枸杞多糖联合LAK／IL－2疗法对75例晚期肿瘤的疗效观察

用枸杞多糖（ＬｙｃｉｕｍＢａｒｂａｒｕｍＰｏｌｙｓａｃｃｈａｒｉｄｅｓ，ＬＢＰ）联合ＬＡＫ／ＩＬ－２疗法临床试验治疗７９例晚期肿瘤患者，其中７５例可评估病人资料分析提示，ＬＢＰ联合ＬＡＫ／ＩＬ－２疗法组疗效（４０．９％）显著优于ＬＡＫ／ＩＬ－２疗法组（１６．１％）。两种治疗方案对恶性黑色素瘤、肾癌、直结肠癌、肺癌、恶性胸水和鼻咽癌有一定的疗效。ＬＢＰ联合ＬＡＫ／ＩＬ－２治疗组的缓解持续时间显著长于ＬＡＫ／ＩＬ－２治疗组。ＬＢＰ联合ＬＡＫ／ＩＬ－２治疗组治疗前后外周血淋巴细胞（ＰＢＬ）的ＮＫ、ＬＡＫ活性增高程度均显著大于ＬＡＫ／ＩＬ－２治疗组，说明ＬＢＰ能够提高ＬＡＫ／ＩＬ－２疗法对晚期肿瘤的治疗效果。     

枸杞多糖联合LAK／IL—2疗法对75例晚期肿瘤的疗效观察

用枸杞多糖（ＬＢＰ）联合ＬＡＫ／ＩＬ－２疗法临床试验治疗７９例晚期肿瘤患者，其中７５例可评估病人资料分析提示，ＬＢＰ联合ＬＡＫ／ＩＬ－２疗法组疗效（４０．９％）显著优于ＬＡＫ／ＩＬ－２疗法组（１６．１％）。两种治疗方案对恶性黑色素瘤、肾癌、直结肠癌、肺癌、恶性胸水和鼻咽癌有一定的疗效。ＬＢＰ联合ＬＡＫ／ＩＬ－２治疗组的缓解持续时间显著长于ＬＡＫ／ＩＬ－２治疗组。ＬＢＰ联合ＬＡＫ／ＩＬ－２治疗组治疗     

LAK细胞对晚期肿瘤免疫治疗

观察胎脾、胸腺ＬＡＫ细胞治疗晚期肿瘤的疗效。方法从胎儿脾脏、胸腺制备ＬＡＫ细胞。ＬＡＫ细胞和ＩＬ┐２经外周静脉输注。治疗前后测患者ＮＫ活性。结果ＬＡＫ＋小剂量ＩＬ┐２治疗１４例，ＳＤ１２例，ＰＤ２例。ＬＡＫ＋中剂量ＩＬ┐２治疗５２例，ＣＲ６例，ＰＲ１４例，ＳＤ２８例，ＰＤ４例，有效率３８．４％。治疗后患者ＮＫ活性显著提高。结论ＬＡＫ细胞治疗效果依赖于ＩＬ┐２用量。静注疗效有限     

白介素－2的Ⅱ期临床试验报告

共１５９例各种类型的恶性肿瘤病人进入了Ⅱ期临床试验。２５例病人接受了白介素－２（ＩＬ－２）单独全身治疗（静脉或皮下注射）；６０例病人接受了ＩＬ－２＋ＬＡＫ细胞全身性治疗；４１例癌性胸水病人接受了ＩＬ－２胸腔内灌注；６例癌性腹水病人接受了ＩＬ－２腹腔灌注；２７例病人接受了ＩＬ－２瘤内注射。单用ＩＬ－２全身治疗的病人没有病例获得临床缓解，２３晚期肾癌接受了ＩＬ－２＋ＬＡＫ细胞治疗，５例获得部分缓解，有效率２２％：癌件胸水和腹水的有效率分别为６８％和６７％：ＩＬ－２瘤内注射的有效率为３０％。Ｔ４／Ｔ８比值、ＮＫ细胞活性和ＬＡＫ细胞活性在全身性ＩＬ－２治疗后均有显著升高，并有统计学意义。病人接受本试验所用的ＩＬ－剂量后的毒副反应主要为发热、畏寒或寒战、疲乏，全组病人均无发生严重低血压、液体潴留等毛细血管渗漏现象。     

