局部应用IL—2联合治疗口腔癌的临床疗效

目的 探讨局部应用ＩＬ－２联合化疗治疗口腔鳞癌的临床疗效。方法 对２４例口腔鳞癌患者，分别行单纯化疗、化疗联合瘤体局部应用ＩＬ－２，比较给药前后肿瘤的大小变化级病理表现。结果 局部应用ＩＬ－２联合化疗治疗口腔鳞癌１４例，其中ＣＲ２例，ＰＲ８例，ＭＲ４例，有效率为７１．４％，而单纯化疗的１０例患者，ＰＲ５例，ＭＲ３例，ＮＲ２例，有效率为５０％．病理切片显示：ＩＬ－２联合化疗组大片癌细胞崩解、坏死，间     

小剂量IL-2和IFNα与TNFα联合治疗恶性肿瘤的免疫学与临床研究

目的:研究小剂量细胞因子在恶性肿瘤免疫治疗中的意义。方法:全身应用小剂量重组干扰素(ＩＦＮα２ｂ)、白细胞介素－２(ＩＬ－２)和肿瘤坏死因子(α－ＴＮＦ)联合治疗多种恶性肿瘤６０例。应用ＡＰＡＡＰ法和免疫单向扩散法(ＲＩＤ)分析了治疗前后患者外周血中Ｔ、Ｂ淋巳细胞、ＮＫ细胞、免疫球蛋白(Ｉｇ)和补体Ｃ３活性。结果:治疗１个疗程后外周血中ＣＤ４＋的Ｔ淋巴细胞和ＣＤ２３＋的Ｂ淋巴细胞显著的高于治疗前水平(Ｐ＜０．０５);ＣＤ４＋/ＣＤ８＋比值也明显增高(Ｐ＜０．０１)。免疫球蛋白(ＩｇＭ)活性亦显著的高于治疗前水平(Ｐ＜０．０５)。ＫＰＳ积分较治疗前明显增高(Ｐ＜０．００１)。治疗后细胞因子加化疗组的ＫＰＳ积分平均增高２８．５分(Ｐ＜０．００１);ＣＲ ２６例(６５．０%);ＰＲ １１例(２７．５%),总有效率８２．５%。单纯细胞因子治疗组的ＫＰＳ积分平均增高２３分(Ｐ＜０．００１);ＰＲ １３例(６５．０%),总有效率６５．０%。结论:本方案可以显著的提高多种恶性肿瘤患者的细胞免疫和体液免疫。有可能提高肿瘤的化疗效果和患者的生存质量,延长生存期。     

LAK细胞和IL－2联合化疗治疗晚期肺癌的近期疗效观察

ＬＡＫ细胞和ＩＬ－２是目前常用的肿瘤生物制剂。自１９９２年以来，对１８例晚期肺癌，男１５例，女３例，年龄２９～６４岁，进行ＬＡＫ细胞和重组ＩＬ－２联合化疗治疗。选择胎脾、胸腺的淋巴细胞做前体细胞，体外用重组ＩＬ－２诱导制备ＬＡＫ细胞，每输３次ＬＡＫ细胞为一疗程、每次输入细胞数０．５～１．０×１０９。化疗采用环磷酰胺，长春新碱，阿霉素为主的方案。治疗结果：完全缓解（ＣＲ）５例，部分缓解（ＰＲ）７例，无效（ＮＲ）３例，病情平稳３例，有效率ＣＲ＋ＰＲ达６６％。采用本疗法后病人精神及饮食好转，能有效缓解胸痛、减轻病人痛苦。提示ＬＡＫ细胞和重组ＩＬ－２联合化疗对晚期肺癌是一种可行的有效治疗，但在临床应用中要注意毒性反应。     

