WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study.
Apr. 2018 | Yanagisawa, Ryu; Koizumi, Tomonobu; Koya, Terutsugu; Sano, Kenji; Koido, Shigeo; Nagai, Kazuhiro; Kobayashi, Masanori; Okamoto, Masato; Sugiyama, Haruo; Shimodaira, Shigetaka
Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination with chemotherapy in patients with surgically resected pancreatic cancer. PMID 29599342
WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study.
The clinical benefit of hyperthermia in pancreatic cancer: a systematic review.
Nov. 2017 | van der Horst, Astrid; Versteijne, Eva; Besselink, Marc G H; Daams, Joost G; Bulle, Esther B; Bijlsma, Maarten F; Wilmink, Johanna W; van Delden, Otto M; van Hooft, Jeanin E; Franken, Nicolaas A P; van Laarhoven, Hanneke W M; Crezee, Johannes; van Tienhoven, Geertjan
In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients. PMID 29168401
Dendritic cells based immunotherapy.
Nov. 2017 | Shang, Na; Figini, Matteo; Shangguan, Junjie; Wang, Bin; Sun, Chong; Pan, Liang; Ma, Quanhong; Zhang, Zhuoli
Dendritic cells (DCs) are the most potent antigen-presenting cells, and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes (CTLs) in lymphatic tissues. DC vaccination is a newly emerging and potent form of cancer immunotherapy and has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The efficacy of DC-vaccines is strongly influenced by various techniques for the priming antigen loading onto DCs and their ability to migrate to the draining lymph nodes (LNs). Therefore, it is critical to improve DC-vaccines homing to draining LNs after administration in order to optimize DC-based therapy for individual patients. This review underlines 1) appropriate strategy to load tumor antigens onto DCs and 2) to optimize vaccine administration methods to ensure loaded DCs can migrate to LNs, in particular, Intraperitoneal (IP) injection. IP injection of DC-based vaccine may be a potential regimen for gastrointestinal tumors including hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PDAC) since huge populations of LNs are present throughout the gastrointestinal track. Which might improve the subsequent migration to LNs. PMID 29119057
Newcastle disease virus mediates pancreatic tumor rejection via NK cell activation and prevents cancer relapse by prompting adaptive immunity.
Aug. 2017 | Schwaiger, Theresa; Knittler, Michael R; Grund, Christian; Roemer-Oberdoerfer, Angela; Kapp, Joachim-Friedrich; Lerch, Markus M; Mettenleiter, Thomas C; Mayerle, Julia; Blohm, Ulrike
Pancreatic cancer is the 8th most common cause of cancer-related deaths worldwide and the tumor with the poorest prognosis of all solid malignancies. In 1957, it was discovered that Newcastle disease virus (NDV) has oncolytic properties on tumor cells. To study the oncolytic properties of NDV in pancreatic cancer a single dose was administered intravenously in a syngeneic orthotopic tumor model using two different murine pancreatic adenocarcinoma cell lines (DT6606PDA, Panc02). Tumor growth was monitored and immune response was analyzed. A single treatment with NDV inhibited DT6606PDA tumor growth in mice and prevented recurrence for a period of three months. Tumor infiltration and systemic activation of NK cells, cytotoxic and helper T-cells was enhanced. NDV-induced melting of Panc02 tumors until d7 pi, but they recurred displaying unrestricted tumor growth, low immunogenicity and inhibition of tumor-specific immune response. Arrest of DT6606PDA tumor growth and rejection was mediated by activation of NK cells and a specific antitumor immune response via T-cells. Panc02 tumors rapidly decreased until d7 pi, but henceforth tumors characterized by the ability to perform immune-regulatory functions reappeared. Our results demonstrated that NDV-activated immune cells are able to reject tumors provided that an adaptive antitumor immune response can be initiated. However, activated NK cells that are abundant in Panc02 tumors lead to outgrowth of nonimmunogenic tumor cells with inhibitory properties. Our study emphasizes the importance of an adaptive immune response, which is initiated by NDV to mediate long-term tumor surveillance in addition to direct oncolysis. PMID 28857157
Efficacy of vaccination with tumor-exosome loaded dendritic cells combined with cytotoxic drug treatment in pancreatic cancer.
