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Lung adenocarcinoma may be a more susceptive subtype to a dendritic cell-based cancer vaccine than other subtypes of non-small cell lung cancers: a multicenter retrospective analysis.
Aug. 2016 | Takahashi, Hidenori; Shimodaira, Shigetaka; Ogasawara, Masahiro; Ota, Shuichi; Kobayashi, Masanori; Abe, Hirofumi; Morita, Yuji; Nagai, Kazuhiro; Tsujitani, Shunichi; Okamoto, Masato; Suzuki, Yukio; Nakanishi, Yoichi; Yonemitsu, Yoshikazu; ,
The J-SICT DC Vaccine Study Group provides dendritic cell (DC) vaccines for compassionate use under unified cell production and patient treatment regimens. We previously reported beneficial effects of DC vaccines on the overall survival of 62 patients with advanced non-small cell lung cancer (NSCLC) in a single-center analysis. Here, we extended analysis to 260 patients with NSCLC who were treated at six centers. PMID 27448677

Pilot study of radiofrequency hyperthermia in combination with gefitinib in gefitinib-effective patients with advanced NSCLC.
Juli 2016 | Qin, Yijia; Sun, Yu; Liu, Yongmei; Luo, Yiqiao; Zhu, Jiang
Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer in China. Gefitinib is effective for patients with positive epidermal growth factor receptor gene mutation; however, acquired drug resistance counteracts the duration response. Hyperthermia is widely clinically applied in the treatment of solid tumors. This pilot study was designed to evaluate the feasibility of the combination of gefitinib and hyperthermia. PMID 27385984

Thermosensitive liposomal cisplatin in combination with local hyperthermia results in tumor growth delay and changes in tumor microenvironment in xenograft models of lung carcinoma.
Juni 2016 | Dou, Yannan Nancy; Dunne, Michael; Huang, Huang; Mckee, Trevor; Chang, Martin C; Jaffray, David A; Allen, Christine
Treatment efficacy of a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, was determined in xenograft models of non-small-cell lung carcinoma. The short-term impact of local hyperthermia (HT) on tumor morphology, microvessel density and local inflammatory response was also evaluated. The HTLC formulation in combination with local HT resulted in a significant advantage in therapeutic effect in comparison with free drug and a non-thermosensitive liposome formulation of CDDP (i.e. Lipoplatin(TM)) when administered at their maximum tolerated doses. Local HT-induced widespread cell necrosis and a significant reduction in microvessel density in the necrotic regions of tumors. CD11b-expressing innate leukocytes were demonstrated to infiltrate and reside preferentially at the necrotic rim of tumors, likely as a means to phagocytose-damaged tissue. Colocalization of CD11b with a marker of DNA damage (i.e. γH2AX) revealed a small portion of CD11b-expressing leukocytes that were possibly undergoing apoptosis as a result of HT-induced damage and/or the short lifespan of leukocytes. Overall, HT-induced tissue damage (i.e. at 24-h post-treatment) alone did not result in significant improvements in treatment effect, rather, the enhancement in tumor drug availability was correlated with improved therapeutic outcomes. PMID 27310112

Dendritic cell vaccine and cytokine-induced killer cell therapy for the treatment of advanced non-small cell lung cancer.
Apr. 2016 | Zhang, Lihong; Yang, Xuejing; Sun, Zhen; Li, Jiali; Zhu, Hui; Li, Jing; Pang, Yan
The present study aimed to evaluate the survival time, immune response and safety of a dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell therapy (DC-CIK) in advanced non-small cell lung cancer (NSCLC). The present retrospective study enrolled 507 patients with advanced NSCLC; 99 patients received DC-CIK [immunotherapy group (group I)] and 408 matched patients did not receive DC-CIK, and acted as the control [non-immunotherapy group (group NI)]. Delayed-type hypersensitivity (DTH), quality of life (QOL) and safety were analyzed in group I. The follow-up period for the two groups was 489.2±160.4 days. The overall survival (OS) time was calculated using the Kaplan-Meier method. DTH was observed in 59 out of 97 evaluated patients (60.8%) and 67 out of 98 evaluated patients (68.4%) possessed an improved QOL. Fever and a skin rash occurred in 36 out of 98 patients (36.7%) and 7 out of 98 patients (7.1%) in group I. DTH occurred more frequently in patients with squamous cell carcinoma compared with patients with adenocarcinoma (77.1 vs. 40.4%; P=0.0013). Radiotherapy was not associated with DC-CIK-induced DTH (72.7 vs. 79.6%; P=0.18), but chemotherapy significantly reduced the rate of DTH (18.2 vs. 79.6%; P=0.00). The OS time was significantly increased in group I compared with group NI (P=0.03). In conclusion, DC-CIK may induce an immune response against NSCLC, improve the QOL, and prolong the OS time of patients, without adverse effects. Therefore, the present study recommends DC-CIK for the treatment of patients with advanced NSCLC. PMID 27073525

Oncolytic newcastle disease virus triggers cell death of lung cancer spheroids and is enhanced by pharmacological inhibition of autophagy.
Feb. 2016 | Hu, Lulu; Sun, Sulan; Wang, Tianpeng; Li, Yingchun; Jiang, Ke; Lin, Guibin; Ma, Yan; Barr, Martin P; Song, Fei; Zhang, Guirong; Meng, Songshu
Lung cancer stem cells (CSCs) have recently been isolated from lung cancer patient samples and have been reported to be responsible for tumor initiation, treatment resistance and tumor recurrence. We have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW) induces apoptosis in drug-resistant lung cancer cells. However, how NDV exerts its oncolytic effect on lung CSCs remains to be investigated. Here we show that NDV/FMW replicates in, and lyses CSC-enriched lung cancer spheroids and inhibits the 3D growth potential of lung cancer spheroid and agar colonies. We demonstrate that NDV/FMW triggers caspase-dependent apoptosis in lung cancer spheroids as shown by increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage. Notably, NDV/FMW infection results in the degradation of microtubule-associated protein 1 light chain 3 (LC3) II and P62, two hallmarks of autophagy maturation, indicating that NDV/FMW promotes autophagy flux in lung cancer cell spheroids. This was further confirmed by the appearance of an increased number of double-membrane vesicles as detected by transmission electron microscopy. We also show that NDV/FMW promotes autophagy degradation in lung cancer spheroids via inhibition of the AKT/mTOR pathway. In addition, treatment of spheroids with the autophagy inhibitor, chloroquine increases NDV/FMW-induced cytotoxicity. Collectively, our data show that oncolytic NDV/FMW may be a potential strategy in targeting lung CSCs. PMID 26885450

Vaccine immunotherapy in lung cancer: Clinical experience and future directions.
Aug. 2015 | Freeman-Keller, Morganna; Goldman, Jamie; Gray, Jhanelle
Lung cancer remains the most common cause of cancer-related deaths in the United States, with SEER data showing lung cancer accounting for 29% of all male-related cancer mortality and 26% of all female-related mortality. Patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) who have localized disease both have 5-year survival rates of 52.2%, whereas patients with metastatic disease have 5-year survival rates of only 3.7%. Traditional anti-cancer therapies (surgery, radiotherapy, and chemotherapy) have limited effectiveness in curbing progression. However, advances in immunology and molecular biology in the past two decades have resulted in improved prognosis for those with SCLC and NSCLC, although novel therapies are still needed to make significant improvements in median overall and progression-free survival rates. Notable progress on the importance of tumor immunology has included work on immune surveillance, antigenic targets, and immune checkpoints. Immunotherapies, including vaccines, which can induce antitumor responses by harnessing the power of the immune system, may help to fill this void, and the cancer vaccine continues to be studied as adjunctive therapy. Here, we review recently reported results from clinical trials as well as the possible future roles of vaccine therapy in the treatment of SCLC and NSCLC patients. PMID 25989231

