Antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC) of breast cancer cells mediated by bispecific antibody, MDX-210

Background: MDX-210 is a bispecific antibody (BsAb) with specificity for both the proto-oncogene product of HER-2/neu (c-erbB-2) and FcRI (CD64). HER-2/neu is overexpressed in malignant tissue of approximately 30% of patients with breast cancer, and FcRI is expressed on human monocytes, macrophages, and IFN- activated granulocytes. We investigated phagocytosis and cytolysis of cultured human breast cancer cells by human monocyte-derived macrophages (MDM) mediated by BsAb MDX-210, its partially humanized derivative (MDX-H210), and its parent MoAb 520C9 (anti-HER-2/neu) under various conditions.Materials and Methods: Purified monocytes were cultured with GM-CSF, M-CSF, or no cytokine for five or six days. Antibody dependent cellular phagocytosis (ADCP) and cytolysis (ADCC) assays were performed with the MDM and HER-2/neu positive target cells (SK-BR-3). ADCP was measured by two-color fluorescence flow cytometry using PKH2 (green fluorescent dye) and phycoerythrin-conjugated (red) monoclonal antibodies (MoAb) against human CD14 and CD11b. ADCC was measured with a non-radioactive LDH detection kit.Results: Both BsAb MDX-210 (via FcRI) and MoAb 520C9 (mouse IgG1, via FcRII) mediated similar levels of ADCP and ADCC. ADCP mediated by BsAb MDX-H210 was identical to that mediated by BsAb MDX-210. Confocal microscopy demonstrated that dual-labeled cells represented true phagocytosis. Both ADCP and ADCC were higher when MDM were pre-incubated with GM-CSF than when incubated with M-CSF.Conclusions: BsAb MDX-210 is as active in vitro as the parent MoAb 520C9 in inducing both phagocytosis and cytolysis of MDM. MDX-210 and its partially humanized derivative, MDX-H210, mediated similar levels of ADCP. GM-CSF appears to superior to M-CSF in inducing MDM-mediated ADCC and ADCP. These studies support the ongoing clinical investigations of BsAb MDX-210 and its partially humanized derivative.     

Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial

Background and Objectives: CIK cells are a novel population of efficient immune effector cells with high antitumour activity mainly due to the high proliferation of CD3⁺CD56⁺ cells, so may play a role in the development of new forms of adoptive cellular immunotherapy. We started a pilot clinical trial with autologous CIK cells in patients with refractory lymphoma and metastatic solid tumours. This study was aimed at determining the feasibility of generating a sufficient number of CIK cells in heavily pretreated patients and at assessing treatment toxicity. Design and Methods: CIK cells were generated from peripheral blood mononuclear cells (MNC) and incubated in the presence of IFN‐γ followed by OKT3 and IL‐2. Treatment schedule consisted of three cycles of CIK cells infusions at an interval of 3 weeks. Results: At present 12 patients were enrolled: 6 advanced lymphomas, 5 metastatic kidney carcinoma and 1 hepatocellular carcinoma (HCC). The median number of transferred cells per patient was 28 × 10⁹ (range, 6–61). Protocol adherence was excellent and the toxicity profile was favourable. After CIK cells infusion, the absolute median count of lymphocytes, CD3⁺, CD8⁺ and CD3⁺CD56⁺ cells significantly increased in patient's peripheral blood. Clinical outcome appeared promising: three patients had complete response (CR) and two patients had stabilization of disease with a median follow‐up of 33 months (range, 9–44). Interpretations and Conclusions: These preliminary data showed that adoptive immunotherapy with CIK cells is a safe therapy with some suggestion of efficacy that significantly enhances immune functions increasing absolute numbers of effector cells without side effects. If confirmed in larger scale studies, these promising results may have a favourable impact on conventional treatment strategy of malignancies. Copyright © 2009 John Wiley & Sons, Ltd.     