CD3AK细胞和LAK细胞治疗晚期恶性肿瘤的临床和实验研究

将５１例晚期恶性肿瘤患者（男性２３例，女性２８例）分成两组，其中一组（３１例）以ＣＤ３ＭｃＡｂ（ＣＤ３单克隆抗体）和小剂量ＩＬ－２（５００ｕ／ｍｌ）共同诱导的ＣＤ３ＡＫ细胞治疗，另一组（２０例）输注大剂量ＩＬ－２（１０００ｕ／ｍｌ）诱导的常规ＬＡＫ细胞治疗，以探讨降低ＩＬ－２用量、提高杀伤细胞细胞毒活性的可能性。结果显示ＣＤ３ＡＫ组患者生活质量改善、症状缓解均优于ＬＡＫ组。ＣＤ３ＡＫ组ＰＲ＋ＭＲ率较ＬＡＫ组高２９．０％，Ｓ＋Ｐ率和死亡率分别较ＬＡＫ组低１２．４％和９．６％。同时比较了ＣＤ３ＡＫ细胞与ＬＡＫ细胞的体外增殖和细胞毒活性，结果表明ＣＤ３ＡＫ细胞增殖率高于ＬＡＫ细胞（Ｐ＜０．０１），靶细胞抑制率二者在０．０５水平无显著差异。提示ＣＤ３ＭｃＡｂ在刺激杀伤细胞活性，尤其在提高其增殖能力方面，具有显著的作用，ＣＤ３ＡＫ／ＩＬ－２能更有效地治疗晚期恶性肿瘤。     

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。     

人天然白介素－2治疗恶性肿瘤的Ⅱ期临床观察

目的评价人天然白介素－２（ＩＬ－２）治疗恶性肿瘤的效果。方法采用ＩＬ－２加淋巴因子激活的杀伤细胞（ＬＡＫ细胞）全身输注治疗１４例实体瘤（恶性黑素瘤４例，肾癌２例，原发性肝癌和肠癌各３例，恶性淋巴瘤和恶性腮腺混合瘤各１例）和胸腹腔内注入治疗１０例癌性胸腹水（胃癌４例，卵巢癌２例，肠癌、乳腺癌、胰腺癌和肺癌各１例）。结果实体瘤缓解率为２１．４％（３／１４），胸腹水缓解率为７０％（７／１０）。不良反应有发热（＜３９℃）３例；恶心１例；肾功能障碍１例，停药后恢复正常。结论人天然ＩＬ－２具有一定的抗肿瘤作用。     

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。     

低剂量IL-2诱导的人胚胎脾脏CD_3AK细胞治疗晚期恶性肿瘤效果及实验研究

用ＣＤ３ＭｃＡｂ和低剂量ＩＬ－２（５００Ｕ／ｍｌ）诱导的人胎脾ＣＤ３ＡＫ细胞治疗４３例晚期恶性肿瘤患者，取得疗效。经２～８疗程治疗，多数患者症状缓解，生活质量改善，ＰＲ＋ＭＲ１８例（４１．９％），Ｓ＋Ｐ２５例（５８．１％），死亡９例（２０．９％）。全组无严重毒副反应发生。同时比较ＣＤ３ＡＫ细胞和常规ＬＡＫ细胞体外增殖及其杀伤活性，表明前者１４４ｈ增殖力高于后者（Ｐ＜０．０１），靶细胞抑制率二者无显著差异（Ｐ＞０．０５）。初步表明ＣＤ３ＡＫ／ＩＬ－２疗法效果肯定，毒副作用小，可能成为继ＬＡＫ／ＩＬ－２之后更为有效的肿瘤辅助治疗。     

LICC细胞和LAK细胞治疗晚期恶性肿瘤的疗效观察

采用淋巴因子诱导的细胞毒细胞（ＬＩＣＣ）和ＩＬ—２／ＬＡＫ细胞治疗３２例晚期恶性肿瘤患者，ＬＩＣＣ治疗２０例，ＩＬ—２／ＬＡＫ治疗１２例，结果发现６８．８％（２２／３２）卡氏得分上升，多数患者癌性症状减轻，生活质量提高，以ＬＩＣＣ组优于ＬＡＫ组，ＣＲ＋ＰＲ＋ＭＲ率，ＬＩＣＣ为４０．０％（１２／２０），ＬＡＫ组为１６．７％（２／１２）。作者认为过继免疫作为一种癌症辅助治疗方法应予肯定；ＬＩＣＣ治疗安全、副反应小，抗瘤谱广，费用低，疗效优于ＩＬ—２／ＬＡＫ，值得扩大应用性研究。     

Locoregional adoptive immunotherapy using LAK cells and IL-2 against liver metastases from digestive tract cancer