Immunotherapy for lung cancer: for whom the bell tolls?
März 2015 | Madureira, Pedro; de Mello, Ramon Andrade; de Vasconcelos, Alessandro; Zhang, Yan
Lung cancer is the leading cause of cancer-related death and accounts for approximately 30% of all cancer deaths. Despite the recent developments in personalized therapy, the prognosis in lung cancer is still very poor. Immunotherapy is now emerging as a new hope for patients with lung cancer. It is well known that standard chemotherapeutic regimens have devastating effects for the patient's immune system. Therefore, the aim of immunotherapy is to specifically enhance the immune response against the tumour. Recently, many trials addressed the role of such therapies for metastatic non-small cell lung cancer (NSCLC) treatment: ipilimumab, tremelimumab, nivolumab and pembrolizumab are immunotherapeutic agents of high relevance in this field. Anti-tumour vaccines, as well as dendritic cell-based therapies, have emerged as potent inducers of immune response against the tumour. Herein, we will review some of the most promising cancer immunotherapies, highlighting their advantages and try to understand, in an immunological perspective, the missteps associated with the current treatments for cancer. PMID 25736929

Immunotherapy prospects in the treatment of lung cancer and mesothelioma.
März 2015 | Aerts, Joachim G; Lievense, Lysanne A; Hoogsteden, Henk C; Hegmans, Joost P
A very recent finding is the role of immune activation in cancer. The assumption that stimulating the patient's immune system to attack tumors is a valuable treatment option in malignant diseases has gained more acceptance. However the high immunosuppressive effects caused by the tumor limits this beneficial effect. There is a delicate balance between immunoactivation and immunosuppression in a patient. Especially in non small cell lung cancer (NSCLC), the role of immunosuppressive cells hampering immune activation is high. But also in small cell lung cancer (SCLC) and mesothelioma immunosuppressive activity is high. This is suggested to be related to the type of tumor, advanced stage of the disease, and the tumor load. In this review, we provide an overview of the progress and challenges in the immunotherapeutic approaches in lung cancer. We conclude with the concept that immunotherapy in thoracic malignancies must be tailored made to the balance of the immune system. PMID 25806279

Immunotherapy in lung cancer.
März 2015 | Massarelli, Erminia; Papadimitrakopoulou, Vassiliki; Welsh, James; Tang, Chad; Tsao, Anne S
Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC. PMID 25806281

Dendritic cell immunotherapy combined with cytokine-induced killer cells promotes skewing toward Th2 cytokine profile in patients with metastatic non-small cell lung cancer.
März 2015 | Zhao, Peng; Bu, Xiaocui; Wei, Xiaofang; Sun, Weihong; Xie, Xihe; Li, Changyou; Guo, Qingming; Zhu, Danni; Wei, Xiaoqiang; Gao, Daiqing
Dendritic cell (DC) vaccination and cytokine-induced killer (CIK) cell therapy (DC/CIK) have shown limited success in the treatment of advanced non-small cell lung cancer (NSCLC). To investigate the reason for this limited success, the effects of DC/CIK cell therapy on the immune responses of tumor-bearing patients and patients with resected NSCLC were evaluated. In the total 50 patients studied, the serum concentrations of the Th2 cytokines (IL-4 and IL-10) in tumor-bearing patients were significantly higher than those with resected NSCLC before immunotherapy. The post-therapy Th1 cytokine (IFN-γ) level in patients with resected NSCLC significantly increased from the pre-therapy level. In contrast, significantly enhanced post-therapy Th2 cytokine (IL-4 and IL-10) levels were found in tumor-bearing patients. The intracellular staining assay revealed that DC/CIK cell therapy increased the IFN-γ-producing T lymphocyte (CD8(+)IFN-γ(+)) frequency in patients with resected NSCLC, but these lymphocytes were not found in tumor-bearing patients. Furthermore, overproduction of vascular endothelial growth factor (VEGF) in tumor-bearing patients showed a statistically positive correlation with IL-4, suggesting that VEGF might be responsible for the predominance of serum Th2 cytokines. In a word, tumor-bearing patients developed a Th2-dominant status that could not be reversed toward Th1 following immunotherapy. A combined regiment of DC vaccination and CIK cell therapy with other treatments to overcome systemic Th2-dominant immune response might improve the current clinical benefit. PMID 25698555

Randomized controlled phase III trial of adjuvant chemo-immunotherapy with activated killer T cells and dendritic cells in patients with resected primary lung cancer.
Jan. 2015 | Kimura, Hideki; Matsui, Yukiko; Ishikawa, Aki; Nakajima, Takahiro; Yoshino, Mitsuru; Sakairi, Yuichi
We conducted a phase III randomized controlled trial (RCT) to investigate the efficacy of postsurgical adjuvant immunotherapy combined with chemotherapy. The immunotherapy targets were residual micrometastases and clones resistant to chemotherapy. PMID 25262164

Immunotherapy and lung cancer: current developments and novel targeted therapies.
Dez. 2014 | Domingues, Duarte; Turner, Alice; Silva, Maria Dília; Marques, Dânia Sofia; Mellidez, Juan Carlos; Wannesson, Luciano; Mountzios, Giannis; de Mello, Ramon Andrade
Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC. PMID 25496336

Apoptotic induction of lung adenocarcinoma A549 cells infected by recombinant RVG Newcastle disease virus (rL-RVG) in vitro.
Nov. 2014 | Yan, Yulan; Liang, Bing; Zhang, Jin; Liu, Yang; Bu, Xuefeng
Newcastle disease virus (NDV) is a member of the genus Avulavirus in the Paramyxoviridae family and its antitumor properties depend on its ability to kill malignant cells while not affecting normal cells. The present study investigated a recombinant avirulent NDV LaSota strain (wild-type NDV strain) expressing the rabies virus glycoprotein (rL-RVG), examined its oncolytic effect on the lung adenocarcinoma A549 cell line and evaluated its potential to serve as a vaccine against lung cancer. A549 cells were infected with the rL-RVG virus and analyzed by MTT, western blot, polymerase chain reaction (PCR), immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick end labeling and flow-cytometric analyses. PCR, western blot and immunofluorescence showed that the RVG gene and protein were stably expressed in A549 cells following infection with rL-RVG. The growth of A549 cells in the rL-RVG group was inhibited more effectively compared to those infected with the wild-type NDV strain. MTT results showed that cell growth inhibition rates in the rL-RVG group were significantly higher than those in the NDV group (P<0.05). Early apoptosis in the rL-RVG group was also more evident, with the apoptotic index being increased in rL-RVG group. The expression of the pro-apoptotic proteins caspase-3, -8 and -9 increased. The expression of caspase-3 decreased following application of the broad-specificity caspase inhibitor Z-VAD-FMK. However, the expression of the inhibitory apoptosis protein B-cell lymphoma 2 (bcl-2) did not change, but bcl-2-associated X/bcl-2 ratio was higher in the rL-RVG group than that in the NDV group. The rL-RVG strain was able to suppress lung cancer cell growth and promote lung cancer cell apoptosis to a greater extent than the wild-type NDV strain. Therefore, the rL-RVG strain is a potent antitumor agent. PMID 25322856

