Temsirolimus治疗晚期肾细胞癌一例

患者女,43岁,2004年11月23日行右肾癌手术并经病理证实为肾混合细胞癌.2005年11月5日行正电子发射计算机断层扫描仪(PET-CT)检查发现双肺转移,相继经过干扰素联合白细胞介素-2、HLA部分相合异基因单个核细胞输注和索拉非尼治疗.     

Temslrolimus治疗晚期肾细胞癌一例

患者 女,43岁,2004年11月23日行右肾癌手术并经病理证实为肾混合细胞癌。2005年11月5日行正电子发射计算机断层扫描仪（PET-CT）检查发现双肺转移,相继经过干扰素联合白细胞介素-2、HIA部分相合异基因单个核细胞输注和索拉非尼治疗。2007年10月14日,在索拉非尼治疗中肿瘤进展,PET—CT提示双肺、肝、骨、腹腔淋巴结、纵隔淋巴结多发转移,并发右肺感染、右侧胸腔积液。患者有明显的咳嗽、咳痰、咯血、胸闷、气促和骨痛症状,     

CD3单克隆抗体激活细胞用于中晚期癌肿临床治疗初步观察

本文通过对45例中、晚期癌肿瘤患者试用CD3单抗激活细胞输注治疗，初步观察了该项肿瘤继承性免疫治疗的临床应用效果；探讨并分析了该治疗的临床量效关系及治疗后机体免疫状况变化。患者中包括肝癌、肺癌、胃肠道癌等多类肿瘤。效应细胞制备，采用正常献血员外周血经分离所得单个核细胞．加用一定量CD3单克隆抗体（辅以少量IL-2）孵育而成，     

化疗联合亲缘HLA不全相合造血干细胞输注治疗血液系统恶性疾病

 目的　明确化疗联合亲缘HLA不全相合造血干细胞输注治疗血液系统恶性疾病的疗效及安全性。 方法　9例血液系统恶性疾病患者化疗后36 h回输亲缘HLA不全相合造血干细胞,评价其疗效、造血恢复时间及并发症。结果　9例患者包括4例急性髓系白血病、1例急性B淋巴细胞白血病、2例多发性骨髓瘤、1例霍奇金淋巴瘤、1例弥漫大B细胞淋巴瘤;年龄29～67岁;共接受治疗19例（次）,每个疗程平均回输单个核细胞计数（3.12±1.29）×108／kg,CD+34 细胞计数（1.71±1.00）×106／kg;CD+3 细胞计数（2.13±0.99）×108／kg。完全缓解4例,部分缓解1例,疾病进展4例。随访2～14个月,生存4例,死亡5例。9例患者输注亲缘HLA不全相合造血干细胞过程顺利,无病例检测到供者嵌合状态,未出现移植物抗宿主病。结论　化疗联合亲缘HLA不全相合造血干细胞输注治疗血液系统恶性疾病操作简单且经济,供者来源丰富且易获得,具有良好的安全性和耐受性。     

异基因干细胞移植治疗肾细胞癌的研究进展

异基因干细胞移植(allogeneic stem cell transplantation,AlloHSCT)对肾细胞癌(renal cell carcinoma, RCC),尤其是转移性肾细胞癌(metastatic renal cell carcinoma, mRCC ) 的抗肿瘤效应已有许多研究证实。移植预处理方案有清髓性和非清髓性两种,清髓性预处理需要大剂量的     

干细胞移植治疗骨髓增生异常综合征13例

 目的　探讨干细胞移植（HSCT）在骨髓增生异常综合征（MDS）治疗中的疗效以及预处理方式的选择。方法　对13例MDS患者行异基因造血干细胞移植 （allo-HSCT）（包括HLA配型全相合10例、半相合2例、脐血移植1例）。输注单个核细胞（MNC） 6.92（2.65～21.33）×108／kg,CD34细胞4.47（1.49～10.22）×106／kg。其中,5例选择全身照射+氟达拉滨+环磷酰胺（TBI+Flud+Cy）方案预处理,3例白消安（BU）／Cy预处理,3例TBI+CY,2例采用阿糖胞苷（Ara-C）+BU+Cy+替尼泊苷（VM26）预处理。移植物抗宿主病（GVHD）的预防：2例HLA配型半相合者给予抗胸腺细胞球蛋白（ATG）联合环孢素A（CsA）加短程甲氨蝶呤（MTX）治疗,并于移植后1～28 d持续给予霉酚酸酯（MMF）,其他病例仅给予CsA加短程MTX。结果　13例患者中9例造血完全重建,移植相关死亡4例。结论　HSCT是可以治愈MDS的有效方法。预处理选择应采取个体化。     