Novel anti-EPHA2 antibody,DS-8895a for cancer treatment

Overexpression of EPHA2 has been observed in multiple cancers and reported to be associated with poor prognosis. Here, we produced an afucosylated humanized anti-EPHA2 monoclonal antibody (mAb), DS-8895a for cancer treatment. The antibody recognizes the extracellular juxtamembrane region of EPHA2 and therefore can bind to both full-length and truncated forms of EPHA2, which are anchored to cell membranes and recently reported to be produced by post-translational cleavage in tumors. DS-8895a exhibited markedly increased antibody dependent cellular cytotoxicity (ADCC) in vitro and also inhibited tumor growth in EPHA2-positive human breast cancer MDA-MB-231 and human gastric cancer SNU-16 xenograft mouse models. Moreover, DS-8895a in combination with cisplatin (CDDP) showed better efficacy than each of the monotherapies did in the human gastric cancer model. These results suggest that a novel antibody, DS-8895a has therapeutic potential against EPHA2-expressing tumors.     

细胞因子诱导的杀伤细胞治疗恶性黑素瘤临床疗效的初步分析

目的:初步评价细胞因子诱导的杀伤细胞(cytokine-induced killer cell,CIK)在恶性黑素瘤治疗中的效果。方法:收集天津医科大学附属肿瘤医院2005年1月至2010年12月术后接受CIK治疗的38例恶性黑素瘤患者作为CIK治疗组,按1∶3比例选取同期术后未接受CIK治疗的114例恶性黑素瘤患者作为对照组,两组配对因素包括临床分期、性别、年龄、有无溃疡、乳酸脱氢酶(lactate dehyolrogenase,LDH)活性、病理类型、KPS评分(Karnofsky performance status scale)等均衡一致。随访时间为2005年3月至2012年3月,临床疗效的观察终点为总生存(overall survival,OS)期。结果:CIK治疗组与对照组1年OS率分别为86.8%、74.6%(P=0.097),3年OS率分别为76.3%、46.5%(P=0.001),5年OS率分别为71.1%、43.9%(P=0.004);CIK治疗组中位生存期明显长于对照组(CIK治疗组中位生存期未达到观察终点,对照组中位生存期为20.1个月,P=0.004)。单因素和多因素分析显示,病理类型、LDH水平是影响CIK治疗恶性黑素瘤患者疗效的独立影响因素;CIK免疫治疗的疗程数可能与黑素瘤患者OS相关,CIK疗程>8次具有延长黑素瘤患者OS期的趋势。结论:CIK免疫治疗能改善恶性黑素瘤患者的OS期,增加CIK疗程数可能提高其疗效。     

西妥昔单抗联合化疗在结直肠癌中的回顾性研究

Objective:To evaluate the efficacy and safety of cetuximab combined with chemotherapy in colorectal cancer (CRC).Methods:35 cases of CRC were retrospectively analyzed.Efficacy and adverse events were observed.Results:29 cases of CRC were evaluated by RECIST criteria,showing 7 PR (partial response,24.1%) and 15 SD (stable disease,51.8%),disease control rate (DC) was 75.9%.Subgroup analysis showed response rate (RR) of 36.4% and DC of 91% in the 1st line therapy,RR of 20% and DC of 70% in the 2rid line therapy,RR of 12.5% and DC of 62.5% in heavily pre-treated cases.Rash appeared in 74.3% of patients (grade 3 was 8.6%),and the severity was relevant with disease control rate (DC).Neutropenia of grade 3/4 was 14.3%,and infusion related reaction (IRR) of grade 3 happened in 1 case (2.9%).Conclusion:Cetuximab combined with chemotherapy is safe and effective for patients with metastatic colorectal cancer.The combination therapy shows high DC,especially in 1st line therapy.Severity of rash may predict efficacy.     

DC-CIK细胞过继免疫治疗联合XELOX方案化疗对进展期结直肠癌患者的疗效分析

目的探讨树突状细胞-细胞因子诱导杀伤细胞(DC-CIK)细胞过继免疫治疗联合奥沙利铂+卡培他滨(XELOX)方案化疗对进展期结直肠癌(CRC)患者的疗效。方法将104例进展期CRC患者按随机数字表法分为观察组和对照组各52例,观察组行DC-CIK联合化疗,对照组行化疗。检测患者治疗前后血清糖类抗原242(CA242)、糖类抗原19-9(CA19-9)、癌胚抗原(CEA)、T淋巴细胞亚群[自然杀伤性T(NKT)细胞、自然杀伤(NK)细胞、CD4^+、CD3^+、CD8^+]及白细胞介素-6(IL-6)、白细胞介素-2(IL-2)、干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α)水平,评价患者近期疗效。结果观察组患者的缓解率(RR)为61.54%(32/52),疾病控制率(DCR)为75.00%(39/52),分别高于对照组的40.38%(21/52)和55.77%(29/52),差异均有统计学意义(P<0.05)。治疗后,两组患者血清CEA水平均低于治疗前,差异均有统计学意义(P<0.05);治疗后,观察组患者血清IL-2、IFN-γ、TNF-α、CD4^+、CD3^+、CD8^+及NKT细胞水平均高于对照组,差异均有统计学意义(P<0.05)。结论 CRC患者行DC-CIK细胞过继免疫治疗联合XELOX方案化疗可改善机体免疫功能,弥补单纯化疗所造成的免疫抑制,为安全有效的疗法。     

