Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.
Juli 2018 | Matsuda, Tatsuo; Takeuchi, Hiroya; Sakurai, Toshiharu; Mayanagi, Shuhei; Booka, Eisuke; Fujita, Tomonobu; Higuchi, Hajime; Taguchi, Junichi; Hamamoto, Yasuo; Takaishi, Hiromasa; Kawakubo, Hirofumi; Okamoto, Masato; Sunamura, Makoto; Kawakami, Yutaka; Kitagawa, Yuko
In the present study, the immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination combined with docetaxel (DCDOC) in advanced esophageal cancer patients who had already received first-line chemotherapy was investigated. Ten HLA-A*2402 patients were treated with docetaxel (50 mg/m) on day 1 and WT1 peptide-pulsed DC vaccination (1×10 cells) on days 15 and 22 (repeated every 4 weeks for 3 cycles). The delayed-type hypersensitivity skin test, HLA tetramer assay and interferon-γ enzyme-linked immunospot (ELISPOT) assay were used to evaluate the induction of a WT1-specific immune response. Median overall survival was 5 months (range, 1.1-11.6). The clinical effect of DCDOC therapy was not observed and only 1 patient could complete the protocol therapy. Disease progression was observed in 9 patients and 1 patient succumbed to fatality during the second cycle of therapy. As a pilot study, it was not possible to evaluate the safety of WT1 peptide-pulsed DCDOC therapy for esophageal squamous cell cancer. However, a WT1-specific response in 6 patients, as indicated by the ELISPOT or HLA/WT1-tetramer assay, was demonstrated. The results suggested that the positive immune response had significant relevance on the low percentage of CD11b and CD66b granulocytic myeloid-derived suppressor cells in CD15 cells. Furthermore, DCDOC elicited a WT1-specific immune response regardless of the myelosuppression associated with docetaxel. The present findings support future studies and further work to assess DCDOC as an adjuvant therapy for esophageal cancer will be performed. The present clinical trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry on November 11th, 2011, no. UMIN000006704. PMID 29963201
Pilot study of WT1 peptide-pulsed dendritic cell vaccination with docetaxel in esophageal cancer.
A Dendritic Cell Vaccine Combined With Radiotherapy Activates the Specific Immune Response in Patients With Esophageal Cancer.
Jan. 2017 | Wang, Chengshi; Pu, Juan; Yu, Hanxu; Liu, Yanyan; Yan, Honghuan; He, Zhongxiang; Feng, Xin
Dendritic cells (DC) are highly efficient antigen-presenting cells. DC may be used to create DC vaccines against cancer, but the optimal strategies remain to be elucidated. This study aimed to examine the benefits and adverse effects of using esophageal cancer cell antigens to stimulate DC to trigger the specific immune response in patients with esophageal cancer undergoing radiotherapy. This was an observational cohort study performed at Lianshui County People's Hospital between September 2010 and June 2012. Forty patients with esophageal cancer planned to receive radiotherapy were selected, and 28 received the DC vaccine. DC were isolated, loaded with antigens, and intradermally injected after being cultured for 1 week. One week after injection, the patients underwent a delayed-type hypersensitivity test. Serum Th1 cytokines [interleukin (IL)-2, IL-12, and interferon (IFN)-γ] and antigen-specific IFN-γCD8 T cells were tested before and after vaccination. Patients were followed up for 2 years. Adverse events were monitored. Patients in the vaccine group tolerated the DC vaccine. Levels of serum IL-2 (+92.4%), IL-12 (+70.9%), and IFN-γ (+214.3%) as well as the proportion of IFN-γCD8 T cells (3.0-16.4-fold) were significantly increased compared with baseline and the control group (all P<0.05). The 1- (82.1% vs. 50.0%, P=0.04) and 2-year survival (67.8% vs. 33.3%, P=0.04) was improved by vaccination. Only 2 patients showed mild fever. In conclusion, the DC vaccine triggered the specific immune response and induced the secretion of Th1 cytokines. The vaccine may lead to better survival, but this have to be confirmed. Adverse events were rare and mild. PMID 28125513
Chemoradiation combined with regional hyperthermia for advanced oesophageal cancer: a systematic review and meta-analysis.
