抗GD2 抗体疗法用于高危神经母细胞瘤治疗的研究进展

高危神经母细胞瘤是幼儿及青少年中高发型恶性疾病,为胚胎性肿瘤,其表面高度表达神经节苷脂GD2,故GD2 成为此类恶疾的治疗靶标。在过去几十年中,抗GD2 抗体疗法用于神经母细胞瘤的治疗研究取得了巨大进展,其安全性和有效性得到了充分验证。简介GD2 的生物合成、结构与功能,综述用于神经母细胞瘤的抗GD2 抗体疗法及其有效性的提高策略。     

调节性T细胞与胶质瘤的免疫治疗

调节性T细胞（regulatory T cell,Treg）是一群具有抑制其它免疫细胞功能的起负性调控的细胞群. Treg细胞能抑制多种免疫细胞,如CD4+T和CD8+T淋巴细胞、NK细胞、B淋巴细胞以及树突状细胞的活化和增殖,是体内维持免疫系统稳定,防止出现自身免疫性疾病重要因素.最新研究表明,Treg细胞在肿瘤免疫逃逸中也发挥重要作用. 肿瘤细胞通过扩增或招募Treg细胞,抑制机体对肿瘤的免疫作用,由此可知,Treg细胞在肿瘤的发生和发展过程中发挥重要作用. 因此,抑制Treg细胞的活性和数量是包括胶质瘤在内的肿瘤免疫治疗有效的方式.     

肝癌免疫治疗的研究进展

肝细胞肝癌是全球发病率和死亡率最高的恶性肿瘤之一,发病率和死亡率呈逐年上升趋势。我国是肝癌大国,每年肝癌的死亡病例数位居全球第一。免疫治疗是继手术、化疗和放疗之后新兴的癌症治疗手段,其通过解除肿瘤微环境对免疫细胞的抑制作用并激活机体免疫功能,实现控制和杀伤肿瘤细胞。常用的免疫治疗的方法有免疫检查点治疗、过继免疫治疗和肿瘤疫苗治疗等。与传统治疗手段相比,免疫治疗因具有增强机体免疫功能、延缓肿瘤进展、延长患者生存时间等优点,逐渐成为基础和临床研究的热点。文中就免疫治疗在肝癌领域的研究进展作一综述。     

抗神经节苷脂GD2抗体药物的研究现状

神经母细胞瘤(neuroblastoma,NB)是儿童最常见的颅外实体肿瘤,其中高危NB患儿在接受化疗、放疗和手术等联合治疗后仍有约40％因复发而死亡.近年来,随着免疫治疗研究的不断深入,以抗神经节苷脂GD2抗体(anti-ganglioside GD2 antibody,简称抗GD2抗体)药物为基础的免疫治疗已成为高...     

IGFBP7基因的结构与功能的研究进展

胰岛素样生长因子结合蛋白7（IGFBP7）是IGFBPs超家族的新成员,结构上除具有与IGFBPs相似的保守N端结构域外,还有特异的Kazal型丝氨酸蛋白酶抑制结构域和免疫球蛋白样C2结构域。除与IGFs结合发挥作用外,还能独立调控细胞凋亡、增殖和迁移等。而至今尚无对水生无脊椎动物IGFBP7的研究报道,结合本实验室的研究综述了目前IGFBP7基因结构和功能上的研究进展,并对今后的研究工作进行了展望。     

三阴性乳腺癌免疫微环境及免疫治疗研究进展

三阴性乳腺癌(TNBC)是一组高度异质性的恶性肿瘤,目前缺乏明确治疗靶点。随着TNBC基因组学、蛋白质基因组学、免疫微环境和免疫治疗研究取得突破性进展,人们更深入地认识了TNBC的生物学机制,推动TNBC转化医学研究与精准诊疗,但关于TNBC生物学特征及临床进程的许多科学问题仍亟待解决。现对TNBC分子分型、基因组学研究、免疫微环境及免疫治疗进展进行综述。     

胰岛素样生长因子与糖尿病神经病变

糖尿病神经病变给糖尿病患者造成严重危害,但其发生机制至今未明。最近研究表明：胰岛素样生长因子（ＩＧＦｓ）对感觉、运动及交感神经元具有支持营养作用;临床糖尿病患者及实验性糖尿病大鼠体内ＩＧＦｓ活性及ＩＧＦｓ ｍＲＮＡ表达水平下降;补充ＩＧＦｓ可减轻糖尿病神经损害程度。上述研究提示ＩＧＦｓ活性下降在糖尿病神经病变的发生中起重要作用。     

