Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

三列凹顶藻中倍半萜成分的研究

目的从三列凹顶藻Laurenciatristicha中寻找具有多样性结构的倍半萜化学成分,供药理活性筛选。方法采用凝胶柱色谱、硅胶柱色谱、重结晶和高效液相色谱等方法进行分离;借助包括一维和二维NMR等波谱方法和X-单晶衍射鉴定化合物的结构;用MTT法对得到的化合物进行细胞毒活性评价。结果分离得到5个倍半萜类化合物,分别鉴定为海兔阿普里素(aplysin,)、海兔阿普里醇(aplysinol,)、去溴海兔阿普里醇(debro-moaplysinol,)、凹顶藻联苯(laurebiphenyl,)、约翰斯顿醇(johnstonol,);在人肿瘤细胞株HCT-8、Bel-7402、BGc-823、A549和HeLa模型上,化合物对所有细胞株均显示毒性,化合物对HeLa细胞显示中等强度的细胞毒活性,其他化合物对所有细胞株均无明显毒性,IC50均大于10.0μg/mL。结论化合物~均为首次从三列凹顶藻中得到,化合物对HeLa细胞具有中等强度的选择性细胞毒活性,化合物对所有细胞株均显示毒性。     

Mathematical modelling of the spatio-temporal response of cytotoxic T-lymphocytes to a solid tumour.

In this paper a mathematical model describing the growth of a solid tumour in the presence of an immune system response is presented. In particular, attention is focused upon the attack of tumour cells by so-called tumour-infiltrating cytotoxic lymphocytes (TICLs), in a small, multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. At this stage the immune cells and the tumour cells are considered to be in a state of dynamic equilibrium--cancer dormancy--a phenomenon which has been observed in primary tumours, micrometastases and residual disease after ablation of the primary tumour. Nonetheless, the precise biochemical and cellular mechanisms by which TICLs control cancer dormancy are still poorly understood from a biological and immunological point of view. Therefore we focus on the analysis of the spatio-temporal dynamics of tumour cells, immune cells and chemokines in an immunogenic tumour. The lymphocytes are assumed to migrate into the growing solid tumour and interact with the tumour cells in such a way that lymphocyte-tumour cell complexes are formed. These complexes result in either the death of the tumour cells (the normal situation) or the inactivation (sometimes even the death) of the lymphocytes. The migration of the TICLs is determined by a combination of random motility and chemotaxis in response to the presence of chemokines. The resulting system of four nonlinear partial differential equations (TICLs, tumour cells, complexes and chemokines) is analysed and numerical simulations are presented. We consider two different tumour geometries--multi-layered cell growth and multi-cellular spheroid growth. The numerical simulations demonstrate the existence of cell distributions that are quasi-stationary in time and heterogeneous in space. A linear stability analysis of the underlying (spatially homogeneous) ordinary differential equation (ODE) kinetics coupled with a numerical investigation of the ODE system reveals the existence of a stable limit cycle. This is verified further when a subsequent bifurcation analysis is undertaken using a numerical continuation package. These results then explain the complex heterogeneous spatio-temporal dynamics observed in the partial differential equation (PDE) system. Our approach may lead to a deeper understanding of the phenomenon of cancer dormancy and may be helpful in the future development of more effective anti-cancer vaccines.     

Changes in the Eeg Background Activity of Children with Acute Lymphoblastic Leukemia During Cytotoxic Therapy

Thirteen children with acute lymphoblastic leukemia (ALL) were investigated before and during cytotoxic therapy. EEG findings were correlated with the clinical course and the therapy protocol and compared with normal data obtained from 295 healthy children. Frequency analysis of the background activity of the EEG revealed an initial slowing of the background activity prior to therapy and further slowing each time a combination of vincristine (VCR), daunorubicine (DAU) or adriblastine (ADR), prednisone (FRED), and L-asparaginase (L-ASP) was administered. The slowing of the background activity correlated only with the administration of these drugs. DAU, ADR, and FRED are not known to influence the EEG; therefore, VCR and L-ASP remain the primary candidates responsible for the central nervous system alteration.     