Jan. 2017 | Hu, Y; Li, Z; Mi, D-H; Cao, N; Zu, S-W; Wen, Z-Z; Yu, X-L; Qu, Y
Hyperthermia is an effective treatment modality that augments the anticancer effects of radiotherapy and chemotherapy. Hyperthermia-chemo-radiotherapy (HCRT) is a combination therapy that can strengthen anticancer effects through a synergistic interaction between heat, chemotherapy and radiation. Here, we carried out a systematic review and meta-analysis to evaluate the clinical efficacy and safety of chemoradiation combined with regional hyperthermia (HCRT) for oesophageal carcinoma. PMID 28120520
Regional hyperthermia combined with radiotherapy for esophageal squamous cell carcinoma with supraclavicular lymph node metastasis.
Dez. 2016 | Sheng, Liming; Ji, Yongling; Wu, Qiner; Du, Xianghui
To assess the efficacy and toxicity of Intensity-modulated radiotherapy (IMRT) and hyperthermia for upper and middle thoracic esophageal squamous cell carcinoma (UMT-ESCC) with supraclavicular lymph node metastasis. A total of 50 patients with UMT-ESCC with supraclavicular lymph node metastasis were evaluated in this retrospective study. All patients received IMRT. Hyperthermia was delivered simultaneously with irradiation, in 45 minutes twice a week for 5-6 weeks. Hyperthermia included supraclavicular lymph node metastasis. Forty-four patients (88.0%) received concurrent chemoradiotherapy based on cisplatin regimens. The most common types of hematological toxicities were anemia (62.0%) and leukopenia (60.0%). Most of these events were grade 1-2 and transient. The 3-year progression-free survival (PFS) rate and overall survival (OS) rate were 34.9% and 42.5%, respectively. Cox regression revealed that tumor length and number of supraclavicular lymph node metastasis were two independent predictors of OS (tumor length: HR=3.65, p=0.008; nodal stage: HR=8.07, p=0.019). The IMRT combined with supraclavicular regional hyperthermia has low toxicity and well tolerated with excellent local control in UMT-ESCC with supraclavicular lymph node metastasis. PMID 28029663
Hyperthermia induces apoptosis by targeting Survivin in esophageal cancer.
Okt. 2015 | Qin, Sida; Xu, Chongwen; Li, Shuo; Wang, Xifang; Sun, Xin; Wang, Peili; Zhang, Boxiang; Ren, Hong
Hyperthermia is considered the fifth pillar of cancer treatment. It induces cancer cell apoptosis, however, its molecular mechanisms remain unclear. In the present study, the role of Survivin in hyperthermia-induced apoptosis in esophageal cancer was investigated. Different temperatures were used to treat EC109 esophageal cancer cells, and their viability was found to be significantly inhibited with a concomitant increase in apoptosis and necrosis. Necrosis increased in a temperature‑dependent manner, whereas peak apoptosis was reached at 43˚C. The hyperthermia-induced apoptosis was due to the inhibition of Survivin and the activation of caspase-3. Subsequently, overexpression of Survivin inhibited the activation of caspase-3 and hyperthermia-induced apoptosis, however, this inhibition was reversed in the absence of XIAP. Immunoprecipitations showed that Survivin did not directly bind to caspase-3, whereas XIAP interacted with Survivin and caspase-3. Immunohistochemistry was performed to detect the expression of Survivin in esophageal cancer patient samples. A higher expression of Survivin in esophageal cancer tissues compared to normal tissues was observed, and a high expression correlated with poor prognosis. The results indicated that hyperthermia decreases the expression of Survivin, prevents its binding to XIAP, activates caspase-3 and induces apoptosis. Due to its correlation with poor prognosis, Survivin may be a target for hyperthermia in the treatment of esophageal cancer. PMID 26352384
Hyperthermia combined with chemotherapy for patients with residual or recurrent oesophageal cancer after definitive chemoradiotherapy.