非清髓化疗和异体干细胞移植治疗肾细胞癌

难治性、转移性肾细胞癌 (ＲＣＣ)是一种对放化疗抗拒而免疫治疗有一定疗效的恶性疾病 ,鉴于Ｔ淋巴细胞在治疗及异体移植中的作用 ,选择并观察了免疫抑制性化疗后进行异体干细胞移植治疗ＲＣＣ的疗效 ,主要目的是评价有效免疫抑制化疗后非清髓性异体干细胞移植治疗难治性转移ＲＣＣ的可行性和安全性 ,以及移植成功和肿瘤退缩方面的效用。在 2 84例转移性ＲＣＣ中 ,仅 15例合乎要求的患者进行了移植。患者均为经组织病理确诊为进展性、有可测转移灶的ＲＣＣ。主要为透明细胞癌 ,ＥＣＯＧ评分 0或 1,至少在手术、放疗、化疗或免疫治疗后 4周进…     

自体骨髓混合HLA半相合异基因骨髓移植治疗急性白血病

 目的 观察自体骨髓混合HLA半相合异基因骨髓移植治疗急性白血病的疗效及移植相关并发症。方法 对7例急性白血病患者先实施经液体培养（与IL-2共孵育,1 000 U／ml骨髓血）和微波照射法体外净化的自体骨髓移植,2 ~ 5 d后输注一定量HLA半相合同胞兄妹的异基因骨髓。结果 中性粒细胞和血小板恢复的平均时间为+27 d和+29 d,3例发生Ⅲ~ Ⅳ度急性移植物抗宿主病（aGVHD）并死亡,其中1例并发肝静脉闭塞症。另外4例发生Ⅱ度aGVHD,HLA基因检测和（或）性染色体分析均呈混合嵌合现象并持续半年左右,这4例长期无病存活时间分别117,106,101,85个月,5年无病生存4例。结论 混合骨髓移植具有疗效好、复发率低、患者可获长期生存及相对安全可行等特点,但仍有必要进一步优化同／异基因骨髓细胞的比例及植入时机,并采取一定程度的移植物抗宿主病（GVHD）预防措施。     

大剂量IL-2活化的HLA 半相合异基因造血干细胞治疗10例晚期难治性肾癌的疗效观察

目的:传统的免疫治疗对晚期难治性肾癌的疗效非常有限,因为肿瘤自身产生了免疫耐受,本研究的目的是探讨大剂量IL-2活化的HLA半相合异基因造血干细胞治疗晚期难治性肾癌的临床疗效.方法:10例晚期肾癌患者以及作为供者的其HLA半相合的亲属入组.所有患者均接受1个疗程的haplo-PBSCs治疗,评估临床疗效和免疫学反应.结...     

非清髓性异基因骨髓移植治疗白血病的动物实验研究

[目的]探讨非清髓性异基因骨髓移植及加供者淋巴细胞输注治疗小鼠白血病的疗效.[方法]荷L7212白血病的615(H-2K)小鼠,于接种白血病细胞后第2天接受60Co-γ射线全身照射(TBI 8.5Gy或5Gy)分为若干组,照射当天移植供鼠BALB/C(H-2d)小鼠的骨髓细胞(5×106)和脾细胞(1.5×107),移植后第2天腹腔注射环磷酰胺(200mg/kg);供者淋巴细胞输注组分别于移植后第7天、14天、21天再次输注供鼠脾细胞5×106、1×107、2×107,观察受鼠的移植物植入、移植物抗宿主病(GVHD)、受鼠生存时间及移植相关并发症等.[结果]非清髓性预处理能保证移植物的稳定植入,非清髓性异基因骨髓移植组小鼠生存时间为22.3±4.8天,与非清髓空白组14.7±3.4天和传统移植组18.3±3.2天比较均有显著性差异(P＜0.05),供者淋巴细胞输注(DLI)组小鼠平均生存时间明显延长,为34.3±2.5天,与非清髓移植组比较均有显著性差异(P＜0.05),且无明显GVHD表现和病理学改变,移植相关并发症减少.[结论]非清髓性异基因骨髓移植能在减轻GVHD的同时保留一定的移植物抗白血病(GVL)效应,移植后行DLI可在减轻移植相关并发症的基础上进一步增强GVL效应.     