Juli 2017 | Xiao, Li; Erb, Ulrike; Zhao, Kun; Hackert, Thilo; Zöller, Margot
Pancreatic cancer (PaCa) has a dismal prognosis and adjuvant immunotherapy frequently is of low efficacy due to immunosuppressive features of PaCa and PaCa-stroma. We here explored, whether the efficacy of vaccination with tumor-exosome (TEX)-loaded dendritic cells (DC) can be improved by combining with drugs affecting myeloid-derived suppressor cells (MDSC). Experiments were performed with the UNKC6141 PaCa line. UNKC6141 TEX-loaded DC were weekly intravenously injected, mice additionally receiving Gemcitabine (GEM) and/or ATRA and/or Sunitinib (Sun). UNKC6141 grow aggressively after subcutaneous and orthotopic application and are consistently recovered in peripheral blood, bone marrow, lung and frequently liver. Vaccination with DC-TEX significantly prolonged the survival time, the efficacy of DC-TEX exceeding that of the cytotoxic drugs. However, ATRA, Sun and most efficiently GEM, sufficed for a pronounced reduction of MDSC including tumor-infiltrating MDSC, which was accompanied by a decrease in migrating and metastasizing tumor cells. When combined with DC-TEX vaccination, a higher number of activated T cells was recovered in the tumor and the survival time was prolonged compared with only DC-TEX vaccinated mice. As ATRA, GEM and Sun affect MDSC at distinct maturation and activation stages, a stronger support for DC-TEX vaccination was expected by the drug combination. Intrapancreatic tumor growth was prevented beyond the death of control mice. However, tumors developed after a partial breakdown of the immune system by the persisting drug application. Nonetheless, in combination with optimized drug tuning to prevent MDSC maturation and activation, vaccination with TEX-loaded DC appears a most promising option in PaCa therapy. PMID 28680753
Treatment outcomes of concurrent hyperthermia and chemoradiotherapy for pancreatic cancer: Insights into the significance of hyperthermia treatment.
Juni 2017 | Maebayashi, Toshiya; Ishibashi, Naoya; Aizawa, Takuya; Sakaguchi, Masakuni; Sato, Tsutomu; Kawamori, Jiro; Tanaka, Yoshiaki
Patients with locally advanced unresectable pancreatic cancer (LAUPC) have a poor prognosis. In addition their quality of life impaired by cancer pain and biliary tract infections. Therefore, multimodality therapy and selection of optimal treatment methods are essential for achieving prolonged survival. The present study investigated the significance of using hyperthermia concurrently with multimodality therapy to improve treatment outcomes in patients with LAUPC. In total, 13 patients receiving concurrent hyperthermia and chemoradiotherapy (HCR) or chemoradiotherapy (CR) alone for LAUPC between 2002 and 2013 were analyzed retrospectively. Of the 13 patients, 5 received concurrent HCR and 8 received CR. The chemotherapy regimens were 5-fluorouracil (5-FU) in 5 patients and gemcitabine hydrochloride (GEM) in the other 8. Patients who gave consent for hyperthermia treatment received GEM plus CR. The median overall survival period for all patients was 12 months and the 1-year survival rate was 55%; the corresponding values were 12 months and 57% in the GEM CR group, and 15 months and 80% in the HCR group. Univariate analyses was perfomed to identify factors predicting recurrence after treatment. The potential prognostic factors analyzed were: Age, sex, performance status, location, tumor size, the tumor marker CA 19-9, total radiation dose, chemotherapy and hyperthermia. Univariate analysis for factors associated with outcomes revealed a significant difference favoring the HCR group [relative risk=15.97 (95% confidence interval: 12.87-19.83) P=0.021]. In conclusion, hyperthermia merits active recommendation to pancreatic cancer patients who have a positive attitude toward this treatment and whose performance status is satisfactory. PMID 28588736
Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer.
Apr. 2017 | Mehrotra, Shikhar; Britten, Carolyn D; Chin, Steve; Garrett-Mayer, Elizabeth; Cloud, Colleen A; Li, Mingli; Scurti, Gina; Salem, Mohamed L; Nelson, Michelle H; Thomas, Melanie B; Paulos, Chrystal M; Salazar, Andres M; Nishimura, Michael I; Rubinstein, Mark P; Li, Zihai; Cole, David J
Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). PMID 28388966
Viro-immune therapy: A new strategy for treatment of pancreatic cancer.
Jan. 2016 | Ibrahim, Andrea Marie; Wang, Yao-He
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses (TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1 (PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer. PMID 26811622
Enhanced therapeutic effect using sequential administration of antigenically distinct oncolytic viruses expressing oncostatin M in a Syrian hamster orthotopic pancreatic cancer model.
Dez. 2015 | Nistal-Villan, Estanislao; Bunuales, Maria; Poutou, Joanna; Gonzalez-Aparicio, Manuela; Bravo-Perez, Carlos; Quetglas, Jose I; Carte, Beatriz; Gonzalez-Aseguinolaza, Gloria; Prieto, Jesus; Larrea, Esther; Hernandez-Alcoceba, Ruben
The limited efficacy of current treatments against pancreatic cancer has prompted the search of new alternatives such as virotherapy. Activation of the immune response against cancer cells is emerging as one of the main mechanisms of action of oncolytic viruses (OV). Direct oncolysis releases tumor antigens, and viral replication within the tumor microenvironment is a potent danger signal. Arming OV with immunostimulatory transgenes further enhances their therapeutic effect. However, standard virotherapy protocols do not take full advantage of OV as cancer vaccines because repeated viral administrations may polarize immune responses against strong viral antigens, and the rapid onset of neutralizing antibodies limits the efficacy of redosing. An alternative paradigm based on sequential combination of antigenically distinct OV has been recently proposed. PMID 26671477
Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4.