Inhibition of cell proliferation by mild hyperthermia at 43˚C with Paris Saponin I in the lung adenocarcinoma cell line PC-9.
Nov. 2014 | Zhao, Pengjun; Jiang, Hao; Su, Dan; Feng, Jianguo; Ma, Shenglin; Zhu, Xinhai
Rhizoma paridis is widely used for cancer therapy due to its potential involvement in the suppression of tumor growth. However, at present there is no clear explanation for the mechanism underlying the inhibitory effects of Rhizoma paridis combined with hyperthermia on tumor growth. The aim of the present study was to evaluate the effects of Paris saponin I (PSI) combined with hyperthermia on a variety of non-small cell lung cancer (NSCLC) cell lines. An MTT assay was used to determine the levels of growth inhibition. The cell cycle was analyzed using flow cytometry and cell apoptosis was analyzed with Annexin V/propidium iodide staining and the Hoechst assay. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and caspase-3 proteins were detected using western blotting. The inhibition rates significantly increased with PSI in combination with hyperthermia at 43˚C. PSI with hyperthermia at 43˚C caused G2/M phase arrest and significantly induced apoptosis. The expression level of Bcl-2 decreased, while Bax expression increased following treatment with PSI with hyperthermia at 43˚C. In addition, the protein expression of caspase-3 was significantly enhanced. PSI combined with hyperthermia is a potent antitumor treatment through the inhibition of proliferation of NSCLC cells and may be developed as a new antitumor therapy. PSI combined with hyperthermia significantly induced apoptosis through a multi regulatory process involving G2/M arrest and regulation of Bax, Bcl-2 and caspase-3 expression, resulting in cell death and tumor inhibition. PMID 25322761

Effect of recombinant Newcastle disease virus transfection on lung adenocarcinoma A549 cells in vivo.
Nov. 2014 | Yan, Yulan; Jia, Lijuan; Zhang, Jin; Liu, Yang; Bu, Xuefeng
Newcastle disease virus (NDV) has been reported to selectively duplicate in and then destroy tumor cells, whilst sparing normal cells. However, the effect of NDV on lung cancer has yet to be elucidated. In the present study, recombinant NDV (rl-RVG) was applied to lung adenocarcinoma A549 cell tumor-bearing mice to explore its effect on the proliferation of the cells and the immune response of the mice. Following rl-RVG transfection, RVG and NDV gene expression, decreased tumor growth, subcutaneous tumor necrosis, tumor apoptosis and an increased number of cluster of differentiation (CD)3(-)/CD49(+) natural killer cells were more evident in the rl-RVG group. The present study demonstrated that rl-RVG transfection effectively restrained lung adenocarcinoma A549 cell growth in vivo, which may have been accomplish by inducing tumor cell apoptosis and regulating the cell immune response. PMID 25364430

Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells.
Aug. 2014 | Jiang, Ke; Li, Yingchun; Zhu, Qiumin; Xu, Jiansheng; Wang, Yupeng; Deng, Wuguo; Liu, Quentin; Zhang, Guirong; Meng, Songshu
Oncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells. PMID 25078870

Oncolytic therapy of a recombinant Newcastle disease virus D90 strain for lung cancer.
Juni 2014 | Chai, Zheng; Zhang, Peiyi; Fu, Fang; Zhang, Xueyun; Liu, Ying; Hu, Lihua; Li, Xi
Lung cancer is one of the leading causes of deaths from cancer worldwide. Tumor virotherapy using naturally oncolytic Newcastle disease virus (NDV) has been shown to be safe and effective in preclinical studies and clinical trials. Previously, we have reported the NDV D90 strain that was isolated from natural source has an antiproliferative effect in human lung cancer cell line A549. PMID 24885546

Current status of oncothermia therapy for lung cancer.
Apr. 2014 | Szasz, Andras
Lung cancer is one of the most common malignant tumors, and it has the highest death rate. Oncothermia is a feasible and successful treatment for lung cancer. Results show a remarkable survival benefit for patients, with a good quality of life. The treatment has no, or in some cases mild, side-effects and could decrease the adverse effects of the complementary treatment. Applying oncothermia together with other treatment methods could increase the effects and result in better performance. A comparison of studies demonstrates a good correspondence in the data, which strengthens the reliability of the studies, and clearly shows the feasibility of the application of oncothermia to treating all kinds of pulmonary malignancies including non-small-cell and small-cell primary tumors, and all of the metastatic diseases of the pulmonary system. PMID 24782955

Superior anti-tumor protection and therapeutic efficacy of vaccination with dendritic cell/tumor cell fusion hybrids for murine Lewis lung carcinoma.
Jan. 2014 | Chen, Xiaodan; Liu, Zhimin; Huang, Yunchao; Li, Ruilei; Zhang, Hongqing; Dong, Suwei; Ge, Chunlei; Zhang, Zhiwei; Wang, Ying; Wang, Ying; Xue, Yuanbo; Li, Zhen; Song, Xin
The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research into their potential use in immunotherapy in the treatment of cancer. In this study, we examined the efficacy of dendritic cell-tumor cell fusion hybrid vaccines in eliciting an immune response against Lewis lung carcinoma (LLC) cells, as compared to other types of tumor vaccines. In addition, we also tested whether the efficacy of the vaccines was affected by the route of administration. Four different tumor vaccines were compared: (1) HC (hybrid cell), consisting of DC/LLC hybrids; (2) DC+LLC (DCs pulsed with apoptotic LLCs); (3) DC without antigen loading/pulsing; (4) LLC (apoptotic/irradiated tumor cells). We also compared four different routes of administration for each vaccine: (1) Preimmunization; (2) Vaccination therapy; (3) Adoptive immunotherapy; (4) Vaccination therapy combined with adoptive immunotherapy. Anti-tumor immunity was assessed in vivo and the CTL (cytotoxic T lymphocyte) response as well as the expression of key cytokines, IFN-γ and IL-10 were further evaluated using in vitro assays. PMID 24191684

Therapeutic outcomes of combining cryotherapy, chemotherapy and DC-CIK immunotherapy in the treatment of metastatic non-small cell lung cancer.
Sep. 2013 | Yuanying, Yuan; Lizhi, Niu; Feng, Mu; Xiaohua, Wang; Jianying, Zeng; Fei, Yao; Feng, Jiang; Lihua, He; Jibing, Chen; Jialiang, Li; Kecheng, Xu
Currently there are no effective therapies for the treatment of metastatic non-small cell lung cancer (NSCLC). Here, we conducted a retrospective study of 161 patients to evaluate the therapeutic effects of combining cryosurgery, chemotherapy and dendritic cell-activated cytokine-induced killer cells (DC-CIK) immunotherapy. The overall survival (OS) after diagnosis of metastatic NSCLC to patient death was assessed during a 5-years follow-up period. OS of patients who received comprehensive cryotherapy was (median OS, 20 months; n = 86) significantly longer than that of patients who did not received cryotherapy (median OS, 10 months; n = 75; P < 0.0001). Five treatment combinations were selected: chemotherapy (n = 44); chemo-immunotherapy (n = 31); cryo-chemotherapy (n = 32); cryo-immunotherapy (n = 21); and cryo-chemo-immunotherapy (n = 33). A combination of cryotherapy with either chemotherapy or immunotherapy lead to significantly longer OS (18 months and 17 months, respectively) compared to chemotherapy and chemo-immunotherapy (8.5 months and 12 months, respectively; P < 0.001); however, the median OS of patients who underwent cryo-chemo-immunotherapy was significantly longer (27 months) compared to the other treatment programs (P < 0.001). In conclusion, a combination of cryotherapy, chemotherapy and DC-CIK immunotherapy proved the best treatment option for metastatic NSCLC in this group of patients. PMID 23948179

Harnessing the immune system for the treatment of non-small-cell lung cancer.
März 2013 | Brahmer, Julie R
Over the last several years, new therapeutic targets have emerged in immunotherapy, particularly the immune checkpoint pathways. Blocking inhibitory pathways via monoclonal antibodies, such as the anti-cytotoxic T-lymphocyte antigen-4 antibody (ipilimumab), anti-programmed cell death-1 antibody (BMS-936558), and anti-programmed cell death-1 ligand antibody (BMS-936559), has the ability to break down the shield that tumors co-opt for their defense. Vaccines are able to help the immune system develop immune memory that can have long-lasting, tumor-specific effects. Newer vaccines, particularly the tumor cell vaccine, belagenpumatucel-L, and the antigen-specific vaccines, melanoma-associated antigen-A3, liposomal BLP-25, TG4010, and recombinant human epidermal growth factor, are being evaluated in some of the largest trials ever attempted in lung cancer therapy. These therapies alone or in combination may hold the key to making immunotherapy a reality in the treatment of lung cancer. PMID 23401435