食管、贲门癌围手术期细胞免疫功能动态变化的临床研究

目的：探讨食管、贲门癌全身、局部细胞免疫功能状态及生物治疗的可行性。方法：采用免疫组化观察分析５０例食管、贲门癌局部肿瘤浸润淋巴细胞（ＴＩＬ）、肿瘤相关性巨噬细胞（ＴＡＭ）的分布特征，采用ＥＬＩＳＡ法和硝酸还原酶法分别地体内可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）表达和一氧化氮（ＮＯ）生成水平进行动态检测。结果：１）癌周物浸润密度大于癌果间质；２）２术前血清ｓＩＬ－２Ｒ水平高于正常对照组，根治术后ｓ     

恶性淋巴瘤患者脑脊液可溶性白细胞介素2受体水平的动态观察及其临床意义

用双抗体夹心ＥＬＩＳＡ方法动态监测４６例恶性淋巴瘤（ＭＬ）患者脑脊液（ＣＳＦ）中可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）水平变化。发现ＭＬ患者脑脊液中ｓＩＬ－２Ｒ比正常人显著升高（Ｐ＜０．００１），且６例有中枢神经系统（ＣＮＳ）浸润者ｓＩＬ－２Ｒ与无ＣＮＳ浸润者相比有显著性差异（Ｐ＜０．０１）；而治疗达ＣＲ或ＰＲ后ｓＩＬ－２Ｒ显著降低（Ｐ＜０．０５），与正常人者相比Ｐ＞０．０５，脑脊液ｓＩＬ－２Ｒ水平与血清中ｓＩＬ－２Ｒ水平无显著相关性。认为动态监测ＭＬ患者脑脊液ｓＩＬ－２Ｒ水平有助于估价病变严重程度、ＣＮＳ有无浸润及疗效评定     

急性白血病患者血清可溶性白细胞介素2受体测定及其临床意义

测定９８例急性白血病（ＡＬ）患者血清可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）水平，各型ＡＬ患者ｓＩＬ－２Ｒ均明显升高，且ＡＬＬ〉Ｍ５〉Ｍ２〉Ｍ３。ｓＩＬ－２Ｒ水平与骨髓中原始细胞数、外周白血细胞数、外周成熟淋巴细胞绝对值无关。动态观察发现化疗后不能获得完全缓解（ＣＲ）患者治疗前ｓＩＬ－２Ｒ明显高于获得ＣＲ患者。各型ＡＬ患者化疗ＣＲ后，ｓＩＬ－２Ｒ水平较治疗前均明显下降，除急性淋巴细胞白血病外，Ｍ２、     

恶性淋巴瘤患者脑脊液可溶性白细胞介素2受体水平的动态观？…

用双抗体夹心ＥＬＩＳＡ方法动态监测４６例恶性淋巴瘤（ＭＬ）患者脑脊液（ＣＳＦ）中可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）水平变化。发现ＭＬ患者脑脊液中ｓＩＬ－２Ｒ比正常人显著升高（Ｐ〈０．００１），且６例有中枢神经系统（ＣＮＳ）浸润者ｓＩＬ－２Ｒ与无ＣＮＳ浸润者相比有显著性差异（Ｐ〈０．０１）；而治疗达ＣＲ或ＰＲ后ｓＩＬ－２Ｒ显著降低（Ｐ〈０．０５），与正常人者相比Ｐ〉０．０５，脑脊液ｓＩＬ－２Ｒ水     

33例头颈部恶性肿瘤患者局部过继免疫治疗的疗效观察

目的评价ＩＬ－２／ＬＡＫ细胞局部过继免疫疗法在头颈部恶性肿瘤治疗中的疗效。方法对３３例头颈部恶性肿瘤患者进行局部过继免疫治疗,采用ＩＬ－２每日１０～２０万单位局部注射,共１０天;于ＩＬ－２治疗的第４～８天同时于局部注射ＬＡＫ细胞１．０×１０８～５．０×１０８／ｄ。结果完全缓解１例,部分缓解６例,好转２０例,稳定６例,治疗总缓解率２１．２％,总有效率８１．８％。治疗后１,２,３年生存率分别为９６．３％、８３．３％、和７５．０％。组织病理学检查证实免疫治疗后肿瘤局部大量ＣＤ３、ＣＤ４阳性Ｔ淋巴细胞浸润。治疗过程中未见严重的毒副作用。结论局部应用ＬＡＫ细胞与ＩＬ－２治疗头颈部恶性肿瘤疗效明显,方法安全。     