We investigated the clinical efficacy of locoregional and systemic adoptive immunotherapy (AIT) with or without interleukin-2 (IL-2) against solid metastatic lesions from digestive tract cancer. Eighteen patients, who were treated with more than 10(10) lymphokine-activated killer (LAK) cells, were enrolled in this study. Seven of the 18 patients received hepatic arterial infusion (HAI) of LAK cells with or without IL-2 against metastatic liver tumors (locoregional therapy group). The remaining 11 patients received systemic transfer of LAK cells with IL-2 against metastatic lesions located in organs other than the liver (systemic therapy group). Three of 7 locoregional therapy group patients showed clinically significant tumor regressions that were evaluated as being equivalent to partial response (PR). Two of the 11 systemic therapy group patients showed significant tumor regressions, but this response rate was much lower than that of the locoregional therapy group. The 2 effective cases in the systemic therapy group were esophageal cancer patients. Locoregional AIT with or without IL-2 against liver metastases from digestive tract cancer could be an effective therapeutic modality in some patients who are refractory to conventional therapies (e.g., chemotherapy and radiotherapy). It is necessary to find a new way to augment the anti-tumor effect of this therapy in combination with prior or concomitant chemotherapy.     

胎儿LAK细胞治疗中晚期肝癌的疗效观察

自1989年1月至1991年10月,我们应用6~7个月龄的胎儿脾脏细胞和白细胞介素-2(IL-2)共培养3天后制备成胎儿LAK细胞,静脉输注或肝动脉插管灌注治疗中晚期肝癌18例.结果疼痛减轻16例,占88.9%;食欲增加14例,占77%;临床完全缓解2例,占11%;部分缓解14例,占77%;总有效率占88.9%(16/18).而且LAK细胞治疗后患者周围血OKT_4比率升高,OKT_8比率下降,说明治疗后患者免疫功能有一定改善.结果提示:①胎儿脾脏含有丰富的LAK前身细胞;②胎儿LAK细胞治疗中晚期肝癌有明显疗效.     

Inhibition by fibrin coagulation of lung cancer cell destruction by human interleukin-2-activated killer cells.

We examined the effect of fibrin coagulation on tumor cytotoxicity mediated by human lymphokine (IL-2)-activated killer (LAK) cells. LAK cells were induced from peripheral blood mononuclear cells (MNC) by culture with recombinant IL-2 for 4 or 5 days, and LAK cell-mediated cytotoxicity against tumor cells was assessed by 51Cr release assay in the presence or absence of plasma from normal subjects and lung cancer patients. Plasma did not affect the phase of induction of LAK activity by IL-2, but dose-dependently inhibited the effector phase of LAK cell-mediated cytotoxicity against Daudi cells. Similar inhibition of LAK cell-mediated cytotoxicity was observed on pretreatment of Daudi cells and human lung cancer cell lines with human fibrinogen plus thrombin. A parallel relationship was found between the amount of fibrinogen in plasma of lung cancer patients and inhibition of LAK cytotoxicity. This inhibition was reduced by addition of anticoagulants (heparin or argatroban). These findings suggest that fibrin coagulation on tumor cells protects them from LAK cell-mediated tumor cytotoxicity in malignant lesions and that a combination of an anticoagulant drug and IL-2/LAK therapy may be effective for treatment of lung cancer patients.     

Adoptive immunotherapy of human cancer using low-dose recombinant interleukin 2 and lymphokine-activated killer cells

The adoptive transfer of recombinant-methionyl human interleukin 2 (rIL-2)-activated autologous peripheral blood mononuclear lymphokine-activated killer (LAK) cells to cancer patients is being evaluated as an alternative to conventional cancer therapy. We have independently developed an alternative regimen to previously reported adoptive immunotherapy protocols using rIL-2 and LAK cells which features the prolonged administration of low-dose rIL-2 (30,000 units/kg) and an automated, entirely enclosed system of peripheral blood cell procurement, culture, harvest, and reinfusion of activated cells. The cell culture system was tested with a murine tumor model in which LAK cells generated in plastic culture bags were reinfused into tumor-bearing mice. Tumor regression was as effective with cells activated in the bags as in conventional culture flasks. Twenty-eight cancer patients were treated for 5 consecutive days with low-dose rIL-2, followed by leukapheresis, infusion of LAK cells, and prolonged IL-2 administration. At least 50% tumor regression was observed in 46% of all patients treated. These data imply that human peripheral blood mononuclear cells retain fully their capacity for rIL-2-induced activation and effector cell function under this alternative approach, and further, that a low-dose rIL-2 regimen with markedly reduced toxicities can be as effective as high-dose rIL-2 regimens if low-dose rIL-2 is given for a prolonged period of time following LAK cell infusion.     