Successful treatment of solitary bone metastasis of non-small cell lung cancer with bevacizumab and hyperthermia.
Jan. 2013 | Rubovszky, Gábor; Nagy, Tünde; Gődény, Mária; Szász, András; Láng, István
Non-small cell lung cancer (NSCLC) represents 85 % of all malignant lung cancers. In metastatic disease the principle goal of palliative therapy is to prolong survival with least toxicity and best patients' quality of life. Bevacizumab (BEV) has been approved as first line treatment in combination with platinum based chemotherapy and maintenance therapy in NSCLC. BEV can be added safely to several chemotherapeutic agents, however there is no data on coadministration with thermotherapy. Even in localized disease no robust evidence exists about the beneficial effect of loco-regional thermotherapy on overall survival, but it might be used successfully in symptom palliation. In this article a successful co-administration of BEV and hyperthermia is reported in a patient with monolocalized bone metastasis from previously operated NSCLC. This case suggests that electrohyperthermia can probably be incorporated in palliative therapy added not only to radiotherapy or chemotherapy but also to anti-angiogenic BEV treatment. PMID 22752712

Hyperthermia induces cytoskeletal alterations and mitotic catastrophe in p53-deficient H1299 lung cancer cells.
Nov. 2012 | Pawlik, Andrzej; Nowak, Jakub Marcin; Grzanka, Dariusz; Gackowska, Lidia; Michalkiewicz, Jacek; Grzanka, Alina
Hyperthermia is used in cancer therapy, however much remains to be discovered regarding its mechanisms of action at the cellular level. In this study, the effects of hyperthermia on cell death, survival, morphology and the cytoskeleton were investigated in a non-small cell lung cancer cell line, H1299. Despite the fact that this cell line is widely used in research, it has not yet been tested for heat shock sensitivity. Cells were given a 30-min heat shock at 43.5°C and 45°C and left to recover at 37°C for 24 and 48 h. 24 h after heat shock treatment, we monitored changes in the organization of the cytoskeleton using immunofluorescence microscopy. The number of actin stress fibers was significantly reduced, microtubules formed a looser meshwork, a portion of the cells possessed multipolar mitotic spindles, whereas vimentin filaments collapsed into perinuclear complexes. 48 h following heat stress, most of the cells showed recovery of the cytoskeleton, however we observed a considerable number of giant cells that were multinucleated or contained one enlarged nucleus. The data obtained by MTT assay showed a dose-dependent decrease of cell viability, while flow cytometric analysis revealed an increase in the number of cells with externalized phosphatidylserine. The results suggest that one of the modes of heat-induced cell death in H1299 cells is mitotic catastrophe, which probably ends in apoptosis. PMID 22483983

Re-irradiation plus regional hyperthermia for recurrent non-small cell lung cancer: a potential modality for inducing long-term survival in selected patients.
Juni 2012 | Ohguri, Takayuki; Imada, Hajime; Yahara, Katsuya; Moon, Seung Dae; Yamaguchi, Shinsaku; Yatera, Kazuhiro; Mukae, Hiroshi; Hanagiri, Takeshi; Tanaka, Fumihiro; Korogi, Yukunori
The purpose of this study was to assess the toxicity and efficacy of re-irradiation plus regional hyperthermia for recurrent NSCLC and to identify the predictors of long-term survival. PMID 22445656

Newcastle disease virus induces apoptosis in cisplatin-resistant human lung adenocarcinoma A549 cells in vitro and in vivo.
Jan. 2012 | Meng, Songshu; Zhou, Zhizhi; Chen, Fei; Kong, Xiangang; Liu, Huairan; Jiang, Ke; Liu, Wenbo; Hu, Maozhi; Zhang, Xiaorong; Ding, Chan; Wu, Yantao
Cisplatin (DDP) is widely used in lung cancer chemotherapy. However, cisplatin resistance represents a major obstacle in effective clinical treatment. This study aims to investigate whether Newcastle disease virus (NDV) exhibits an oncolytic effect on cisplatin-resistant A549 lung cancer cells. We found that NDV induced A549/DDP cell apoptosis via the caspase pathway, particularly involving caspase-9, while the mitogen-activated protein kinase (MAPK) and Akt pathways also contributed to apoptotic induction. Furthermore, NDV displayed oncolytic effects in a mouse A549/DDP lung cancer model. Collectively, our data indicate that NDV could overcome the cisplatin resistance in lung cancer cells in vitro and in vivo. PMID 22095029

Immunotherapy of lung adenocarcinoma patient with Peptide-pulsed dendritic cells: a case report.
Jan. 2012 | Wojas-Krawczyk, Kamila; Krawczyk, Paweł; Buczkowski, Jarosław; Walkowska, Anna; Jankowska, Olga; Czekajska-Chehab, Elżbieta; Milanowski, Janusz
Immunotherapy with ex vivo generated dendritic cells (DCs) is reported to be of low toxicity and of diverse effectiveness in cancer treatment. The synthetic antigens are frequently used for immunotherapy especially for patients with stable disease after prior treatment. We described the effect of peptide-loaded DCs-based immunotherapy on patient with recurrent surgically resected adenocarcinoma with bronchoalveolar feature with co-existing of Takayasu arteritis and chronic hepatitis B. In January 2010, 61-year-old patient received subcutaneously four bi-weekly vaccinations of DCs loaded with MUC1 and MAGE-3 epitopes. Additionally, he received three bi-weekly booster vaccinations after 7 months from the first course of immunotherapy. Delayed-type hypersensitivity test was positive only for MAGE-3 antigen. The evidence expansion of MAGE-3-specific CD8(+) cells after first vaccination and after third vaccination during boosters injections was observed (from 0.08% before vaccination to 0.5% after first vaccination; from 0.05% before booster vaccination to 0.24% after third injection). Computed tomography scans performed after first course and after booster course of vaccination until April 2011 did not shown any presence of lung tumour or metastases. Based on clinical factors (no completed wedge-resection and recurrent character of cancer) as well as on the presence of the tumour-antigen-specific immunological response, we could speculated that immunotherapy prolonged disease free-survival in our patient. Over 16 months from first vaccination, the patient remains without symptoms of cancer. PMID 22143160

Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer.
Sep. 2011 | Zhong, Runbo; Teng, Jiajun; Han, Baohui; Zhong, Hua
Lung cancer is the leading cause for cancer-related mortality and morbidity, and the survival of late-stage non-small cell lung cancer (NSCLC) remains poor. We hereby evaluate conventional chemotherapy followed by immunotherapy using dendritic cells and cytokine-induced killer cells in the treatment for late stage of NSCLC. PMID 21681372

Caspase- and p38-MAPK-dependent induction of apoptosis in A549 lung cancer cells by Newcastle disease virus.
Juli 2011 | Bian, Jianchun; Wang, Kai; Kong, Xiangang; Liu, Huairan; Chen, Fei; Hu, Maozhi; Zhang, Xiaorong; Jiao, Xinan; Ge, Baoxue; Wu, Yantao; Meng, Songshu
Newcastle disease virus (NDV) has a potential oncolytic effect due to its ability to induce apoptosis in tumor cells. However, previous studies have indicated discrepancies regarding the apoptosis signaling pathways induced by NDV in tumor cells. Here, we show that NDV infection induces simultaneous activation of intrinsic and extrinsic death pathways in A549 human lung cancer cells. In contrast, endoplasmic reticulum (ER) stress is not activated in NDV-induced apoptosis. We demonstrate for the first time that mitogen-activated protein kinase (MAPK) pathways are activated in NDV-infected A549 cells, and p38 MAPK is involved in NDV-induced cell death. Together, our findings provide novel insights into the underlying mechanisms by which NDV induces apoptosis in tumor cells. PMID 21625975

Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study.
Juli 2011 | Perroud, Maurício W; Honma, Helen N; Barbeiro, Aristóteles S; Gilli, Simone Co; Almeida, Maria T; Vassallo, José; Saad, Sara To; Zambon, Lair
Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. PMID 21682877

Immunotherapy as a strategy for the treatment of non-small-cell lung cancer.
Mai 2011 | Holt, Gregory E; Podack, Eckhard R; Raez, Luis E
Positive modulation of a patient's immune system to produce antitumor immunity is an attractive strategy that may improve the dismal outcomes typically associated with non-small-cell lung cancer (NSCLC). Using methods that either augment specific antitumor immunity or positively influence the patient's immune system to allow the de novo generation of immunity to encompass current strategies used in recent clinical trials of NSCLC. Encouraging results of Phase II trials in antigen-specific immunotherapy have led to three subsequent Phase III trials, which are currently enrolling. Results of these trials will improve our understanding of the role that immunotherapy plays in the treatment of NSCLC. Successful application of a humoral vaccine in Cuba led to its approval for the treatment of advanced NSCLC patients in that country. To date, trials involving nonspecific immunotherapeutic interventions have failed to improve outcomes in NSCLC and may indicate a need to combine them with antigen-specific vaccines. Although these trials will greatly advance our knowledge of NSCLC immunotherapy, we believe truly efficacious immunotherapy may only result from implementation of strategies to both augment antitumor immunity and counteract tumor-mediated immunosuppression. PMID 21359153

Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer.
Sep. 2010 | Um, Soo-Jung; Choi, Young Jin; Shin, Ho-Jin; Son, Cheol Hun; Park, You-Soo; Roh, Mee Sook; Kim, Yun Seong; Kim, Young Dae; Lee, Soo-Keol; Jung, Min Ho; Lee, Min Ki; Son, Choonhee; Choi, Pil Jo; Chung, Jooseop; Kang, Chi-Dug; Lee, Eun-Yup
A dendritic cell vaccine has been developed as a novel strategy for generating antitumor immunity in the treatment of cancer. The purpose of this study was to assess the maximal tolerated dose, safety, and immunologic response of a new dendritic cell vaccine (DC-Vac) into which tumor lysate was loaded by electroporation and pulse in patients with advanced non-small cell lung cancer (NSCLC). PMID 20223553

Mechanisms of murine dendritic cell antitumor dysfunction in aging.
Sep. 2009 | Grolleau-Julius, Annabelle; Abernathy, Lisa; Harning, Erin; Yung, Raymond L
Effective cancer immunotherapy depends on the body's ability to generate tumor antigen-presenting cells and tumor-reactive effector lymphocytes. As the most potent antigen presenting cells (APCs), dendritic cells (DCs) are capable of sensitizing T cells to new and recall antigens. Clinical trials of antigen-pulsed autologous DCs have been conducted in patients with a number of hematological and solid cancers, including malignant melanoma, lymphoma, myeloma, and non-small cell lung cancer. These studies suggest that antigen-loaded DC vaccination is a potentially safe and effective cancer therapy. However, the clinical results have been variable. Since the elderly are preferentially affected by diseases targeted by DC-directed immunotherapy, it is quite striking that few studies to date have focused on the effect of aging on DC function, a key aspect of optimal immunotherapy design in an aging population. In the present paper, we will discuss the consequences of aging on murine bone marrow-derived DC function and their use in cancer immunotherapy. PMID 19082999

Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer.
Sep. 2009 | Yasumoto, Kosei; Hanagiri, Takeshi; Takenoyama, Mitsuhiro
Despite recent advances in surgery, irradiation, and chemotherapy, the prognosis of patients with lung cancer is still poor. Therefore, the development and application of new therapeutic strategies are essential for improving the prognosis of this disease. Significant progress in our understanding of tumor immunology and molecular biology has allowed us to identify the tumor-associated antigens recognized by cytotoxic T lymphocytes. Immune responses and tumor-associated antigens against not only malignant melanoma but also lung cancer have been elucidated at the molecular level. In a theoretical sense, tumor eradication is considered possible through antigen-based immunotherapy against such diseases. However, many clinical trials of cancer vaccination with defined tumor antigens have resulted in objective clinical responses in only a small number of patients. Tumor escape mechanisms from host immune surveillance remain a major obstacle for cancer immunotherapy. A better understanding of the immune escape mechanisms employed by tumor cells is necessary before we can develop a more effective immunotherapeutic approach to lung cancer. We review recent studies regarding the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer. PMID 19756930

Active specific immunotherapy and cell-transfer therapy for the treatment of non-small cell lung cancer.
Juni 2009 | Kakimi, Kazuhiro; Nakajima, Jun; Wada, Hiromi
Lung cancer is an intractable disease urgently requiring more effective treatment approaches. The potential of immunotherapy in this context remains promising, although presently there are no satisfactory protocols available for lung cancer. However, encouraging evidence of clinical benefits from immunotherapy is beginning to accumulate in several lung cancer trials. Better understanding of tumor-specific immune responses, identifying tumor-associated antigens, and manipulating the immunoregulatory environment of the tumor is likely to further increase the efficacy of immune-mediated cancer therapies. Here, we review recent advances in cellular immunotherapy and vaccines for lung cancer, emphasizing an important paradigm shift in the analysis of clinical benefit away from "tumor response" towards "patient response". PMID 19062127

Inoperable Pancoast tumors treated with hyperthermia-inclusive multimodality therapies.
Jan. 2009 | Ebara, Takeshi; Sakurai, Hideyuki; Wakatsuki, Masaru; Nonaka, Tetuso; Ishikawa, Hitoshi; Kawamura, Hidemasa; Yoshida, Daisaku; Shioya, Mariko; Nakayama, Yuko; Nakano, Takashi
This study aimed to assess the feasibility, efficacy and complication of hyperthermia-inclusive multimodality therapies for patient with inoperable Pancoast tumor. PMID 18620779

Radiotherapy with 8-MHz radiofrequency-capacitive regional hyperthermia for stage III non-small-cell lung cancer: the radiofrequency-output power correlates with the intraesophageal temperature and clinical outcomes.
Dez. 2008 | Ohguri, Takayuki; Imada, Hajime; Yahara, Katsuya; Morioka, Tomoaki; Nakano, Keita; Terashima, Hiromi; Korogi, Yukunori
To assess the efficacy of radiotherapy (RT) combined with regional hyperthermia (HT) guided by radiofrequency (RF)-output power and intraesophageal temperature and evaluate the potential contribution of HT to clinical outcomes in patients with Stage III non-small-cell lung cancer (NSCLC). PMID 18513887

