co-expressing IL-12 to achieve local expression, NK cells can be recruited at the tumor site, or directly Reversing the depleted tumor infiltrating T lymphocytes, effectively overcoming the tumor immunosuppressive microenvironment and enhancing the cytotoxicity of CD8+ T cells and NK cells. As shown below, Armored CAR-T co-expressing IL-12 can improve CAR-T efficacy [1].
Since the current co-expression of cytokines is mostly, the narrow fourth-generation CAR-T, Armored CAR-T, can be understood as co-expressing cytokines, broadly expressing immunoregulatory factors, such as CD40L (CD40 ligand of TNFR family) and 4-1BBL (co-stimulatory ligands), which can additionally stimulate co-stimulation of antigen-presenting cells and enhance T cell activity [1]. The following figure shows the expression of 4-1BBL. The costimulatory receptor 4-1BB/4-1BBL promotes T cell proliferation, promotes DC cell activation and secretion of cytokines, and enhances cell lysis ability. 
Therefore, the addition of cytokines (IL-7, IL-15, IL-18, IL-21, etc.) to the CAR-T design can promote the proliferation, activation and killing function of T cells. Following the previous issue, we have already understood the immune function of IL-7 . In this issue, we will introduce the function of cytokine IL- 18 and its relationship with tumor immunity.
IL-18 (interleukin-18, IL18) is an important immunoregulatory factor discovered in recent years, which can induce the proliferation and enhance the activity of immune cells. In recent years, its role in anti-tumor, anti-infection and immune regulation has been more It is widely studied, and these provide a theoretical basis and basis for the improvement of the effectiveness of CAR-T to break through the traditional limitations. Let's take a look at the immune function of IL-18.
First, the discovery of IL-18
IL-18 was discovered in 1995. It is called IFN-γ Inducing Factor (IGIF) because it induces IFN-γ production. It is also found to promote granulocyte-macrophage colony-stimulating factor ( The production of GM-CSF) and the reduction of IL-10 production were renamed IL-18 and belonged to the IL-1 family. Human and mouse IL-18 are mainly produced by macrophages, and various immune and non-immune cells such as monocytes, dendritic cells, epithelial cells, and fibroblasts can also be produced [2].
Second, IL-18 signaling pathway ( as shown below )
1 The IL-18 precursor present in the cell is processed and released to the extracellular;
2 mature IL-18 binds to the receptor complex IL-18Rα/IL-18Rβ;
3 Finally activates the NF-κB transcription factor, regulates gene transcription, and produces pro-inflammatory factors.
IL-18 regulates immune cell responses primarily by producing IFN-γ, which is dependent on IL-12 or IL-15, and studies have shown that IL-18 can induce IFN-γ in the presence of IL-12/15. When produced, and when they are not present, no trace or IFN-γ production is induced or induced [3]. 
Third, the function of IL-18 (as shown in the figure below [4])
1. Regulation of T cells 1 Under the stimulation of IL-12, IL-18 can promote the proliferation of Th1 cells and secrete a large amount of IFN-γ, which can better eliminate antigens, especially intracellular bacteria, fungi and protozoa. ;
2 In the presence of some other stimuli, IL-18 can induce primitive or Th1-polarized cells to produce Th2 cytokines such as IL-13;
3 IL-18 also has an effect on Treg cells, and studies have shown that IL-18 can effectively inhibit the accumulation and function of Treg cells [5].
2. Regulation of NK cells 1 IL-18 stimulates the synthesis and secretion of IFN-γ in NK cells under the stimulation of IL-12;
2 IL-18 can increase the cytotoxicity of NK cells by increasing the expression of perforin, TNF and FASL;
3 For natural killer T cells (NKT cells), IL-18 can promote the synthesis of IFN-γ by natural killer T cells under the synergistic effect of IL-12. Under the stimulation of TCR, IL-18 can enhance the production of IL by NKT cells. 4. IL-5, IL-13, GM-CSF, TNF [6].
In addition, basophils and mast cells can also produce a large amount of IL-13 under the stimulation of IL-18, releasing chemical regulators such as histamine to protect the body from external pathogens.
Fourth, the anti-tumor effect of IL-18 
Micallef After intraperitoneal injection of Meth A sarcoma cells in BALB/c mice, intraperitoneal injection or intravenous injection of IL-18 showed significant anti-tumor effects. The mice were pretreated with 1 μg of IL-18 3 h and 6 h before inoculation of the tumor cells, and the mice inoculated with the tumor survived, while the control mice died within 3 weeks. In vitro tests have shown that IL-18 itself has no anti-tumor effect, so its anti-tumor effect should be indirectly exerted by inducing NK cells and cytotoxic cells in mice. The following figure shows the effect of IL-18 treatment on NK cell activity [7].