Antineoplastic effects of partially HLA-matched irradiated blood mononuclear cells in patients with renal cell carcinoma.

PURPOSE: Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease. PATIENTS AND METHODS: Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives. RESULTS: There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients. CONCLUSION: Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach.     

The combined administration of partially HLA-matched irradiated allogeneic lymphocytes and thalidomide in advanced renal-cell carcinoma: a case report

Renal-cell carcinoma (RCC) is susceptible to immune therapy including the use of the nonmyeloablative allogeneic transplantation (NST). However, NST can produce severe toxicity, might not be appropriate for many patients with metastatic RCC. Other novel allogeneic immunotherapies are designed to induce an autologous immune response directed against the malignancy. In single-arm phase II trials, thalidomide has demonstrated a modest activity in the treatment of advanced RCC. Here we present a case report in which a patient with advanced RCC in the absence of transplant conditioning, that was receiving thalidomide, was infused with partially HLA-matched irradiated allogeneic lymphocytes. In this patient a complete response with weak acute graft-versus-host disease (GVHD) was observed. No evidence of the disease was present over the subsequent 36 months survival of the patient, suggesting that the infusions may have played a major role in the antineoplastic effect. A potential mechanism of this protocol may involve a host-versus-graft reactions-mediated antitumor effect against the malignancy. In addition, the present results suggest that a combination protocol with alternate treatment (e.g., chemotherapy) schedules merit further investigation in the management of various malignancies.     

Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes.

Immunotherapy with interleukin 2 (IL-2) is not an effective anti-cancer treatment in the majority of patients with renal cell carcinoma (RCC), suggesting that the activation of cytotoxic T cells or NK cells may be impaired in vivo in these patients. The production of immunosuppressive factors by RCC was investigated. Using immunohistochemistry, IL-10 was detectable in 10 of 21 tumour samples tested. IL-10 was undetectable in the supernatant of cell lines derived from these RCCs. However, these cell lines or their conditioned medium (RCC CM), but not normal renal epithelial cells adjacent to the RCC or breast carcinoma cell lines, were found to induce IL-10, as well as prostaglandin E2 (PGE2) and tumour necrosis factor (TNF)alpha production by autologous or allogeneic peripheral blood mononuclear cells (PBMCs) and monocytes. IL-10 production induced by RCC CM was found to be dependent on TNF-alpha and PGE2 since an anti-TNF-alpha antibody (Ab) inhibited 40-70% of IL-10 production by monocytes, and the combination of anti-TNF-alpha Ab and indomethacin, an inhibitor of PGE2 production, inhibited 80-94% of RCC CM-induced IL-10 production by monocytes. The RCC CM of the five cell lines tested were found to induce a down-regulation of the expression of HLA-DR and CD86, as well as a strong inhibition of mannose receptor-dependent endocytosis by monocytes. The blockade of HLA-DR and CD86 expression was partially abrogated by indomethacin and anti-IL-10 Ab respectively, and completely abrogated by an anti-TNF-alpha Ab. The inhibition of mannose receptor-dependent endocytosis was partially abrogated by an anti-IL-10 Ab and completely abrogated by an anti-TNF-alpha Ab. These results indicate that RCCs induce IL-10, PGE2 and TNF-alpha production by monocytes, which down-regulate the expression of cell-surface molecules involved in antigen presentation as well as their endocytic capacity.     