Antitumor effect of lung cancer vaccine with umbilical blood dendritic cells in reconstituted SCID mice.
Juli 2008 | Lin, Ping; Lu, Yan-Rong; Zhang, Jie; Wei, Yu-Quan; Wang, Xiu-Jie; Li, Sheng-Fu; Wang, Qi; Xiong, Zhu-Juan; Ning, Qi-Zhi; Lei, Song; Mao, Yong-Qiu; Cheng, Jing-Qiu
Dendritic cells (DCs) are important cells in initiating an immune response. A generation of functional DCs has potential clinical use in treating cancer. However, the source of DCs and patient immunodeficiency with cancer have been hindrances in clinical therapy. We generated DCs from human umbilical cord blood mononuclear cells (UBMCs) with recombinant human granulocyte-macrophage colony stimulating factor, recombinant human interleukin-4, and recombinant human tumor necrosis factor-alpha. The mature DC-A549 lung cancer vaccine (AgL-DC) was prepared through loading A549 lysate, treating with lipopolysaccharide (LPS) and positive selecting with CD83 magnetic beads. AgL-DC can secrete interleukin (IL)-12 and IL-1. Further in vitro analysis showed that AgL-DC notably induced human UBMC lymphocyte proliferation (p < 0.01) by 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, increased the cytotoxic T-lymphocyte (CTL) activity of UBMC lymphocytes against A549 cells (p < 0.05, at effector cells:target cells ratios of 50:1 and 100:1) by lactate dehydrogenase (LDH) cytotoxic assay, and improved production of IL-6 and tumor necrosis factor-beta (p < 0.01, p < 0.05) by enzyme-linked immunosorbent assay. Subsequently, the reconstitute immunity model in severe combined immunodeficiencies (SCID) mice has been established using human UBMC transplantation, and similar trends to results of UBMC in vitro experiments have been shown in lymphocyte proliferation, CTL activity, and IL-6 and tumor necrosis factor-beta secretion levels in these models. AgL-DC also significantly (p < 0.01) increased the antitumor effect in vivo. The tumor infiltrating immunocytes were positively expressed human CD83 and CD3 molecules, and they were negatively expressed in tumor tissue treated with control. These results have demonstrated that umbilical cord DCs are a useful source of vaccine cells for augmenting CTL-mediated cytotoxicity and have potential usefulness in cellular therapy for human cancer in a new vaccination strategy. PMID 18593365

IFN-gamma down-regulates Hsp27 and enhances hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo.
Mai 2008 | Oba, Mariko; Yano, Shuichiro; Shuto, Tsuyoshi; Suico, Mary Ann; Eguma, Ayaka; Kai, Hirofumi
Hyperthermia is used as one of the treatment modalities for various types of cancer, but the acquisition of thermotolerance in cancer cells, through the induction of heat shock proteins (Hsps), renders hyperthermia less effective. Among the Hsp family members, Hsp27 is frequently associated with thermotolerance and chemoresistance. Thus, down-regulation of Hsp27 expression during hyperthermic or chemotherapeutic applications is a promising approach to efficient tumor treatment. In the present study, we found that the cytokine interferon-gamma (IFN-gamma) suppresses the basal, the heat shock-induced and the cisplatin-induced expression of Hsp27 in HSC-2 (oral squamous carcinoma) and A549 (lung cancer) cells but not in 16HBE14o- (normal bronchial epithelial cells). Neither IFN-alpha nor IFN-beta affected Hsp27 expression, suggesting the specificity of IFN-gamma. We also demonstrate here that IFN-gamma suppresses Hsp27 basal transcription and promoter activity, and this is mediated specifically through one of the two Sp1 sites in the proximal region of the Hsp27 promoter. More importantly, pre-treatment of cells with IFN-gamma enhanced the induction of cell death by hyperthermia and cisplatin treatments in the tumor cell lines, HSC-2 and A549, but has no effect in 16HBE14o-, indicating a tumor cell-specific effect of IFN-gamma. Furthermore, the combination treatment of hyperthermia and IFN-gamma suppressed tumor growth in vivo more effectively than hyperthermia treatment alone. Together, our findings propose that IFN-gamma could be a useful potentiator of hyperthermia and cisplatin in cancer therapy. PMID 18497994

Delivery of whole tumor lysate into dendritic cells for cancer vaccination.
März 2008 | Liu, Linda N; Shivakumar, Rama; Allen, Cornell; Fratantoni, Joseph C
Results from multiple human studies have continued to spur the development of dendritic cells (DCs) as therapeutic vaccines for the treatment of cancer, chronic viral infections, and autoimmune diseases. The antigen-specific activity of DCs is dependent on the ability of the DCs to take up and process tumor-associated antigens for presentation to the immune system. Although immature DCs have been shown to naturally take up tumor-associated antigens by phagocytosis, approaches that significantly affect antigen delivery need further evaluation, especially if such methodologies can be demonstrated to result in the elicitation of more robust and comprehensive immune responses. We have developed a rapid, robust, scalable, and regulatory-compliant process for loading DCs with whole tumor lysate. The use of whole tumor lysate facilitates the generation of a more robust immune response targeting multiple unique antigenic determinants in patient's tumors and likely reduces the tumor's potential of immune escape. We demonstrate that DCs electroloaded with tumor lysate elicit significantly stronger antitumor responses both in a tumor challenge model and in a therapeutic vaccination model for preexisting metastasic disease. These effects are observed in a processing scheme that requires 20- to 40-fold lower amounts of tumor lysate when compared with the standard coincubation/coculture methods employed in loading DCs. PMID 18370195

Hyperthermia switches glucose depletion-induced necrosis to apoptosis in A549 lung adenocarcinoma cells.
März 2008 | Han, Song Iy; Duong, Hong-Quan; Choi, Jeong Eun; Lee, Tae-Bum; Kim, Cho Hee; Lee, Su Yeon; Jeon, Hyun Min; Shin, Sung-Heui; Lim, Sung-Chul; Kang, Ho Sung
Both cellular and clinical studies have shown that hyperthermia is one of the most potent sensitizers for the action of ionizing radiation. Although hyperthermic improvement in clinical outcome is suggested to be linked to its ability to induce cell cycle arrest and apoptosis, and to activate the immune system and to cause increases in blood flow and tumor oxygenation, the mechanism behind this is still unclear. Previously, we demonstrated that glucose deprivation (GD), a common characteristic of the tumor microenvironment, induced necrosis, which is implicated in tumor progression and aggressiveness, through the production of reactive oxygen species (ROS) in A549 lung carcinoma cells. We examined the effects of heat shock on ROS production and necrosis in response to GD. Here we show that mild, but not harsh, heat shock prevented GD-induced necrosis and switched the cell death mode to apoptosis in A549 cells through the ERK1/2 pathway that could suppress GD-induced CuZnSOD release and ROS production. These results demonstrate that contrary to severe heat shock, mild heat shock has the ability to decrease oxidative stress in cells, thereby causing the cell death mode switch from tumor promoting necrosis to tumor suppressive apoptosis, which may contribute to its anti-neoplastic activities. PMID 18360712

[Study on the cell apoptosis induced by intracellular hyperthermia in human lung adenocarcinoma SPC-A1 cells].
Jan. 2008 | Ma, Yongjie; Li, Hong; Yan, Zhubing; Gu, Hongchen
This is a comparative study on the efficacy of differential cell apoptosis induced by three methods (intracellular hyperthermia, with water bath hyperthermia and extracellular hyperthermia) in human lung adenocarcinoma SPC-A1 cells in vitro. The effects of hyperthermia on cell apoptosis were determined by Transmission electron microscopy(TEM), agarose gel electrophoresis and flow cytometry methods, respectively. The intracellular effect of particle heating was compared with that of water bath hyperthermia and extracellular hyperthermia; significant differences between these heating methods were detected, the rate of apoptosis being 36.59%, 5.66%, 7.78% respectively. When treated with intracellular hyperthermia, the SPC-A1 cells manifested typical morphological characters of apoptosis by TEM observation, and the SPC-A1 cell DNA was degraded into large fragments by agarose gel electrophoresis assay. Our results showed that amino-silane Fe3O4 induced intracellular hyperthermia was superior to water bath hyperthermia and extracellular hyperthermia. It is mainly the interaction between intracellular nanoparticles and cell that induced apoptosis. Therefore, the aminosilane-coated Fe3O4 may be used in hyperthermia or chemotherapeutics on cancer cells for further clinical application. PMID 18232482

Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells.
Aug. 2007 | Hirschowitz, Edward A; Foody, Terry; Hidalgo, Giovanna E; Yannelli, John R
Only a handful of NSCLC patients have been included in dendritic cell (DC) vaccine clinical trials. We had previously reported a series of 16 individuals with stages IA-IIIB NSCLC who received autologous DC vaccines matured with dendritic cell/T cell-derived maturation factor (DCTCMF). Here we report the results of a continuation study with similar inclusion criteria, immunization protocol, and analysis, using an immature DC vaccine. Of the 14 participants, 7 had undergone surgical resection (stage I/II), with or without adjuvant therapy, and 7 with unresectable stage III had been treated with chemo-radiation alone. Autologous DCs were pulsed with apoptotic bodies derived from an allogeneic NSCLC cell line that over-expresses Her2/neu, CEA, WT1, Mage2, and survivin. DCs were not exposed to any maturation stimulus. Individuals received two intradermal vaccines (average 8.1x10(7) DC per immunization) 1 month apart. Immune responses were measured by IFN-gamma ELISPOT, comparing relative number of antigen-reactive T-cells from pre-vaccine to timepoints post-immunization. Immunologic responses were seen in 4/7 stage III unresectable, and 6/7 stage I/II surgically resected patients, including 3/3 resected patients who had also received adjuvant chemo-radiation. There were no related adverse events. One of seven surgically resected patients recurred and 4/7 stage III patients progressed. Three of five patients with progressive disease showed no immunologic response. Data indicate that immature DC pulsed with apoptotic tumour cells have similar biologic activity to a DCTCMF-matured DC preparation delivered in a similar clinical protocol. Therapeutic efficacy is unknown and clinical outcomes are anecdotal. PMID 17509725

Regional hyperthermia combined with radiotherapy for locally advanced non-small cell lung cancers: a multi-institutional prospective randomized trial of the International Atomic Energy Agency.
Juni 2007 | Mitsumori, Michihide; Zeng, Zhi-Fan; Oliynychenko, Praskovya; Park, Jeong Ho; Choi, Ihl Bohng; Tatsuzaki, Hideo; Tanaka, Yoshiaki; Hiraoka, Masahiro
An International Atomic Energy Agency (IAEA)-sponsored, multi-institutional prospective randomized trial was conducted to clarify whether the combination of hyperthermia and radiotherapy improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by radiotherapy alone. PMID 17566842

Artificial cytokine storm combined with hyperthermia induces significant anti-tumor effect in mice inoculated with lewis lung carcinoma and B16 melanoma cells.
März 2007 | Kushida, Shigeki; Ohmae, Hiroshi; Kamma, Hiroshi; Totsuka, Rumiko; Matsumura, Masayuki; Takeuchi, Akira; Saiki, Ikuo; Yanagawa, Toru; Onizawa, Kojiro; Ishii, Tetsuro; Ohn, Tadao
In cancer immunotherapies combined with hyperthermia, one or two cytokines have been tested to augment the anti-tumor effect. However, the therapies have not shown sufficient improvement. The aim of this study is to find a new potent tumor immunotherapy in order to augment antitumor effect of hyperthermia by the cytokine cocktails in vivo. We used a combination therapy of local hyperthermia (LH) and various cytokine cocktails composed of IFNs (IFN-alpha, -beta, and -gamma), Thl cytokines (IL-2, -12, -15, and -18), a Th2 cytokine (IL-4), inflammatory cytokines (IL-lalpha and TNF-alpha), and dendritic cell-inducible cytokines (IL-3 and GM-CSF). These cytokines in a proper combination augmented the anti-tumor effect of LH and prolonged survival time in Lewis lung carcinoma or B16 melanoma significantly. Moreover, the 12-cytokine cocktail suppressed B 16 metastasis to the lung and lymph nodes, and complete regression of the tumors without regrowth occurred in 3 of 5 mice. In the cured three B16 mice, there was hyperplasia of lymphatic organs with many CD3-positive T lymphocytes. The most effective cytokine combination should be able to augment the anti-tumor effect of other therapies besides hyperthermia that induce the necrosis of tumor cells. PMID 17390999

Hyperthermia-enhanced tumor accumulation and antitumor efficacy of a doxorubicin-conjugate with a novel macromolecular carrier system in mice with non-small cell lung cancer.
Feb. 2007 | Oyama, Takahiko; Kawamura, Masafumi; Abiko, Tomohiro; Izumi, Yotaro; Watanabe, Masazumi; Kumazawa, Eiji; Kuga, Hiroshi; Shiose, Yoshinobu; Kobayashi, Koichi
A novel drug delivery system (DDS) compound was formed by binding doxorubicin hydrochloride (DXR) to the macromolecular carrier carboxymethyldextran polyalcohol (CM-Dex-PA) via the peptidyl spacer (GGFG: Gly-Gly-Phe-Gly). Its use in a murine tumor model confirmed that the DDS (CM-Dex-PA-GGFG-DXR) was retained in the blood and distributed in tumor tissue. The combined use of hyperthermia (HT: 41-42 degrees C for 40 min) and DXR-conjugate (5, 10 or 20 mg/kg i.v.) on tumor accumulation and efficacy was investigated in a murine model of non-small cell lung cancer. Tumor size was measured and the tumor inhibition rate (IR) was calculated. The mean tumor concentration of conjugated DXR in the DXR-conjugate group was 9.40 microg/g compared with 19.04 microg/g in the DXR-conjugate + HT group (p=0.0008). The antitumor efficacy of the DXR-conjugate was significantly enhanced in the groups receiving the combination therapy (p=0.0039, p=0.0250). Significant differences were found between the groups given DXR and those given DXR-conjugate (p=0.0492, p=0.0104). The results demonstrate that the antitumor efficacy of DXR-conjugate is significantly superior to that of DXR alone and the combined use of DXR-conjugate and HT increases the drug's concentration in the tumor, with significant enhancement of antitumor efficacy. PMID 17273747

Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells.
Nov. 2005 | Babatz, Jana; Röllig, Christoph; Löbel, Bärbel; Folprecht, Gunnar; Haack, Michael; Günther, Heinrich; Köhne, Claus-Henning; Ehninger, Gerhard; Schmitz, Marc; Bornhäuser, Martin
Dendritic cells (DCs) are characterized by their extraordinary capacity to induce T-cell responses, providing the opportunity of DC-based cancer vaccination protocols. In the present study, we conducted a phase I/II clinical trial to determine the capability of DCs differentiated from immunomagnetically isolated CD14+ monocytes and pulsed with a carcinoembryonic antigen-derived altered peptide (CEAalt) to induce specific CD8+ T cells in cancer patients. PMID 16034561

Synergistic interaction of hyperthermia and Gemcitabine in lung cancer.
Nov. 2005 | Vertrees, Roger A; Das, Gokul C; Popov, Vsevolod L; Coscio, Angela M; Goodwin, Thomas J; Logrono, Roberto; Zwischenberger, Joseph B; Boor, Paul J
Hyperthermia increases cytotoxicity of various antineoplastic agents. We investigated the cytotoxic effects of Gemcitabine and/or hyperthermia on BZR-T33 (human non-small-cell lung cancer cells) in vitro and in immune-suppressed athymic nude mice. Isobologram analysis of monolayer cell cultures for cytotoxicity demonstrates a synergistic interaction between hyperthermia and Gemcitabine. Clonogenic results show significant reductions in surviving fractions and colony size for both therapies; greatest reduction was for the combined therapy group. Using cell cycle analysis, hyperthermia enhanced Gemcitabine-induced G2-M arrest resulting in destruction of 3.5 log cells. Apoptotic studies (Annexin-V FITC staining) showed that hyperthermia augmented Gemcitabine-induced apoptosis. Transmission electron microscopy demonstrated pathology observed in cultures exposed to either therapy present in cultures exposed to both therapies. Studies in nude mice show that the combination therapy group had both an initial decrease in tumor size, and a significantly delayed rate of growth. Additionally, using tumor material harvested from nude mice two days after end to treatment reveals a significantly greater apoptotic index and significantly smaller mitotic index for the combined therapy group. Western blots of the same tumor material, showed that heat shock protein 70 was not significantly increased, however, caspase-3 activity of was significantly increased because of the combined therapy. In conclusion, the combined therapy is synergistic in effect because of hyperthermia enhancing Gemcitabine-induced apoptosis. PMID 16138007