胰岛素样生长因子研究进展

胰岛素样生长因子（ＩＧＦ）是一类多功能细胞增殖凋控因子。因其化学结构民胰岛素原类似而得名。ＩＧＦ系统由２个多肽类生长因子、２类受体和至少６种结合蛋白组成。本仅不ＩＧＦ系统成员的分子生物学方面的最新进展及其主要生物学功能作一综述。     

Wnt/β-catenin信号通路与癌症发生发展及其免疫治疗

经典的Wnt/β-catenin信号通路参与调控机体的多种生物学功能,包括干细胞自我更新,细胞的增殖、分化、凋亡以及胚胎早期发育和组织再生等,与癌症发生发展紧密相关.此外,该信号通路在胸腺T细胞的发育和分化过程中发挥重要作用,影响抗肿瘤免疫效应的多个环节.异常激活的Wnt/β-catenin信号通路可诱导恶性肿瘤的形成...     

胃癌的过继性免疫治疗研究进展

胃癌是目前世界上发病率及致死率较高的恶性肿瘤之一,在东亚地区尤其显著。针对胃癌的治疗手段仍是传统的手术联合化疗、放疗为主,尽管靶向药物治疗提供了新的选择,但其对晚期胃癌的疗效仍然有限。胃癌的免疫治疗作为独特的治疗手段,在近十多年发展较为活跃,特别是过继性免疫治疗手段不断有创新。过继性免疫治疗主要依赖回输具有抗肿瘤活性的细胞,目前回输的细胞由具有非特异性抗肿瘤作用向具有特异性抗肿瘤作用演变,特别是嵌合性抗原T细胞治疗的出现,为进展期胃癌患者提供了有一种潜在的选择。本文对胃癌过继性免疫治疗中采用的不同免疫活性细胞的作用机制、临床应用等进行总结,并针对其不足提出利用基因工程技术增强治疗靶向性、降低免疫逃逸的研究方向。     

Phase I trial of combined treatment with ch14.18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma

Purpose: We conducted a phase I trial of interleukin 2 (IL-2) in combination with chimeric 14.18 (ch14.18) and murine R24 antibodies to determine the maximal tolerated dose (MTD), immunological effects, and toxicity of this treatment combination. Experimental Design: Twenty-seven patients with either melanoma (23 patients) or sarcoma (4 patients) were enrolled to receive a combination therapy with ch14.18 and R24 antibodies together with continuous infusion of Roche IL-2 (1.5×10⁶ U/m²/day, 26 patients) or Chiron IL-2 (4.5×10⁶ U/m²/day, 1 patient) given 4 days/week for 3 weeks. The antibodies ch14.18 (2–7.5 mg/m²/day) and R24 (1–10 mg/m²/day) were scheduled to be administered for 5 days during the second week of IL-2 therapy. Results: When given in combination in this study, the MTD for ch14.18 was 5 mg/m²/day and the MTD for R24 was 5 mg/m²/day. Dose-limiting toxicities were severe allergic reactions to both ch14.18 and R24 as well as pain related to ch14.18. This ch14.18 MTD was lower than the 7.5 mg/m²/day MTD previously determined for ch14.18 given alone with the same dose and schedule of IL-2. Immunological effects included the induction of lymphokine-activated killer (LAK) activity and antibody-dependent cell-mediated cytoxicity (ADCC). Anti-idiotype response to ch14.18 was seen in six patients, including two melanoma patients who had a partial response to treatment. In addition to two partial responses, four patients had a stable disease and one patient remained without any evidence of disease. Conclusions: Immunotherapy with IL-2 in combination with ch14.18 and R24 antibodies augments LAK function and ADCC measured in vitro in all patients. While there exist theoretical advantages of combining these two antibodies, the MTD of ch14.18 and of R24 were lower than the MTD of each antibody in prior studies evaluating single antibody therapy with IL-2. As such, the combination of these two antibodies together with IL-2 therapy appeared to influence the MTD and toxicity of each of the administered antibodies. This work is supported by NIH grants M01-RR03186, R01-CA32685, and P30-CA14520     

Immunotherapy with intralesional and systemic interleukin-2 of patients with non-small-cell lung cancer