Okt. 2015 | Kang, Tae Heung; Kim, Young Seob; Kim, Seokho; Yang, Benjamin; Lee, Je-Jung; Lee, Hyun-Ju; Lee, Jaemin; Jung, In Duk; Han, Hee Dong; Lee, Seung-Hyun; Koh, Sang Seok; Wu, T-C; Park, Yeong-Min
Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants. PMID 26336989
Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell.
Okt. 2015 | Chen, Jiang; Guo, Xiao-Zhong; Li, Hong-Yu; Wang, Di; Shao, Xiao-Dong
Pancreatic cancer (PC) is a deadly human malignancy. Dendritic cell (DC)-based immunotherapy with whole tumor antigens demonstrates potential efficiency in cancer treatment. Tumor RNA and tumor fusion hybrid cells are sources of whole tumor antigens for preparing DC tumor vaccines. However, the efficacy of these sources in eliciting immune responses against PC has not yet to be directly compared. In the present study, patient-derived PC cells and DCs were fused (DC-tumor hybrids) and primary cultured PC cell-derived total RNA was electroporated into autologous DCs (DC-tumor RNA). The antitumor immune responses induced by DC-tumor hybrids and DC-tumor RNA were compared directly. The results showed that both RNA and hybrid methodologies could induce tumor-specific cytotoxic T lymphocyte (CTL) responses, but pulsing DCs with total tumor RNA could induce a higher frequency of activated CTLs and T-helper cells than fusing DCs with autologous tumor cells. In addition, DC-tumor RNA triggered stronger autologous tumor cell lysis than DC-tumor hybrids. It could be concluded that DCs pulsed with whole tumor RNA are superior to those fused with tumor cells in priming anti-PC CTL responses. Electroporation with total tumor RNA may be more suitable for DC-based PC vaccination. PMID 25736302
A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.
Sep. 2015 | Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique; Mas, Eric; Béraud, Evelyne
Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID 26405163
Recombinant Newcastle Disease Virus Encoding IL-12 and/or IL-2 as Potential Candidate for Hepatoma Carcinoma Therapy.
Aug. 2015 | Ren, Guiping; Tian, Guiyou; Liu, Yunye; He, Jinjiao; Gao, Xinyu; Yu, Yinhang; Liu, Xin; Zhang, Xu; Sun, Tian; Liu, Shuangqing; Yin, Jiechao; Li, Deshan
Interleukins as immunomodulators are promising therapeutic agents for cancer therapy. Previous studies showed that there was an improved antitumor immunity in tumor-bearing mice using recombinant Newcastle disease virus carrying for interleukin-2. Interleukin-12 is a promising antitumor cytokine too. So we investigated and compared the antitumor effect of genetically engineered Newcastle disease virus strains expressing both interleukin-12 and/or interleukin-2 (rClone30-interleukin-2, rClone30-interleukin-12, and rClone30-interleukin-12-interleukin-2). In vitro studies showed that rClone30s could efficiently infect tumor cells and express interleukin-12 and/or interleukin-2. 3-(4,5-Dimethylthiazol-2-y)-2,5-diphenyl-tetrazolium bromide results showed rClone30s possessed strong cytotoxic activities against multiple tumor cell lines (U251, HepG2, A549, and Hela). Animal studies showed that rClone30-interleukin-12-interleukin-2 was more effective in inhibition of murine hepatoma carcinoma tumors, with the mean tumor volume (day 14) of 141.70 mm(3) comparing 165.67 mm(3) of rClone30-interleukin-12 group, 210.47 mm(3) of rClone30-interleukin-2 group, 574.70 mm(3) of rClone30 group, and 1206.83 mm(3) of phosphate-buffered saline group. Moreover, the rClone30-interleukin-12-interleukin-2 treated mice secreted more interferon γ (333.518 pg/mL) and its downstream cytokine interferon-γ induced protein 10 (16.006 pg/mL) in tumor than the rClone30-interleukin-12 group (interferon γ: 257.548 pg/mL; interferon-γ induced protein 10: 13.601 pg/mL), rClone30-interleukin2 group (interferon γ: 124.601 pg/mL; interferon-γ induced protein 10: 9.779 pg/mL), or rClone30 group (interferon γ: 48.630 pg/mL; interferon-γ induced protein 10:1.650 pg/mL). For the survival study, rClone30-interleukin12-interleukin2 increased the survival rate (12 of 16) of the tumor-bearing mice versus 11 of 16 in rClone30-interleukin-12 group, 10 of 16 in rClone30-interleukin-2 group, 7 of 16 in Clone30 group, and 0/16 in phosphate-buffered saline group, respectively. To determine whether the mice treated with recombinant virus developed protective immune response, the mice were rechallenged with the same tumor cells. The results showed that viral-treated mice were significantly protected from rechallenge. These results suggest that expressing both interleukin-2 and/or interleukin-12 could be ideal approaches to enhance the antitumor ability of Newcastle disease virus, and rClone30-interleukin-12-interleukin-2 is slightly superior over rClone30-interleukin-12 and rClone30-interleukin-2 alone. PMID 26303327
Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma.