Apr. 2015 | Nishimura, Sho; Saeki, Hiroshi; Nakanoko, Tomonori; Kasagi, Yuta; Tsuda, Yasuo; Zaitsu, Yoko; Ando, Koji; Nakashima, Yuichiro; Imamura, Y U; Ohgaki, Kippei; Oki, Eiji; Ohga, Saiji; Nakamura, Katsumasa; Morita, Masaru; Maehara, Yoshihiko
Definitive chemoradiotherapy (dCRT) is frequently administered in oesophageal cancer. We carried out hyperthermochemotherapy (HCT) for residual or recurrent cases after dCRT for oesophageal cancer. The aim of this study was to elucidate the usefulness of salvage HCT for these patients. PMID 25862892
Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine.
Feb. 2015 | Narita, Miwako; Kanda, Tatsuo; Abe, Takashi; Uchiyama, Takayoshi; Iwafuchi, Minami; Zheng, Zhiyin; Liu, Aichun; Kaifu, Tsutomu; Kosugi, Shinichi; Minagawa, Masahiro; Itoh, Kyogo; Takahashi, Masuhiro
Patients with advanced stage of squamous cell carcinoma of esophagus have a poor prognosis with a lethal outcome. In order to explore the feasibility and effectiveness of dendritic cell (DC)-based immunotherapy for squamous cell carcinoma of esophagus, we performed a phase I/II clinical trial of monocyte-derived dendritic cells (moDCs) pulsed with SART1 peptide in seven patients with advanced stage of this disease. Although the feasibility of this therapy was definite, the effectiveness was not clearly confirmed in advanced stage of squamous cell carcinoma of esophagus. However, in vitro study revealed that moDCs generated for this therapy possessed a potent ability of inducing SART1 peptide-specific cytotoxic T lymphocytes (CTLs). In addition, these moDCs were demonstrated to be able to produce exosomes with an antigen presenting ability for inducing SART1 peptide-specific CTLs. ELISPOT assay using cryopreserved patient's lymphocytes demonstrated that IFN-γ ELISPOTs were increased after four times of SART1 peptide-pulsed moDC vaccinations compared with before the vaccination in a patient. The present study demonstrated that moDCs prepared from advanced stage of squamous cell carcinoma of esophagus possess a good immune function and in vivo immune responses (detected by ELISPOT assay) were evoked by the infusion of these moDCs. These findings suggest that DC-based immunotherapy could be one of the modalities applicable for squamous cell carcinoma of esophagus. PMID 25625346
[WT1 peptide pulsed dendritic cell therapy with activated T lymphocytes therapy for advanced cancers].
Jan. 2011 | Kato, Yoichi
We assessed the efficacy of WT1 peptide pulsed dendritic cell (DC) therapy for various advanced cancers. All patients were vaccinated 5 times for 10 weeks with autologous monocytes derived DC and activated T lymphocytes. We treated a total of 26 patients who had HLA-A2402 or/and HLA-A0201. We evaluated 20 of the 26 patients who finished 5-time vaccination (10 men and 10 women, aged 48-81 years, Mean 64 years) and were diagnosed as follows: 3-pancreas cancer, 2-colorectal, 2-breast, 2-esophageal, 2-lung, 2-uterus, 2-ovarian and 5 others. In Clinical response (RECIST), the result was assessed as CR/PR/SD/PD, 0/7/8/5, respectively. Furthermore, the 7 PRs were resulted from 2-colorectal, and one of each was lung, laryngeal, axis, pancreas and smooth muscle sarcoma cancer. The 4 of 7 PR patients were treated with chemotherapy. PMID 21224534
Vaccination with multiple peptides derived from novel cancer-testis antigens can induce specific T-cell responses and clinical responses in advanced esophageal cancer.