Interleukin-2-inducible Killer Activity and Its Regulation by Blood Monocytes from Autologous Lymphocytes of Lung Cancer Patients

The ability of blood lymphocytes of newly diagnosed lung cancer patients to respond to interleukin 2 (IL-2) to become IL-2-activated killer (LAK) cells and its regulation by autologous monocytes were examined. LAK activity was measured by ³¹Cr release assay. The abilities of lymphocytes among blood mononuclear cells (MNC) of subjects of different ages without malignancies to generate LAK activity against NK-cell resistant Daudi cells and lung adenocarcinoma (PC-9) cells were very similar. The LAK activity of blood MNC of lung cancer patients was also nearly the same as that of blood MNC of control subjects. There was no significant difference in IL-2-inducible LAK activity between MNC of patients with small cell lung cancer (SCLC) and those of patients with non-SCLC. Monocytes and lymphocytes were separated from blood MNC on a one-step Percoll gradient. Monocytes of lung cancer patients were found to augment in vitro induction of LAK activity by IL-2 of autologous blood lymphocytes. In contrast, endotoxin-stimulated monocytes suppressed LAK induction of autologous lymphocytes of cancer patients. These findings suggest that administration of IL-2 and LAK cells induced in vitro may be of benefit in the treatment of lung cancer.     

Inhibition by Fibrin Coagulation of Lung Cancer Cell Destruction by Human Interleukin-2-activated Killer Cells

We examined the effect of fibrin coagulation on tumor cytotoxicity mediated by human lymphokine (IL-2)-activated killer (LAK) cells. LAK cells were induced from peripheral blood mononuclear cells (MNC) by culture with recombinant IL-2 for 4 or 5 days, and LAK cell-mediated cytotoxicity against tumor cells was assessed by ⁵¹Cr release assay in the presence or absence of plasma from normal subjects and lung cancer patients. Plasma did not affect the phase of induction of LAK activity by IL-2, but dose-dependently inhibited the effector phase of LAK cell-mediated cytotoxicity against Daudi cells. Similar inhibition of LAK cell-mediated cytotoxicity was observed on pretreatment of Daudi cells and human lung cancer cell lines with human fibrinogen plus thrombin. A parallel relationship was found between the amount of fibrinogen in plasma of lung cancer patients and inhibition of LAK cytotoxicity. This inhibition was reduced by addition of anticoagulants (heparin or argatroban). These findings suggest that fibrin coagulation on tumor cells protects them from LAK cell-mediated tumor cytotoxicity in malignant lesions and that a combination of an anticoagulant drug and IL-2/LAK therapy may be effective for treatment of lung cancer patients.     

Interleukin-2-inducible killer activity and its regulation by blood monocytes from autologous lymphocytes of lung cancer patients.

The ability of blood lymphocytes of newly diagnosed lung cancer patients to respond to interleukin 2 (IL-2) to become IL-2-activated killer (LAK) cells and its regulation by autologous monocytes were examined. LAK activity was measured by 51Cr release assay. The abilities of lymphocytes among blood mononuclear cells (MNC) of subjects of different ages without malignancies to generate LAK activity against NK-cell resistant Daudi cells and lung adenocarcinoma (PC-9) cells were very similar. The LAK activity of blood MNC of lung cancer patients was also nearly the same as that of blood MNC of control subjects. There was no significant difference in IL-2-inducible LAK activity between MNC of patients with small cell lung cancer (SCLC) and those of patients with non-SCLC. Monocytes and lymphocytes were separated from blood MNC on a one-step Percoll gradient. Monocytes of lung cancer patients were found to augment in vitro induction of LAK activity by IL-2 of autologous blood lymphocytes. In contrast, endotoxin-stimulated monocytes suppressed LAK induction of autologous lymphocytes of cancer patients. These findings suggest that administration of IL-2 and LAK cells induced in vitro may be of benefit in the treatment of lung cancer.     

对逆转录病毒为载体基因治疗的两点研究

用健康人外周血淋巴细胞,经羧甲基茯苓多糖促诱生剂制备而成的高效价临床级IL-2可用于肌注、静滴或动脉输注,IL-2与LAK细胞和化疗结合治疗晚期肿瘤44例,其中CR PR13例(29.3％),CR PR MR 22例(50％),SR16例,无效死亡6例,总有效率(CR PR MR SR)为86.4％。IL-2与~(60)Co放射综合治疗肿瘤37例,CR为51.4％,PR为46.8％,SR者例(2.7％),总有效率为97.3％,一年生存率为86.2％。应用CMP促诱生的低剂量IL-2和低剂量放/化综合治疗16例晚期癌症,CR占37.5％,总有效率(CR PR)为93.8％,一年生存率为87.5％,结果表明:该低剂量IL-2/LAK继免疫化疗与放/化疗综合治疗晚期癌症是一种有效的治疗手段。