术前使用国产重组白细胞介素2对大肠癌患者全身及局部细胞免疫功能的影响

本研究设计了对大肠癌患者接受二周ｒＩＬ－２处理并配合手术的治疗方案，以克服ＩＬ－２在临床应用中需长期用药，用药量大，有一定毒性及价格昂贵的问题。研究中着重观察了术前使用ＩＬ－２对大肠癌患者全身及肿瘤局部细胞免疫功能的影响。结果发现：（１）大肠癌癌周浸润淋巴细胞（ＴＩＬ）总数与大肠良性疾患无明显区别，但ＣＤ４／ＣＤ８比值、ＮＫ、Ｍφ以及ＩＬ－２Ｒ＾＋细胞数明显低于大肠良性疾患（Ｐ〈０．０１），提示大     

局部晚期乳腺癌术前动脉内灌注化疗的临床研究

本文报告１５例局部晚期乳腺癌采用动脉内灌注化疗作为术前诱导治疗，其中１例ＣＲ，１１例ＰＲ，３例ＭＲ，有效率为８０％（１２／１５）。在６例曾接受ＣＭＦ或ＦＡＣ方案全身化疗无效者中，１例ＣＲ，４例ＰＲ，１例ＭＲ，有效率８３％（５／６）。灌注化疗后，全部病例均进行手术，放疗，全身化疗等综合治疗。术后满３年的８例中，有２例死于远处转移，６例健在，未见有局部复发者。作者认为对局部晚期乳腺癌，灌注化疗能有效地为手术等综合治疗提供良好的条件。全身化疗无效者，动脉内灌注化疗仍有可能取得较好的效果     

CPT-11 hepatic arterial injection plus oral UFT administration for liver metastasis of rectal cancer--report of two cases

The first patient was a 51-year-old male who had 5-fluorouracil-resistant recurrent rectal cancer with multiple liver metastases. He was given our new combination chemotherapy consisting of hepatic arterial injection of CPT-11 (20 mg/body) on day 1 and day 2 and oral administration of UFT (300 mg/day) on days 3 to 6 of a 7 day cycle starting in January 2001. Six weeks after the beginning of chemotherapy, the liver metastatic lesions were reduced. He is now living with outpatient treatment. The second patient was a 76-year-old male who had initial recurrent rectal cancer with multiple liver metastases. Thirty-two weeks after the same chemotherapy, the metastatic lesions had completely disappeared. Twelve months have passed since this chemotherapy, and we have not found any recurrent tumor. While significant antitumor effects were observed, there were few adverse events in either patient. These results suggest that combined chemotherapy of CPT-11 by hepatic arterial injection and oral administration of UFT is an effective treatment for liver metastases of rectal cancer.     

重组人p53腺病毒联合治疗晚期恶性肿瘤的临床观察

目的：探讨重组人p53腺病毒注射液（rAd-p53）治疗恶性肿瘤的疗效及安全性。方法：对67例晚期无法行手术切除的恶性肿瘤患者,或术后肿瘤转移、无法再手术的患者,采用瘤内注射、血管介入和静脉滴注rAd-p53联合化疗和放疗,至少1个疗程以上,通过临床观察、KPS评分、CT或MRI检查以及随访,评价rAd-p53联合化、放疗的临床疗效。结果：67例患者治疗有效率为47.8%,疾病控制率为89.6%,其中CR患者4例,分别为卵巢癌1例,皮肤癌1例,鼻咽癌2例。rAd-p53联合放疗41例,联合化疗26例,有效率分别为56.1%和34.6%（P〈0.05）,疾病控制率分别为95.1%和80.8%（P〈0.05）。全组中位生存时间为60个月（6～117个月）;联合治疗后,全组中位生存时间为24个月（2～34个月）。不良反应主要为自限性发热,另有个别胃肠道反应及肌肉酸痛。结论：rAd-p53对多种恶性肿瘤具有一定疗效,临床应用安全;局部给药联合放疗可能比联合化疗更能提高肿瘤的局控率。     