A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer

Background:

Pre-clinical data indicate enhanced anti-tumour activity when combining recombinant human interleukin-21 (rIL-21), a class 1 cytokine, with cetuximab, a monoclonal antibody, targeting the epidermal growth factor receptor. This phase 1 trial assessed the safety and tolerability of escalating doses of rIL-21 in combination with cetuximab in chemo-naïve patients with stage IV colorectal cancer.

Patients and methods:

Sequential cohorts of PS 0–1, asymptomatic patients, were treated weekly with cetuximab 250 mg m⁻² intravenously (i.v.) plus escalating i.v. doses of rIL-21 following an initial loading dose of cetuximab 400 mg m⁻². Initial treatment period was 8 weeks, with extension permitted in patients without disease progression.

Results:

In all, 15 patients were included in this study. Adverse events related to rIL-21 or rIL-21 plus cetuximab included lethargy, nausea/vomiting, stomatitis, lymphopenia and pyrexia and were mainly ⩽ grade 2. One dose limiting toxicity occurred (grade 3 diarrhoea). Maximum tolerated dose was not determined because of the premature study closure. Maximum administered dose was 100 μg kg⁻¹ rIL-21 weekly. In all, 60% of the patients had stable disease. Immune activation was confirmed by various T- and NK-cell activation biomarkers, including dose-dependent increases in serum sCD25.

Conclusion:

rIL-21 weekly combined with cetuximab is well tolerated at doses up to 100 μg kg⁻¹ and results in activation of immune response biomarkers.     

Neoadjuvant chemo-immunotherapy modifies CD4CD25 regulatory T cells (Treg) in non-small cell lung cancer (NSCLC) patients

Background

Regulatory T cells (Treg) are critical for cancer immune evasion; whereas natural killer (NK) cells are central for effective anti-tumor immunity including antibody-induced cellular cytotoxicity (ADCC). The predictive role of Treg levels for clinical response to chemo-immunotherapy in non-small cell lung cancer (NSCLC) as well as therapy-induced Treg changes remain to be defined.

Patients and methods

The impact of Treg on NK-mediated cetuximab-dependent cellular cytoxicity was tested in vitro. Frequency and functional activity of Treg was analyzed in 31 NSCLC stage IB-IIIA patients treated by neoadjuvant Cetuximab/Docetaxel/Cisplatin prior to surgery. Data were correlated with clinical outcome variables and Treg tumor infiltration.

Results

Treg potently inhibit NK-mediated and cetuximab-induced ADCC in vitro. In addition, a significant correlation between Treg reduction and clinical response was seen. However, the grade of tumor infiltrating Treg in resected tumors did not correlate with peripheral Treg levels. Moreover, Treg levels at diagnosis did not predict clinical response to chemo-immunotherapy.

Conclusions

The drop of Treg levels during neoadjuvant chemo-immunotherapy in NSCLC patients significantly correlates with clinical response. However, Treg at diagnosis are not linked to inferior clinical response to chemo-immunotherapy in NSCLC in vivo even though Treg efficiently inhibit ADCC in vitro.     

Insulin‐like growth factor 1 expression correlates with clinical outcome in K‐RAS wild type colorectal cancer patients treated with cetuximab and irinotecan

Seventy to 40% of K‐RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF‐1 system, altered activation colorectal cancer cells may escape anti‐EGFR mediated cell death. The interaction between IGF‐1 expression and K‐RAS mutational analysis was tested to verify the ability of IGF‐1 to identify a subgroup of patients more likely to benefit from EGFR‐targeted antibodies treatment. IGF‐1 expression and K‐RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF‐1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF‐1 negative and IGF‐1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression‐free survival was 7.5 mo in patients showing IGF‐1 negative tumors and 3 mo for IGF‐1 expressing tumors (p = 0.002). Among K‐RAS wild type patients, IGF‐1 negative and positive tumors showed a partial response to cetuximab‐irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression‐free survival in IGF‐1 negative tumors was 10 mo and 3.2 mo in IGF‐1 positive colorectal cancers (p = 0.02). IGF‐1 proved to be a possible predictive factor for resistance to anti‐EGFR monoclonal antibodies in K‐RAS wild type colorectal cancer. Combined IGF‐1 and K‐RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.     

Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer.

BACKGROUND: The monoclonal antibody 3H1 mimics the external structure of the carcinoembryonic antigen (CEA). It therefore has the potential, via the anti-idiotypic network, to stimulate immune responses to CEA that may benefit colorectal cancer patients. PATIENTS AND METHODS: A total of 630 patients with previously untreated metastatic colorectal cancer were randomised in a 2:1 fashion to receive bolus 5-fluorouracil (5-FU) and leucovorin (LV) plus either 3H1 (n = 422) or placebo (n = 208). RESULTS: The addition of 3H1 to 5-FU and LV did not result in increased toxicity. Survival for the full intent-to-treat population was 14.7 months for the 3H1 arm and 15.2 months for the placebo arm (P = 0.80). Anti-CEA antibody responses were observed in 70% of patients treated with 3H1. Patients with a negative CEA response had a median survival of 8.3 months (95% CI 7.5-11.0) compared with patients with a strong response: median survival not reached (P <0.001). CONCLUSION: 3H1 is safe and effectively induces immune responses to CEA. Addition of 3H1 to 5-FU and LV was not shown to improve overall patient outcomes. However, improved survival in patients developing anti-CEA responses to 3H1 are provocative and should be studied in further clinical trials.     

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.     

A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours

Antibody-directed enzyme prodrug therapy is a targeted therapy in which a prodrug is activated selectively at the tumour site by an enzyme, which has been targeted to the tumour by an antibody (antibody-enzyme conjugate). Previous clinical trials have shown evidence of tumour response, however, the activated drug had a long half-life, which resulted in dose-limiting myelosuppression. Also, the targeting system, although giving high tumour to blood ratios of antibody-enzyme conjugate (10 000 : 1) required administration of a clearing antibody in addition to the antibody-enzyme conjugate. The purpose of this current study therefore was to attempt tumour targeting of the antibody-enzyme conjugate without the clearing antibody, and to investigate a new prodrug (bis-iodo phenol mustard, ZD2767P) whose activated form is highly potent and has a short half-life. Twenty-seven patients were treated with antibody-directed enzyme prodrug therapy using A5CP antibody-enzyme conjugate and ZD2767P prodrug, in a dose-escalating phase I trial. The maximum tolerated dose of ZD2767P was reached at 15.5 mg m(-2)x three administrations with a serum carboxypeptidase G2 level of 0.05 U ml(-1). Myelosuppression limited dose escalation. Other toxicities were mild. Patients' quality of life was not adversely affected during the trial as assessed by the measures used. There were no clinical or radiological responses seen in the study, but three patients had stable disease at day 56. Human anti-mouse antibody and human anti-carboxypeptidase G2 antibody were produced in response to the antibody enzyme conjugate (A5CP). The antibody-enzyme conjugate localisation data (carboxypeptidase G2 enzyme levels by HPLC on tumour and normal tissue samples, and gamma camera analysis of I-131 radiolabelled conjugate) are consistent with inadequate tumour localisation (median tumour: normal tissue ratios of antibody-enzyme conjugate of less than 1). A clearance system is therefore desirable with this antibody-enzyme conjugate or a more efficient targeting system is required. ZD2767P was shown to clear rapidly from the circulation and activated drug was not measurable in the blood. ZD2767P has potential for use in future antibody-directed enzyme prodrug therapy systems.     

Autologous cytokine-induced killer cells combined with chemotherapy in the treatment of advanced colorectal cancer: a randomized control study

Objective:To evaluate the ef icacy of autologous cytokine-induced kil er (CIK) cells transfusion combined with chemotherapy in patients suf ered from advanced colorectal cancer. Methods: Sixty untreate...     

Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer.