人端粒酶逆转录酶在肿瘤免疫治疗中的应用

寻找有效的抗原表位是近期肿瘤免疫治疗的热点．人端粒酶逆转录酶(hTERT)的免疫学特性使其成为肿瘤免疫治疗中一个吸引人的目标。从人和鼠系统获得的数据证实，细胞毒淋巴细胞(CTL)能识别hTERT特异的肽并杀死多种组织类型hTERT表达的肿瘤细胞。由于hTERT在人肿瘤组织中的广泛表达，在极少正常组织的低水平表达，临床试验已开始检验将hTERT作为肿瘤免疫治疗目标的可行程度。近期树突状细胞(DC)转运系统及其相关技术的发展和成熟提供了一个快速有效筛选抗原肽的方法。     

哮喘患者CD8+T细胞对单核/巨噬细胞抗原递呈功能的影响

目的：探讨支气管哮喘患者CD8⁺T细胞对单核/巨噬细胞抗原递呈功能的影响。方法：哮喘患者20例，健康对照22例，分别取静脉血5 mL，并分离MΦ、CD8⁺T细胞和B细胞。每份血样分成4组：MΦ递呈抗原组、CD8⁺T细胞参与MΦ递呈抗原组、CD8⁺T细胞体外活化后对MΦ递呈抗原影响组及自然状态下CD8⁺T细胞对MΦ细胞递呈抗原影响组。各组用CTLL₂P抗原刺激18 h后，洗去刺激原，与自体B细胞共同孵育10 d，吸取上清液，测定特异性IgM、IgE、IgG含量。 结果:①哮喘患者MΦ单独递呈抗原，自体B细胞特异性IgM(A490值)（0.034±0.022）明显低于健康人(0.116±0.080)（P<0.05）；CD8⁺T细胞与MΦ共同培养递呈抗原时，产生的特异性IgM(A490值)(0.031±0.021)低于健康人(0.079±0.064)（P<0.05）；②哮喘患者CD8⁺T细胞与MΦ共同培养递呈抗原时，产生的特异性IgG(A490值)(0.102±0.041)明显高于健康人(0.081±0.067)（P<0.05），自然状态下及体外活化后CD8⁺T细胞与递呈抗原MΦ共同培养，产生的特异性IgG(A490值)(0.105±0.066, 0.079±0.059)与健康人(0.066±0.038, 0.069±0.047)无明显差别(P>0.05)；③哮喘患者CD8⁺T细胞与MΦ共同培养递呈抗原产生的特异性IgE(A490值)(0.171±0.154)高于健康人(0.147±0.059)（P<0.05）。 结论:哮喘患者CD8⁺T细胞对MΦ递呈抗原产生免疫球蛋白有调节作用,而且参与哮喘发病。     

乌贼墨诱生小鼠细胞毒因子活性的检测

用乌贼墨处理小鼠后，采集血清。经体外细胞毒实验证明：乌贼墨诱生的血清对人和鼠的肿瘤细胞株均有不同程度的杀伤作用。这一结果提示：乌贼墨可能具有诱生内源性细胞毒因子产生的活性。     

Immunohistochemical characterization of cellular infiltrates in squamous cell carcinoma and Bowen's disease occurring in one patient.

We investigated populations of the infiltrating cells in Bowen's disease (BD) and squamous cell carcinoma (SCC), both of which arose in the same patient, using the Avidin-Biotin-peroxidase complex method with eight monoclonal antibodies. T lymphocytes were most predominant among infiltrating cells; NK cells, B cells, and monocytes were rarely seen in either BD or SCC. Analysis of subsets of the infiltrating T lymphocytes revealed that the number of suppressor/cytotoxic (s/c) T cells was twice that of helper/inducer (h/i) T cells in BD, while the number of s/c T cells was lower than that of h/i T cells in SCC. The immunohistochemical results in the present case differed from those of predominant infiltration of h/i T cells and of s/c T cells in three other reports of BD and SCC. These results suggest that the population of the cellular infiltrates may be modulated by the nature of tumors and by the immuno-competent state of the hosts.     

Synthesis and cytotoxic activity of new alkyl[3-(2-chloroethyl)ureido]benzene derivatives

Several alkyl[3-(2-chloroethyl)ureido] (CEU) benzene derivatives were prepared as potential anticancer agents. These new compounds were readily prepared in good yields by addition of anilines to 2-chloroethylisocyanate. Their cytotoxic activity was evaluated on human breast cancer (MDA-MB-231), human colon adenocarcinoma (LoVo) and mouse lymphocytic leukemia (P388D₁) tumor cell lines. Several new CEUs were significantly more cytotoxic than the nitrogen mustard chlorambucil. The biological activity of these aromatic urea derivatives seems to be related to the nature and position of the alkyl substituents on the aromatic ring. Substitution by branched alkyl groups on position 4 of the aromatic ring led to cytotoxic molecules which are up to 5 times more potent than the standard chlorambucil.     

The Effects of Astragalus membranaceus and Tripterygium hypoglaucum on NK Activity in Systemic Lupus Erythematosus

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