EFFICIENT ACTIVATION OF ANTITUMOR IMMUNITY BY IL-6 GENE-MODIFIED LEUKEMIA VACCINE IN COMBINATION WITH LOW DOSE CYCLOPHOSPHAMIDE AND LOW DOSEIL-2

ＰｒｏｄｕｃｅｄＩＬ６ｉｓａｃｙｔｏｋｉｎｅｗｉｔｈｍｕｌｔｉｆｕｎｃｔｉｏｎＩｔｉｓｐｏｒｄｕｃｅｄｂｙａｎｕｍｂｅｒｏｆｃｅｌｔｙｐｅｓａｎｄｉｎｖｏｌｖｅｄｉｎｔｈｅｒｅｓｐｏｎｓｅｓｏｆｉｍｍｕｎｅｒｅｓｐｏｎｓｅ，ｈｅｍａｔｏｐｏｉｅｓ...     

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells

We studied interleukin (IL)-12 gene therapy using a gene gun as a new autologous vaccination strategy for cancer. In the first experiment, BALB/c mice were inoculated with syngeneic murine renal cancer cells (Renca) intradermally in the abdomen. This was followed by an injection of IL-12 expression plasmid using the gene gun. About 40% of the mice exhibited rejection of the tumor after the treatment and these mice also acquired immunological resistance against a secondary challenge with Renca cells. Based on these results, we examined whether antitumor activity can be potentiated when mice undergo combination treatment with intradermal inoculation of irradiated Renca cells and transfection with IL-12 gene. Inoculation of irradiated Renca cells alone was partially effective in inducing antitumor immunity, whereas the combined treatment remarkably intensified this effect. Moreover, this combined treatment inhibited tumor establishment and enhanced survival of the mice with tumor infiltration by CD4(+) and CD8(+) T cells, even when the treatment was started after tumor-implantation at a distant site. This antitumor effect was antigen specific and we confirmed the induction of antitumor cytotoxic T cells by this treatment. These results show that local cutaneous transfer of IL-12 expression plasmid using gene gun technology enhances systemic and specific antitumor immunity primed by irradiated tumor cells.     

Therapeutic effect of multimodal therapy, such as cryosurgery, locoregional immunotherapy and systemic chemotherapy against far advanced breast cancer]

A total of 6 breast cancer patients, 5 with local recurrent tumors on their anterior chest wall and 1 with far advanced primary breast tumor, underwent multimodal therapy in which cryosurgery was performed in combination with local injection of the non-specific immunopotentiator OK-432. This multimodal therapy was repeated as many times as possible. In addition, 3 patients whose general condition was relatively good were treated with mild chemotherapy. In every patient who underwent cryosurgery combined with locoregional immunotherapy, eradication or reduction of tumor was observed for several months. Of 3 patients who underwent cryosurgery, locoregional immunotherapy and systemic chemotherapy, the tumor burden decreased markedly in 2 patients and rapid tumor growth was suppressed in 1 patient, even though the diameter of tumor was over 5 cm in all cases. There were no side effects caused by either cryosurgery or locoregional immunotherapy. Little toxicity was observed throughout the mild chemotherapy. These results indicated that cryosurgery in combination with local injection of OK-432 should be a feasible modality against unresectable breast cancer on the chest wall, and that this therapeutic effect might be augmented by mild chemotherapy.     