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 and histamine receptor 2 blockers. Other side effects were mild and predictable. Biodistribution studies showed a rapid and intensive hepatic uptake. At the 50 mg/m2 level the half-life and maximum serum concentration were 81 +/- 15 h and 7.9 microg/ml, respectively. One patient developed a low-level human anti-c30.6 response. Tumor response was assessed by computed tomography, positron emission tomography scanning, and serial carcinoembryonic antigen measurements. There were no partial responses, although positron emission tomography scanning demonstrated some reduction in tumor activity in three individuals. The chimerized c30.6 antibody is not immunogenic in humans and appears worthy of further study. It does, however, produce a unique profile of side effects that can be well controlled with premedication.     

Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1)

Background:

S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.

Methods:

Patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, cisplatin (60 mg m⁻²) intravenously on day 1, and trastuzumab (course 1, 8 mg kg⁻¹; course 2 onward, 6 mg kg⁻¹) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.

Results:

A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54–80%), and the disease control rate was 94% (95% CI=84–99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).

Conclusions:

Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.     

细胞因子诱导的杀伤细胞治疗肾细胞癌临床疗效的评价

目的:评价细胞因子诱导的杀伤细胞(cytokine-induced killer cell,CIK)免疫治疗在肾细胞癌治疗中的效果。方法:收集天津医科大学附属肿瘤医院2000年1月至2010年7月接受CIK治疗的119例肾细胞癌患者作为治疗组,IL-2联合IFN治疗的119例肾细胞癌患者作为对照组。119对患者确诊时临床分期为:Ⅰ期21对,Ⅱ期21对,Ⅲ期49对,Ⅳ期28对。配对因素包括临床分期、性别、年龄、中性粒细胞计数、血小板、血红蛋白、乳酸脱氢酶、β2-微球蛋白、KPS评分等,两组配对因素均衡一致。随访时间为2001年1月至2011年4月,临床疗效的观察终点为无进展生存(progression-free survival,PFS)和总生存(overall survival,OS)。结果:治疗组与对照组5年PFS率分别为44%、42%(P=0.056),5年OS率分别为72%、51%(P<0.01)。两组患者中位PFS时间分别为54和43个月(P=0.088),中位OS时间分别为134和60个月(P<0.01)。两组中Ⅰ+Ⅱ期患者的PFS、OS差异无统计学意义;Ⅲ+Ⅳ期患者中,治疗组5年PFS、OS率明显高于对照组(26%vs 18%,P<0.01;58%vs 31%,P<0.01),且中位PFS、OS时间明显长于对照组(36个月vs 13个月,P<0.01;68个月vs 33个月,P<0.01)。多因素分析显示,CIK治疗的疗程数与患者PFS(HR=0.95,95%CI:0.92～0.99,P<0.05)和OS(HR=0.79,95%CI:0.71～0.87,P<0.001)相关,最佳CIK治疗的疗程数为7次以上。结论:CIK免疫疗程可以显著改善Ⅲ、Ⅳ期肾细胞癌患者预后,增加CIK治疗疗程数可以提高疗效。     

Phase I trial of oxaliplatin plus S-1 chemotherapy in patients with metastatic colorectal cancer

Advanced colorectal cancer can be effectively treated with S-1, as well as with a combination of oxaliplatin, 5-fluorouracil (5FU) and leucovorin (LV). However, S-1 together with oxaliplatin may provide a more convenient alternative to 5FU/LV. To evaluate the performance of S-1 combined with oxaliplatin for patients with colorectal cancer, we conducted a Phase I clinical trial in an outpatient setting. We administered S-1 to 15 patients with advanced colorectal adenocarcinoma for two weeks followed by one week of rest. Oxaliplatin was also administered on day 1 of the S-1 cycle. The dose of oxaliplatin was increased from 40 to 85 mg/m(2) to define the maximum tolerated dose and recommended dose in preparation for a Phase II trial. We administered 102 courses of treatment to 15 patients. Grade 3 thrombocytopenia developed in only 1 patient at a dose of 85 mg/m(2) of oxaliplatin plus oral S-1. No other grade 3-4 toxicities developed. No dose-limiting toxicity developed at level 4 of our regimen (oxaliplatin 85 mg/m(2)), and the recommended dose for a Phase II trial was 85 mg/m(2) of oxaliplatin in an outpatient setting.     