Eight patients affected by non-small-cell lung cancer were treated with intralesional and systemic recombinant IL-2(rIL-2) injection with the aim of activating both tumour-infiltrating lymphocytes and circulating cytotoxic or killer cells. The schedule of treatment was as follows: a daily fine-needle transparietal intralesional rIL-2 injection (1×10⁵ Cetus units) from day 1 to day 5 and systemic rIL-2 infusion (1×10⁵ Cetus units kg^–1 day^–1) from day 6 to day 10. One to four cycles of treatment were received by each patient. Clinical and immunological evaluations were performed (a) before treatment, (b) following the intralesional rIL-2 administration, (c) 1 h after the beginning of rIL-2 infusion and (d) at the end of the systemic rIL-2 infusion. No complete remission was achieved, two patients showed a partial remission, three resulted in stable disease and three patients progressed. Natural killer and lymphokine-activated killer cell activity dramatically decreased 1 h after the beginning of rIL-2 infusion and increased at the end of treatment. A progressive increase of circulating CD8⁺ and HLA class II⁺ T cells as well as of CD8⁺ T cell clones, most of which displayed NK activity, was recorded following rIL-2 infusion. Present data indicate that (a) the local administration of rIL-2 coupled with systemic rIL-2 infusion may be suggested as an alternative approach for the immunotherapy of lung cancer, (b) rIL-2 induces different immunological modifications according to the route and the time of its administration and (c) rIL-2 administration increases the amount of circulating immune cells with potential antitumour activity.     

Targeting the immune system: novel therapeutic approaches in squamous cell carcinoma of the head and neck

Despite advances in surgery, radiotherapy, and chemotherapy, the overall survival rates for patients with squamous cell carcinoma of the head and neck (SCCHN) have not changed over the last decades. Clearly, novel therapeutic strategies are needed for this cancer, which is highly immunosuppressive. Therefore, biologic therapies able to induce and/or up-regulate antitumor immune responses could represent a complementary approach to conventional treatments. Because patients with SCCHN are frequently immunocompromised due to the elimination or dysfunction of critical effector cells of the immune system, it might be necessary to restore these immune functions to allow for the generation of more effective antitumor host responses. Simultaneously, to prevent tumor escape, it might be necessary to alter attributes of the malignant cells. The present review summarizes recent advances in the field of immunotherapy of SCCHN, including techniques of nonspecific immune stimulation, the use of monoclonal antibodies, advances in adoptive immunotherapy and genetic engineering, as well as anticancer vaccines. These biologic therapies, alone or in combination with conventional treatment, are likely to develop into useful future treatment options for patients with SCCHN.     

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

Several investigations have been carried out since many years in order to precisely address the function of lipid rafts in cell life and death. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides, sphingomyelin, cholesterol and signaling proteins, a plethora of possible interactions with various subcellular structures has been suggested. Their structural and functional role at the plasma membrane as well as in cell organelles such as endoplasmic reticulum and Golgi apparatus has been analyzed in detail in several studies. In particular, a specific activity of lipid rafts has been hypothesized to contribute to cell death by apoptosis. Although detected in various cell types, the role of lipid rafts in apoptosis has however been mostly studied in lymphocytes where the physiological apoptotic program occurs after CD95/Fas triggering. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation are summarized. Particular attention has been given to the mitochondrial raft-like microdomains, which may represent preferential sites where some key reactions can take place and can be catalyzed, leading to either survival or death of T cells.     

成纤维细胞生长因子6(FGF6)的研究进展

成纤维细胞生长因子6(fibroblast growth factor 6,FGF6)是成纤维细胞生长因子家族(FGFs)的成员之一,主要通过与酪氨酸激酶受体(fibroblast growth factor receptor,FGFR)1和4结合发挥其生物学活性。研究发现,人FGF6几乎都积聚在肌源性细胞系中,参与肌源性细胞系的增殖及分化,在肌肉修复和再生过程中起重要作用,同时它还是一个重要的调节骨生成和骨重建的因子;FGF6在心脏中也有表达,进一步试验结果表明其具有促进心肌细胞增殖及保护心肌细胞凋亡的作用;在成体睾丸和乳腺癌中也检测到有FGF6的转录物,表明其在肿瘤发生发展中的作用。目前,FGF6在多种疾病中的功能和相关机制仍有待进一步研究和确认,但其所具备的生物学活性尤其是在肌肉再生方面具有重要的意义和巨大的应用潜力。     

The insulin-like growth factor axis: A biological mechanism linking physical activity to colorectal cancer survival

Physical activity (PA) is related to colorectal cancer (CRC) mortality, with approximately 15% of CRC deaths worldwide attributable to physical inactivity. Moreover, higher levels of PA in CRC survivors have been associated with a reduced risk of the disease recurring. Despite the recognised nexus between PA and the risk of CRC, the physiological mechanisms underlying the inverse relationship between PA and mortality following CRC diagnosis are less apparent, with evidence primarily drawn from epidemiological studies. The insulin-like growth factor (IGF) axis plays a central role in cellular growth, proliferation regulation, differentiation and apoptosis. Specifically, high levels of insulin-like growth factor 1 (IGF-1) have been consistently linked to the severity of CRC tumours. Further, insulin-like growth factor binding protein 3 (IGFBP-3) regulates the bioavailability of IGF-I and therefore plays a central role in CRC prognosis. Decreasing levels of IGF-1 and increasing levels of IGFBP-3 may thus be a plausible mechanism underlying the inverse association between PA and CRC survival.     