How does the IL-18 anti-tumor mechanism occur?
1 First activate NK cells and secrete a large amount of IFN-γ to specifically kill tumor cells;
2 Under the regulation of NK cells, CD8 + T and CD4 + T cells gradually activate, CTL plays a killing effect, and CD4 + T cells participate in the formation of tumor-specific immune memory;
3 Anti-tumor effects can also be enhanced by activating cytokines produced by Th cells, such as secreted IL-2, which enhances killing activity by activating monocytes and macrophages.
V. Application of IL-18 in tumor immunotherapy <br> The above, the powerful function of IL-18 in immune regulation, its application in tumor immunity has been widely studied, compared with other cytokines, IL -18 showed a stronger anti-tumor effect with lower toxic side effects. It mainly includes the following aspects:
Application 1: A clinical phase I study of renal clear cell carcinoma [8], patients were given different doses of rhIL-18 (recombinant human IL-18), and the results showed that all patients were well tolerated, which also prompted patients The tolerance to IL-18 is 10-1000 times higher than that of IL-12 or IL-2, reflecting its low-level excellent properties.
Application 2: Tumor cells transfected with IL-18 gene have decreased tumorigenicity and prolonged survival of animals, indicating that IL-18 is a new anti-tumor factor, providing a new safe and effective clinical tumor treatment. s method.
Application 3: Tomura et al [9] studied the effect of IL-18 on NK cells in vitro. IL-18 alone was co-cultured with NK cells, and only a small amount of IFN-γ was produced, in the presence of IL-12 or IL-2. , can produce a large amount of IFN-γ. However, the combination of IL-18 and IL-12 has strong toxic and side effects, which can reduce the body weight of the tumor-bearing mice, mucosal erosion, diarrhea and the like. Experiments suggest that this side effect may be caused by IL-18. Therefore, it is also an important research direction to clarify the combination of various factors and dose adjustment.
In summary, IL-18, as an immunoregulatory factor, induces the secretion of IFN-γ, which significantly enhances the Th1-type immune response. Therefore, if the cytokine IL-18 is added to CAR-T, it is likely to enhance CAR- The efficacy of T can also reduce the amount of CAR-T cells used and the side effects of systemic administration. On the other hand, the enhancement effect of IL-18 on NK cells also provides new ideas and targets for our future CAR-NK. This issue is here first, let us look forward to the magical effect of IL-18 in CAR-T treatment! We will see you next time~
references
1. Yeku OO, Brentjens R J. Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy[J]. Biochemical Society Transactions, 2016, 44(2): 412-418 .
2. Wawrocki, S., et al., Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol, 2016. 63(1): p. 59-63.
3. Sedimbi, SK, T. Hagglof, and MC Karlsson, IL-18 in inflammatory and autoimmune disease. Cell Mol Life Sci, 2013. 70(24): p. 4795-808.
4. Tsutsui H, Nakanishi K. Immunotherapeutic applications of IL-18 [J]. Immunotherapy, 2012, 4(12): 1883-1894.
5. Carroll, RG, et al., Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells. PLoS One, 2008. 3(9): p. e3289.
6. Uchida, T., et al., IL-18 time-dependently modulates Th1/Th2 cytokine production by ligand-activated NKT cells. Eur J Immunol, 2007. 37(4): p. 966-77.
7. Micallef, MJ, et al., Interleukin 18 induces the sequential activation of natural killer cells and cytotoxic T lymphocytes to protect syngeneic mice from transplantation with Meth A sarcoma. Cancer Res, 1997. 57(20): p. 4557-63 .
8. Robertson, MJ, et al., A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin Cancer Res, 2008. 14(11): p. 3462-9.
9. Tomura, M., et al., A critical role for IL-18 in the proliferation and activation of NK1.1+ CD3-cell. J Immunol, 1998. 160(10): p. 4738-46.
Anticancer effect of IL-18 with Armored CAR-T cell therapy
CAR-T therapy is one of the most promising treatments for cancer. Its anti-tumor effect is inseparable from the activity and expansion ability of T cells. In the previous issue, we have introduced that the addition of key cytokines will improve the efficacy of T cells. Overcoming the immunosuppressive microenvironment and improving the therapeutic effect of CAR-T therapy in liquid tumors and even solid tumors. Today we continue to introduce this cell therapy called "Armored CAR-T" (armor), and a new star molecule that boosts this CAR-T, the immunomodulator IL-18.