A mechanism of hyperthermia-induced apoptosis in ras-transformed lung cells.
Sep. 2005 | Vertrees, Roger A; Das, Gokul C; Coscio, Angela M; Xie, Jingwu; Zwischenberger, Joseph B; Boor, Paul J
Lung cancer, the leading cause of cancer-related deaths in both men and women, is the consequence of disordered apoptosis, induction of which may have therapeutic utility. Hyperthermia has been identified as a stimulus for apoptosis. We investigated the mechanism of hyperthermia-induced cell death in ras-transformed lung cells. Effect of hyperthermia (43 degrees C for 180 min) was compared between two cell lines, an immortalized (sv-40) normal human bronchial epithelial (BEAS2-B) and its malignant transformed (H-ras transfected) counterpart (BZR-T33). Survival after hyperthermia: 7-d growth culture BEAS2-B, 1.03 +/- 0.007 and BZR-T33, 0.39 +/- 0.008 (P < 0.05); clonogenic assays BEAS2-B, 0.76 +/- 0.003 and BZR-T33, 0.41 +/- 0.004 (P < 0.05). Hoechst positive (apoptotic) cells: BEAS2-B, 11 +/- 3% and BZR-T33, 78 +/- 5% (P < 0.05). TUNEL, DNA fragmentation, and Annexin-V all corroborate this result. Western blot comparing the effect of hyperthermia in BZR-T33 cells to BEAS2-B cells revealed: TRAIL and FAS-L displayed significant increases (threefold and twofold, respectively); caspase-3 showed a decrease in uncleaved form and an increase in cleaved form, and a 50-fold increase in activity effectively blocked with the caspase-3 inhibitor DEVD-fmk; caspase-9 showed near depletion of uncleaved; poly (ADP-ribose) polymerase (PARP) degradation was clearly visible during heating. After hyperthermia, gene expression demonstrates a 5.7-fold increase in TRAIL and insignificant changes in tumor necrosis factor-alpha (TNF-alpha), FAS-L, and caspases 3, 8, 9 in transformed cells. Data demonstrated that hyperthermia induces apoptosis in transformed cells, and that apoptosis is mediated by caspase-3 as a result of activation of cell-death membrane receptors of the tumor-necrosis-factor family. In summary, these data suggest that hyperthermia could become an additional modality in the multidisciplinary approach to the treatment of lung cancer. PMID 16114053

The large scale generation of dendritic cells for the immunization of patients with non-small cell lung cancer (NSCLC).
Feb. 2005 | Yannelli, John R; Sturgill, Jamie; Foody, Terry; Hirschowitz, Edward
In the current study, we generated large numbers of dendritic cells (DCs) from patients with non-small cell lung cancer (NSCLC) for a vaccine trial. The DCs were generated from CD14+ cells obtained by immuno-magnetic bead column separation technique. The CD14+ cells were placed in culture in the presence of granulocyte macrophage colony stimulating factor (GMCSF) and Interleukin 4 (IL-4). At Day 7, apoptotic bodies derived from an allogeneic NSCLC line 1650-TC were added to the cultures at a DC:tumor cell ratio of 1:1. At Day 8, the DCs were harvested, washed and injected intradermally into patients. Using this protocol we have prepared DCs for 16 patients. An average of 9.3 x 10(7) DCs was injected for the priming dose and 8.2 x 10(7) DCs for the boost. Clinical evaluation of the patients and immune assessment are presented in a separate report. The current report provides evidence for the large scale production of functional DCs derived from patients with NSCLC which can be used as vaccines in clinical trials. PMID 15713517

A pilot clinical trial of vaccination with dendritic cells pulsed with autologous tumor cells derived from malignant pleural effusion in patients with late-stage lung carcinoma.
Feb. 2005 | Chang, Gee-Chen; Lan, Haw-Chang; Juang, Shin-Hun; Wu, Yu-Chen; Lee, Hui-Chen; Hung, Yi-Mei; Yang, Hui-Yu; Whang-Peng, Jacqueline; Liu, Ko-Jiunn
The authors conducted a pilot clinical trial to explore the vaccination of patients with late-stage lung carcinoma with dendritic cells (DCs) pulsed with necrotic tumor cells derived from malignant pleural effusion specimens, and to evaluate the antitumor immune response induced by this therapy. PMID 15637694

Autologous dendritic cell vaccines for non-small-cell lung cancer.
Juli 2004 | Hirschowitz, Edward A; Foody, Terry; Kryscio, Richard; Dickson, Larry; Sturgill, Jamie; Yannelli, John
Therapeutic outcomes of definitively treated non-small-cell lung cancer (NSCLC) are unacceptably poor. A wealth of preclinical information, and a modest amount of clinical information indicate that dendritic cell (DC) vaccines have therapeutic potential. Only a handful of NSCLC patients have been included in DC clinical trials. We delivered autologous DC vaccines to 16 individuals with stage IA to IIIB NSCLC treated with surgery, chemoradiation, or multimodality therapy. The objectives of the study were to evaluate tolerability and measure immunologic responses to DC vaccines in a heterogeneous group of NSCLC patients. PMID 15254048

Feasibility of lung cancer hyperthermia using breathable perfluorochemical (PFC) liquids. Part I: Convective hyperthermia.
Juni 2004 | Sekins, K M; Leeper, D B; Hoffman, J K; Wolfson, M R; Shaffer, T H
Clinical studies have shown that hyperthermia in combination with radiotherapy and/or chemotherapy may be effective in the treatment of advanced cancer. No method of lung hyperthermia, however, has been accepted as standard or superior. This investigation sought to demonstrate in animals the thermal and physiologic feasibility of lung hyperthermia induced using heated breathable perfluorochemical (PFC) liquids, a method termed liquid-filled lung convective hyperthermia (LCHT). The ability to use LCHT is rooted in the development of both PFC liquid ventilation, now in clinical development with the PFC perflubron (LiquiVent), and a PFC blood substitute also in late Phase III trials (Oxygent). As LCHT background, the PFC technologies and biology are first reviewed. The physical properties of a variety of PFCs were evaluated for LCHT and it was concluded that more than one liquid is suitable based on such properties. Using total liquid ventilation type devices, LCHT was shown to deliver successfully localized (lobar) lung heating in sheep, and bilateral whole lung heating and whole-body hyperthermia in rabbits, cats and lambs. During LCHT, lung parenchymal temperatures were uniform (<1 degree C) across heated regions. In addition, based on patterns relating lung tissue temperatures to inspiratory and expiratory PFC liquid temperatures in the endotracheal tube, LCHT may minimize invasive thermometry requirements in the lung. Based on acute experiments, it was concluded that LCHT appears feasible and may simplify lung hyperthermia. It was recommended that potentially synergistic combinations of LCHT with other whole-body hyperthermia or local heating modalities, and with chemotherapeutic lung drug delivery, also be explored in the future. PMID 15204525

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.
Feb. 2003 | Bakhshandeh, A; Bruns, I; Traynor, A; Robins, H I; Eberhardt, K; Demedts, A; Kaukel, E; Koschel, G; Gatzemeier, U; Kohlmann, Th; Dalhoff, K; Ehlers, E M; Gruber, Y; Zumschlinge, R; Hegewisch-Becker, S; Peters, S O; Wiedemann, G J
We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated. PMID 12609573

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