胰岛素样生长因子-1、转化生长因子-beta1 水平变化在过敏性紫癜患儿肾损害的临床意义

目的：探讨胰岛素样生长因子-1（IGF-1）、转化生长因子-beta1（TGF-beta1）水平变化在过敏性紫癜患儿肾损害发病机制中作用。 方法：选取HSP患儿30 例、HSPN患儿30 例和30 例健康儿童为对照组,分别采血,用化学发光法检测各组标本IGF-1 浓度,采用 双抗体一步夹心法酶联免疫吸附试验检测各组TGF-茁1 浓度;同时用全自动生化仪检测各组患儿血清Cys C、BUN、SCr 水平。结 果：血IGF-1、TGF-beta1 的水平HSPN组、HSP组与对照组患儿比较,差异均有统计学意义（P<0.05）。血清Cys C 水平对照组、HSP 组与HSPN 组患儿比较,差异有统计学意义（P<0.05）。采用直线相关分析HSPN 组的血清Cys C 水平与血IGF-1、TGF-beta1 水平 比较,存在正相关（r=0.759、r=0.802,均P<0.05）,血IGF-1 与TGF-beta1 也存在正相关（r=0.850,P<0.05）。结论：血IGF-1、TGF-beta1 共同 参与紫癜性肾炎发病,其水平变化与病理损害程度相关。     

High-affinity anti-ganglioside IgG antibodies raised in complex ganglioside knockout mice: reexamination of GD1a immunolocalization

Gangliosides, sialic acid-bearing glycosphingolipids, are highly enriched in the vertebrate nervous system. Anti-ganglioside antibodies are associated with various human neuropathies, although the pathogenicity of these antibodies remains unproven. Testing the pathogenic role of anti-ganglioside antibodies will be facilitated by developing high-affinity IgG-class complement-fixing monoclonal anti-bodies against major brain gangliosides, a goal that has been difficult to achieve. In this study, mice lacking complex gangliosides were used as immune-naive hosts to raise anti-ganglioside antibodies. Wild-type mice and knockout mice with a disrupted gene for GM2/GD2 synthase (UDP-N-acetyl-D-galactosamine : GM3/GD3 N-acetyl-D-glactosaminyltransferase) were immunized with GD1a conjugated to keyhole limpet hemocyanin. The knockout mice produced a vigorous anti-GD1a IgG response, whereas wildtype littermates failed to do so. Fusion of spleen cells from an immunized knockout mouse with myeloma cells yielded numerous IgG anti-GD1a antibody-producing colonies. Ganglioside binding studies revealed two specificity classes; one colony representing each class was cloned and characterized. High-affinity monoclonal antibody was produced by each hybridoma : an IgG1 that bound nearly exclusively to GD1a and an IgG2b that bound GD1a, GT1b, and GT1aalpha. Both antibodies readily readily detected gangliosides via ELISA, TLC immune overlay, immunohistochemistry, and immunocytochemistry. In contrast to prior reports using anti-GD1a and anti-GT1b IgM class monoclonal antibodies, the new antibodies bound avidly to granule neurons in brain tissue sections and cell cultures. Mice lacking complex gangliosides are improved hosts for raising high-affinity, high-titer anti-ganglioside IgG antibodies for probing for the distribution and physiology of gangliosides and the pathophysiology of anti-ganglioside antibodies.     

Expression of the Ganglioside GD3 in Human Meningiomas Is Associated with Monosomy of Chromosome 22

The ganglioside composition of 59 meningiomas has been compared with a molecular genetic analysis of chromosome 22 in the same specimens. Major gangliosides were GM3 (II3NeuAc-LacCer) and/or GD3 [II3(NeuAc)2-LacCer]. In specimens with no or partial deletions of chromosome 22, the GM3 ganglioside predominated, and the mean value for GM3, 61% of total sialic acid, was around four times higher than that for GD3. A loss of chromosome 22, found in 56% of the specimens, was shown to be associated with an increase in the proportion of ganglioside GD3, with the ratio between mean values of GM3 and GD3 being approximately 1:1. Logistic regression revealed that the probability of predicting monosomy of chromosome 22 by the GD3 proportion was 66%.