Juli 2009 | Kono, Koji; Mizukami, Yoshiki; Daigo, Yataro; Takano, Atsushi; Masuda, Ken; Yoshida, Koji; Tsunoda, Takuya; Kawaguchi, Yoshihiko; Nakamura, Yusuke; Fujii, Hideki
We previously identified three novel HLA-A24-restricted epitope peptides, which were derived from three cancer-testis antigens, TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3), as targets for cancer vaccination against esophageal squamous cell carcinoma (ESCC). To examine the safety, immunogenicity, and antitumor effect of vaccine treatment using a combination of these three peptides, 10 HLA-A2402-positive advanced ESCC patients who failed to standard therapy were enrolled in a phase I clinical trial. Each of the three peptides (1 mg each) was intradermally administered with 1 mL of incomplete Freund's adjuvant to the neck in three separate regions weekly for 5 weeks. The cancer vaccination therapy was well tolerated without any treatment-associated adverse events of grade 3 or 4. The TTK-, LY6K-, and/or IMP-3-specific T-cell immune responses were observed by enzyme-linked immunospot assay in peripheral blood lymphocytes obtained from nine of the 10 ESCC patients after their vaccination. The median survival time after the vaccination was 6.6 months. The vaccination could induce good clinical responses in 50% of the 10 patients. One patient experienced a complete response in hepatic metastasis lasting 7 months, one showed objective responses in all lung metastasis lesions, and three patients revealed a stable disease condition for at least 2.5 months. The cancer vaccine therapy using these three peptides demonstrated satisfactory safety and good immunogenicity as well as promising disease control rate, and therefore warrants further clinical studies. PMID 19459850
Novel therapeutic strategies for treating esophageal adenocarcinoma: the potential of dendritic cell immunotherapy and combinatorial regimens.
Okt. 2008 | Milano, Francesca; Krishnadath, Kausilia K
Esophageal adenocarcinoma (EAC) is an extremely aggressive disease with an overall 5 years survival rate of less than 20%. Current treatments, such as surgery, or chemo- and radiotherapy have only little effect on survival. Attempts to combine these treatment modalities were only limited successful with marginal improvement of prognosis. Therefore, novel treatment strategies are urgently needed. In a previous study we demonstrated that dendritic cell (DC) immunotherapy may be an attractive and promising approach to treat EAC. Although potent immune responses can be raised by DC therapy, there are several concerns about the immunosuppressive microenvironment that characterizes these cancers, which may inhibit an effective immune response. Here a general overview is given of the current management of EAC and immunotherapies. More specific focus is on the EAC tumor microenvironment, and several potential combinatorial strategies that can be explored for improving treatment of EAC. PMID 18703104
Experimental evidence for the efficacy of combined therapy of CPT-11 and hyperthermia for squamous cell carcinoma of the esophagus.
Feb. 2008 | Nozoe, Tadahiro; Yasuda, Mitsuhiro; Honda, Masayuki; Imutsuka, Sadaaki; Korenaga, Daisuke
The aim of the current study was to show an anti-tumor effect for esophageal squamous carcinoma cells derived from a combination of hyperthermia and CPT-11, which would ultimately lead to the clinical usage of this therapeutic modality for patients with squamous cell carcinoma of the esophagus. PMID 18265646
Antitumor activity of a fusion of esophageal carcinoma cells with dendritic cells derived from cord blood.
Okt. 2005 | Guo, Guanghua; Chen, Suzuan; Zhang, Juan; Luo, Lili; Yu, Jing; Dong, Hongmei; Xu, Hong; Su, Zhongjing; Wu, Libiao
The aim of this experiment was to develop a cytotoxic cancer vaccine (EC109-DC) prepared by fusions of esophageal carcinoma cells with dendritic cells derived from cord blood and to study the biological characteristics and resultant induction of antitumor immunity. CD34+ hematopoietic stem cells were isolated from cord blood using a CD34+ Progenitor Cell Isolation Kit by magnetic cell sorting system (MACS). CD34+ cells were incubated with rhGM-CSF, rhTNF-alpha and rhSCF for 2 weeks as DC (dendritic cells), and then by PEG-3600 to fuse with an esophageal carcinoma cell line. Selection with MACS marked with HLA-DR MicroBeads generated EC109-DC. Phenotypes and proliferation were analyzed by flow cytometry and cell culture in vitro. The lymphocyte proliferation reaction and CTL cytotoxicity were examined by MTT assay. The EC109-DC cells could proliferate slowly in vitro and highly expressed CD80, CD83 and CD86. The lymphocyte proliferation reaction and specific cytotoxicity against EC109 induced by EC109-DC cells were significantly higher than in control groups (p < 0.05). EC109-DC cells obtained by PEG fusion acquired the immuno-stimulating phenotype and could significantly stimulate the lymphocyte proliferation reaction and CTL activity. The results of this research provide the basis for materials to develop the DC-based vaccine against esophageal carcinoma. PMID 16171908
A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery.