Deficient helper cell function as a cause of diminished pokeweed mitogen blastogenic responses in patients with non-Hodgkin's lymphomas

An investigation has been made of immunoregulatory T-cell function in the non-Hodgkin's lymphomas by comparing immunoregulation of healthy control and patient peripheral blood lymphocyte blastogenic responses to pokeweed mitogen. Normal mononuclear leukocytes (MNL) had significantly higher responses than patient MNL. MNL were subsequently separated into T- and non-T-cell fractions by differential E-rosette sedimentation for co-culture experiments. When normal non-T-cells and autologous irradiated T-cells were recombined, the mitogenic response again exceeded the response of patient non-T-cells recombined with their own irradiated T-cells. However, when normal non-T-cells were co-cultured with patient irradiated T-cells, the mitogenic response was diminished. Moreover, when patient non-T-cells were co-cultured with normal irradiated T-cells, a normal proliferative response occurred. These differences in non-T-cell response are not simply a result of allogeneic effects, since normal non-T-cell responses were the same regardless of whether autologous or normal allogeneic irradiated T-cells were used as helpers. Furthermore, co-culture of normal non-T-cells simultaneously with autologous irradiated T-cells and patient irradiated T-cells revealed no diminution of blastogenic response compared with co-cultures of normal non-T-plus autologous irradiated T only, suggesting no net suppression by patient irradiated T-cells. Studies with monoclonal antibodies revealed that patient T-cells had normal to increased ratios of OK-T4+:OK-T8+ cells. These results suggest that peripheral blood T-cells from patients with non-Hodgkin's lymphomas, despite the presence of a normal to increased ratio of OK-T4+:OK-T8+ cells, are functionally deficient in their helper capacity for non-T-cell blastogenic response to pokeweed mitogen. Abnormal helper T-cell function may explain some of the immune deficits in patients with non-Hodgkin's lymphoma and may be important in the pathogenesis of these diseases.     

Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens.

PURPOSE: This phase I trial assessed the safety, efficacy, and immunologic responses to minor histocompatibility antigens following nonmyeloablative allogeneic hematopoietic cell transplantation as treatment for metastatic renal cell carcinoma. EXPERIMENTAL DESIGN: Eight patients received conditioning with fludarabine and low-dose total body irradiation followed by hematopoietic cell transplantation from an HLA-matched sibling donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for donor engraftment of myeloid and lymphoid cells, for clinical response by serial imaging, and for immunologic response by in vitro isolation of donor-derived CD8(+) CTLs recognizing recipient minor histocompatibility (H) antigens. RESULTS: All patients achieved initial mixed hematopoietic chimerism with two patients rejecting their graft and recovering host hematopoiesis. Four patients developed acute, grade 2 to 3, graft-versus-host disease and four patients developed extensive chronic graft-versus-host disease. Five patients had progressive disease, two patients had stable disease, and one patient experienced a partial response after receiving donor lymphocyte infusions and IFN-alpha. CD8(+) CTL clones recognizing minor H antigens were isolated from five patients studied. Clones from three patients with a partial response or stable disease recognized antigens expressed on renal cell carcinoma tumor cells. CONCLUSIONS: Treatment of metastatic renal cell carcinoma with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning with fludarabine/total body irradiation is feasible and may induce tumor regression or stabilization in some patients. CD8(+) CTL-recognizing minor H antigens on tumor cells can be isolated posttransplant and could contribute to the graft-versus-tumor effect. Such antigens may represent therapeutic targets for posttransplant vaccination or adoptive T-cell therapy to augment the antitumor effects of allogeneic hematopoietic cell transplantation.     