Immunomodulation by adriamycin - effect on the production of cytotoxic and inflammatory antitumor immune-responses

We have recently demonstrated in a mouse renal adenocarcinoma tumor system that the antitumor effect of adriamycin (ADM) in combination with interleukin-2 (IL2) is superior to treatment with either ADM or IL2 alone. Based on this observation we postulated that modulation of host's immune competence by ADM and/or IL2 may be partly responsible for the antitumor effects of the combination treatment. Indeed, pretreatment with ADM was found to potentiate the production of both cytotoxic and non-cytotoxic immune responses. A single dose of ADM significantly increased the number of nucleated cells in the spleen in a time related fashion. A small but selective increase in CD4+ cells without an apparent change in CD8+ subset of T cells was observed following treatment with ADM. ADM potentiated augmentation of NK activity by IL2, but had no effect on the production of lymphokine activated killer (LAK) cells by IL2. In contrast, treatment with a combination of ADM and IL2 resulted in increased LAK activity and the frequency of LAK-precursors in the spleen. ADM also enhanced the development of tumor specific inflammatory delayed hypersensitivity (DH) response. Mice expressing tumor specific DH were resistant to rechallenge with viable tumor cells and their spleen cells inhibited the tumor growth in a local adoptive transfer assay. Thus, antitumor effects of combined ADM/IL2 treatment may in part involve augmented production of cytotoxic and T cell-mediated inflammatory antitumor immune responses.     

Anti‐VEGF antibody enhances the antitumor effect of CD40

As its central immunomodulatory effects, CD40 induces interleukin (IL)‐12‐dependent antitumor immune responses; as its local protumor effects, CD40 induces the expression of vascular endothelial growth factor (VEGF) that promotes tumor angiogenesis and growth. Therefore, using a previously established tumor model in mouse, we examined if the antitumor functions of CD40 are self‐limited by VEGF induction. We observed that as the tumor mass grew during day 6 to day 18, VEGF expression in the tumor peaked with concomitant decrease in expressions of CD40 and IL‐12 but not of IL‐10. Among the angiogenic factors, VEGF‐B, VEGFR‐1, VEGFR‐2, angiopoietin‐1 and Tie2 expressions decreased, whereas the expressions of angiopoietin‐2 and angiopoietin‐3 increased with tumor growth. As significant changes in the expressions of these factors were observed on day 6, we treated the tumor‐bearing mice with the agonistic anti‐CD40 antibody or neutralizing anti‐VEGF antibody—alone or in combination—from the fifth day after the injection of tumor cells. The anti‐VEGF antibody significantly enhanced the antitumor effects of the anti‐CD40 antibody, as observed through increased survival of the mice, accompanied by reduced angiogenesis and angiopoietin‐2 expression but higher T‐cell proliferation in response to tumor antigens, increased interferon‐γ production and tumor cell cytotoxicity and higher levels of tumor antigen‐specific serum IgM, IgG1 and IgG2a, indicating B‐cell activation. Thus, our data show for the first time that the combined treatment with an agonistic anti‐CD40 antibody and a neutralizing anti‐VEGF antibody, which increases antitumor immune response or reduces local angiogenesis, respectively, is a novel antitumor strategy.     

Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo

We investigated the in vivo antitumor effects of intratumoral (i.t.) administration of dendritic cells (DC) after low-dose chemotherapy using cisplatin + 5-FU. Combination of i.t. injection of DC and systemic chemotherapy induced complete rejection of the treated tumor, MC38 murine adenocarcinoma. Furthermore, the antitumor effects were also observed on a distant tumor inoculated in the contralateral flank of the animal. When 10x the number of tumor cells were inoculated, the antitumor effect of the combination of DC after chemotherapy was also confirmed and in comparison to that of DC or chemotherapy alone, thereafter contributed to a greater prolongation of survival. To analyze the mechanisms of the systemic antitumor effect generated in this system, we assessed the cytolytic activity against inoculated tumors. The cytolytic activity of effector cells from treated animals was shown to be tumor-specific and was mainly CD8 and MHC Class-I (p < 0.01) restricted. CD4 and MHC Class-II treatment marginally inhibited the cytolytic activity but not significantly (p = 0.07, 0.08 respectively). The cytolysis of effector cells was enhanced more significantly by the treatment of both DC and chemotherapy, than that of either DC or chemotherapy alone. Our study suggests that the strategy of i.t. injection of DC after low-dose chemotherapy could be a powerful weapon to treat patients with cancer in the clinical settings.     

DC-CIK联合化疗治疗消化道肿瘤临床疗效分析

  目的   分析比较DC-CIK联合化疗治疗胃肠道肿瘤与疗效相关的参数,评估以DC-CIK为基础免疫治疗胃肠道肿瘤的有效性和安全性。   方法   选取2008年10月至2011年10月山西省肿瘤医院生物治疗科58例DC-CIK细胞治疗联合化疗的进展期胃肠道肿瘤患者,同期临床特点相近的病例68例作为对照组接受单纯化疗,比较两组患者治疗后患者细胞免疫功能、近期疗效、生存质量等,并观察DC-CIK细胞治疗的安全性。   结果   DC-CIK联合治疗组患者CD8+、NKT细胞治疗后细胞百分比明显提高,与对照组相比CD3+、CD8+、NKT细胞百分比均提高,差异有统计学意义（P < 0.05）;Th1/Th2细胞胞内细胞因子同治疗前和同期对照组治疗后相比较,Th1细胞胞内细胞因子IFN-γ、IL-2、TNF-α表达升高,差异有统计学意义（P < 0.05）;两组患者近期疗效观察,DC-CIK联合治疗组DCR 75.9 %,与对照组（58.8%）相比较有所提高（P < 0.05）;DC-CIK联合治疗组患者生存质量较对照组有不同程度的提高。   结论   与单纯化疗相比,以DC-CIK为基础的过继性细胞免疫治疗安全、有效,可提高缓解率,改善患者生存质量。      

Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2'-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice.

PURPOSE: Recent findings indicating that many genes related to cancer development are silenced by an aberrant DNA methylation suggest that inhibitors of this process may be effective cancer therapeutics. In this study we investigated the efficacy of low-dose 5-aza-2'-deoxycitydine (DAC), a methylation inhibitor, with interleukin (IL) 12, one of the most potent cytokines with antitumor activity. Experimental Design: Mice inoculated with L1210 leukemia cells or with B16F10 melanoma cells were treated with 7 daily injections of low-dose DAC (0.2 mg/kg) and/or 7 daily doses of IL-12 (100 ng/dose). Scid/scid mice as well as monoclonal antibodies against CD4, CD8, and NK1.1 were used to investigate the mechanisms of the antitumor effects of the combination treatment. The activity of murine lymphocytes was measured with enzyme-linked immunospot and (51)Cr release assays. RESULTS: Treatment with DAC or IL-12 given alone produced moderate antitumor effects. In both tumor models combined treatment resulted in potentiated antitumor effects and produced 70% long-term survivors among mice inoculated with L1210 cells. The antitumor efficacy of combined treatment was abrogated in scid/scid mice, and after depletion of CD4(+) and CD8(+) T cells. Mice inoculated with B16F10 melanoma cells had significantly delayed tumor growth after combined treatment with DAC and IL-12. Strong antitumor effect correlated with a significant activation of lymph node-derived CD8(+) and CD4(+) cells. Transient neutropenia was observed in mice under treatment of DAC alone, but remarkably this effect was not potentiated by IL-12. CONCLUSIONS: This study provides the first evidence that antitumor effects of DAC can be strongly potentiated by IL-12 and could be beneficial in an effective low-dose-based antitumor therapy.