Sep. 2004 | Albregts, M; Hulshof, M C C M; Zum Vörde Sive Vörding, P J; van Lanschot, J J B; Richel, D J; Crezee, H; Fockens, P; van Dijk, J D P; González González, D
This phase I-II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70 MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15-60 min of heating to 41 degrees C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999-February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6 cm. The maximum tumour temperature failed to reach at least 41 degrees C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right = 1:3:3:3, with a power range of 800-1000 W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T(90) = 39.3 degrees C, T(50) = 40 degrees C, T(10) = 40.7 degrees C and a median T(max) = 41.9 degrees C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia. PMID 15370820
Large-scale immunomagnetic selection of CD14+ monocytes to generate dendritic cells for cancer immunotherapy: a phase I study.
Nov. 2003 | Babatz, J; Röllig, C; Oelschlägel, U; Zhao, S; Ehninger, G; Schmitz, M; Bornhäuser, M
Dendritic cells (DC) are professional antigen-presenting cells that are widely used in the experimental immunotherapy of cancer. For clinical use GMP-like protocols for the preparation of functionally active dendritic cells (DC) in large numbers and at high purity are needed. However, the currently available protocols have certain disadvantages. In this study we tested the generation and clinical applicability of DC from monocyte preparations produced by immunomagnetic CD14(+) selection using a semiautomated clinical scale immunomagnetic column. Peripheral blood mononuclear cells (PBMC) of 10 patients with metastatic solid tumors were used. With the immunomagnetic separation, we obtained a cell suspension of high CD14(+) purity (median 97.4%, range 94.9-99.0) with a high monocyte yield (median 82.3%, range 63.9-100.0). Differentiation of CD14(+) cells into mature monocyte-derived DC was induced by incubation with IL-4, GM-CSF, TNF-alpha, PGE(2), IL-1 beta, and IL-6. Mature DC showed a high expression of CD83, HLA-DR, and the co-stimulatory molecules CD80 and CD86. Overall CD83(+) yield was 12.1% (range 4.0-29.4). Allogeneic T stimulatory capacity could be demonstrated for all DC preparations in proliferation assays. No significant differences in marker expression or T cell stimulation was detected between fresh DC and those derived from cryopreserved immature DC. Clinical administration of autologous DC by three different parenteral routes was tolerated by all 10 patients without systemic signs of toxicity. Our results indicate that immunomagnetic isolation of CD14(+) monocytes using the CliniMACS device is a suitable method for clinical-scale generation of functional DC under GMP-grade conditions. The selection can be performed in a closed system. Therefore, immunomagnetic CD14(+) selection can be seen as an alternative way to generate DC for clinical tumor vaccination protocols. PMID 14594508
[Immunotherapy for esophageal carcinoma].
Mai 2002 | Yamana, Hideaki
Recent progress in gene technology has clarified the existence of some cancer-rejection genes and peptides such as MAGE, MART, etc. Many clinical trials with cancer vaccines have been performed. Since the clinical efficacy of HLA class I-restricted peptide vaccines is still poor, many researchers are mainly administering dendritic cell therapies. However, there have been few clinicals trials of cancer-specific immunotherapy for esophageal carcinomas. We have performed cancer vaccine therapy with SART-1 peptide and locoregional adoptive immunotherapy with activated autologous lymphocytes for patients with advanced esophageal carcinoma in a phase I and a phase I/II trial, respectively. The clinical responses were poor in the vaccine trial because of the rapid growth of esophageal cancers and the requirement for more than 2 months to activate and increase killer T cells after in vivo vaccination, while locoregional adoptive immunotherapy was effective for the treatment of esophageal cancers even in advanced stages with organ metastases. Based on these results, we think that a combination immunotherapy with adoptive immunotherapy and vaccine therapy is needed for the treatment of advanced esophageal carcinomas. PMID 11993228