负载自体肿瘤细胞裂解物的DC疫苗联合CIK治疗晚期肾癌的临床观察--附10例报告

背景与目的:肾癌的主要治疗手段是手术,但晚期肾癌术后复发率高,加上肾癌对化疗和放疗不敏感,因此,晚期肾癌预后不佳,需要寻找新的更有效的治疗方法。本研究通过负载自体肿瘤细胞裂解物的树突细胞(dendriticcells,DC)疫苗联合细胞因子诱导的杀伤细胞(cytokine-inducedkillercells,CIK)治疗10例晚期肾癌,观察近期的临床疗效,免疫学反应及副作用。方法:分离患者外周血单核细胞,体外经GM-CSF和IL-4诱导产生DC细胞,并负载自体肿瘤细胞裂解物;T淋巴细胞经IFN-γ、IL-2、CD3单抗、IL-1α体外诱导产生CIK细胞。所有患者在切除原发病灶后,接受每周一次的皮内DC疫苗注射治疗,至少8次治疗;CIK细胞过继细胞免疫治疗,每2周一次,至少接受4次治疗。临床疗效和免疫学反应分别通过影象学检查,外周血T淋巴细胞亚群改变和迟发性超敏(delayed-typehypersensitivity,DTH)反应进行评估。结果:(1)4例有可评价病灶的患者中1例部分缓解(PR),2例疾病稳定(SD),1例进展(PD);6例没有可评价病灶的患者中1例PD,1例失访,另外4例未见疾病进展。随访时间6～20个月(中位时间11个月)。(2)与治疗前比较,治疗2个月后患者CD3 、CD4 、CD4 /CD8 、CD56 明显升高(P<0.05)。(3)包括PR患者在内的6例患者DTH反应呈现阳性。(4)除一过性的发热、畏寒外没有其它不良反应出现。结论:负载自体肿瘤细胞裂解物的DC疫苗联合CIK细胞治疗晚期肾癌有一定的近期临床疗效,能诱导出特异的抗肾癌免疫反应,并且有良好的耐受性。     

Detection and enrichment of disseminated renal carcinoma cells from peripheral blood by immunomagnetic cell separation

We have established an immunomagnetic separation procedure for the detection of circulating tumor cells in the peripheral blood based on the magnetic cell sorting (MACS) technique. In previous in vitro experiments, renal-cell carcinoma (RCC) cells were mixed with peripheral blood. In dilutions of 1:200 to 1:107 tumor cells per mononuclear blood cells, an average recovery rate of 84% of tumor cells was determined. In our study, 104 peripheral blood samples from 59 renal carcinoma patients were analyzed. MACS resulted in significant depletion of leukocytes, permitting a search for tumor cells on just 1 slide. Analyzing 8 ml of peripheral blood per patient, 19/59 RCC patients carried disseminated tumor cells (32%) in the range of 1 to 38 cells (median 8). Interestingly, for the cytokeratin-positive (CK+) patient group, we found a correlation between tumor cell number and grading (G2 vs. G3) and an increased number of CK+ patients with advanced tumor stage. MACS appears to be an efficient technique to detect disseminated tumor cells in peripheral blood.     

Allogeneic stem-cell transplantation in renal-cell carcinoma

Metastatic renal-cell carcinoma (RCC) remains resistant to nearly all standard cytotoxic therapies, but immune-based cytokine therapies benefit a small minority of patients with advanced RCC. Nonmyeloablative allogeneic stem-cell transplantation is a novel approach to harnessing the immune system to combat this cancer. The strategy relies on a T-cell graft-versus-malignancy effect mediated by donor T cells. Preliminary work in using nonmyeloablative allogeneic stem-cell transplant in RCC has identified a graft-versus-RCC effect and yielded encouraging clinical responses.     

A pilot study of allogeneic cellular therapy for patients with advanced hematologic malignancies

Allogeneic hematopoietic stem cell transplantation provides curative therapy for some patients with advanced hematologic malignancies. Disease response after allogeneic transplant is, at least in part, mediated by donor immune cells. In this report we describe a cellular therapy using haploidentical peripheral blood stem cells administered after very low dose total body irradiation (TBI) (100 cGy). The donor cells were anticipated to be rejected, so no graft-versus-host (GVHD) prophylaxis was used. Patients with persistent disease beyond 8 weeks could be further treated with infusions of irradiated haploidentical donor cells. Of the 10 patients enrolled in the study, durable engraftment of allogeneic cells was seen in one patient. Two patients with resistant relapsed acute myelogenous leukemia (AML) had a disease response. Analysis of T cell reactivity from one patient who achieved a complete response but did not have durable engraftment of donor cells indicated that disease response was associated with the generation of host-derived anti-leukemic cytotoxic CD8+ T cells that reacted with an AML-associated proteinase 3 epitope. Results from this patient suggest that allogeneic therapy induced a host anti-tumor response associated with cytotoxic T cells reactive with a low affinity self-antigen.