DC-CIK联合化疗加靶向治疗对晚期结肠癌的临床疗效观察

目的:观察DC-CIK联合化疗加靶向治疗治疗晚期结肠癌的疗效及安全性。方法:选取晚期结肠癌患者,DC-CIK联合化疗加靶向治疗（奥沙利铂+卡培他滨+贝伐单抗）为联合治疗组(30例),同期进行化疗加靶向治疗(奥沙利铂+卡培他滨+贝伐单抗)的晚期结肠癌患者为化疗加靶向治疗组(30例),比较两组患者治疗后的免疫功能、近期疗效、1年生存率、生活质量,并观察DC-CIK细胞治疗的安全性。结果:成功培养患者的DC-CIK细胞,其中CD3+CD8+、CD3+CD56+细胞比例较培养前显著提高(P＜0.05)。与化疗加靶向治疗组相比,联合治疗组患者治疗后外周血细胞CD3+CD8+、CD3+CD56+细胞比例明显升高(P＜0.05)。与治疗前相比,联合治疗组患者治疗后T细胞分泌IFN-γ、IL-2水平显著升高(P＜0.05)。化疗加靶向治疗组患者治疗后外周血各T细胞亚群比例和T细胞分泌IFN-γ、IL-2水平较治疗前降低,但均无统计学差异(P＞0.05)。联合治疗组患者的疾病控制率显著高于化疗加靶向治疗组(86% vs 60%,P＜0.01)。联合治疗组患者1年生存率与化疗加靶向治疗组比较无统计学差异(62% vs 56%,P＞0.05)。治疗后毒副反应(包括骨髓抑制、恶心呕吐、周围神经毒性)联合治疗组明显轻于化疗加靶向治疗组(P＜0.05),治疗后体力食欲改善明显(P＜0.05)。结论:与化疗加靶向治疗组相比,DC-CIK联合化疗加靶向治疗治疗晚期结肠癌安全有效,可以提高缓解率,延长生存期,改善患者的生活质量。     

Phase I trial of intraperitoneal recombinant interleukin-2/lymphokine-activated killer cells in patients with ovarian cancer

Ten patients with ovarian cancer refractory to conventional therapy were treated with intraperitoneal (i.p.) recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK). The 28-day protocol consisted of 6 priming i.p. rIL-2 infusions on days 0, 4, 6, 8, 10, and 12. Leukapheresis was performed for mononuclear cell collection on days 15, 16, 17, and 18 and lymphokine-activated killer cells were given i.p. with the rIL-2 on days 19 and 21. Three additional i.p. rIL-2 infusions were given on days 23, 25, and 27. Three dose levels of rIL-2 were tested: 5 X 10(5), 2 X 10(6), and 8 X 10(6) units/m2 body surface area. The dose-limiting toxicity was abdominal pain secondary to ascites accumulation with significant weight gain. Other toxic effects included decreased performance status, fever, nausea and vomiting, diarrhea, and anemia. Peripheral lymphocytosis and eosinophilia were seen at all dose levels. The maximum tolerated dose is 8 X 10(6) units/m2/dose. Peripheral and peritoneal IL-2 levels were measured with a bioassay using an IL-2-dependent cell line. At the highest dose level, serum IL-2 was greater than 10 units/ml for 18 h. After the first infusion, a 2-log dilution of the i.p. IL-2 was measured in the serum. In the postleukapheresis i.p. IL-2-dosing period less IL-2 was detected in the serum than in the earlier i.p. IL-2-priming period. The induction and persistence of LAK activity were studied. Peritoneal LAK activity was detected as early as 4 days after the first i.p. infusion, by day 11 in all evaluable patients, and persisted for the 6-day interval between priming IL-2 and LAK/IL-2 infusion. Peritoneal lytic activity persisted until day 28 in 5 tested patients. These peritoneal cells retained lytic activity 48 h in culture medium without rIL-2 present. Peritoneal LAK activity correlated with the percentage of mononuclear cells and the percentage of CD56-positive mononuclear cells in the peritoneum. The yield of peripheral lymphocytes after the six i.p. priming doses of rIL-2 correlated with the dose level of rIL-2 infused. Peripheral blood LAK activity showed a minimal, however progressive, increase during the treatment protocol. LAK activity could be enhanced if rIL-2 was present during the 4-h assay. These studies indicate that i.p. rIL-2 infusion induced durable regional LAK activity and primes peripheral blood cells for LAK activity if exposed briefly to additional IL-2.