Juni 2015 | Buijs, Pascal; van Nieuwkoop, Stefan; Vaes, Vincent; Fouchier, Ron; van Eijck, Casper; van den Hoogen, Bernadette
Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F₀) or an IFN antagonistic protein (rNDV-NS1-F₀), as well as rNDV with increased virulence (rNDV-F₃aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F₃aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ -F₀, while inoculation with rNDV-NS1-F₀ resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F₃aa caused markedly more cytotoxicity compared to rNDV-F₀, while inoculation with rNDVβ-hIFN -F₀ and rNDV-NS1-F₀ induced cytotoxic effects comparable to those induced by the parental rNDV-F₀. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F₃aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy. PMID 26110582
Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.
Apr. 2015 | Mayanagi, Shuhei; Kitago, Minoru; Sakurai, Toshiharu; Matsuda, Tatsuo; Fujita, Tomonobu; Higuchi, Hajime; Taguchi, Junichi; Takeuchi, Hiroya; Itano, Osamu; Aiura, Koichi; Hamamoto, Yasuo; Takaishi, Hiromasa; Okamoto, Masato; Sunamura, Makoto; Kawakami, Yutaka; Kitagawa, Yuko
This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855). PMID 25614082
Overexpression of heat shock protein 27 (HSP27) increases gemcitabine sensitivity in pancreatic cancer cells through S-phase arrest and apoptosis.
Jan. 2015 | Guo, Yang; Ziesch, Andreas; Hocke, Sandra; Kampmann, Eric; Ochs, Stephanie; De Toni, Enrico N; Göke, Burkhard; Gallmeier, Eike
We previously established a role for HSP27 as a predictive marker for therapeutic response towards gemcitabine in pancreatic cancer. Here, we investigate the underlying mechanisms of HSP27-mediated gemcitabine sensitivity. Utilizing a pancreatic cancer cell model with stable HSP27 overexpression, cell cycle arrest and apoptosis induction were analysed by flow cytometry, nuclear staining, immunoblotting and mitochondrial staining. Drug sensitivity studies were performed by proliferation assays. Hyperthermia was simulated using mild heat shock at 41.8°C. Upon gemcitabine treatment, HSP27-overexpressing cells displayed an early S-phase arrest subsequently followed by a strongly increased sub-G1 fraction. Apoptosis was characterized by PARP-, CASPASE 3-, CASPASE 8-, CASPASE 9- and BIM- activation along with a mitochondrial membrane potential loss. It was reversible through chemical caspase inhibition. Importantly, gemcitabine sensitivity and PARP cleavage were also elicited by heat shock-induced HSP27 overexpression, although to a smaller extent, in a panel of pancreatic cancer cell lines. Finally, HSP27-overexpressing pancreatic cancer cells displayed an increased sensitivity also towards death receptor-targeting agents, suggesting another pro-apoptotic role of HSP27 along the extrinsic apoptosis pathway. Taken together, in contrast to the well-established anti-apoptotic properties of HSP27 in cancer, our study reveals novel pro-apoptotic functions of HSP27-mediated through both the intrinsic and the extrinsic apoptotic pathways-at least in pancreatic cancer cells. HSP27 could represent a predictive marker of therapeutic response towards specific drug classes in pancreatic cancer and provides a novel molecular rationale for current clinical trials applying the combination of gemcitabine with regional hyperthermia in pancreatic cancer patients. PMID 25331547
Prognostic markers for patient outcome following vaccination with multiple MHC Class I/II-restricted WT1 peptide-pulsed dendritic cells plus chemotherapy for pancreatic cancer.
Dez. 2014 | Takakura, Kazuki; Koido, Shigeo; Kan, Shin; Yoshida, Kosaku; Mori, Masako; Hirano, Yuta; Ito, Zensho; Kobayashi, Hiroko; Takami, Shinichiro; Matsumoto, Yoshihiro; Kajihara, Mikio; Misawa, Takeyuki; Okamoto, Masato; Sugiyama, Haruo; Homma, Sadamu; Ohkusa, Toshifumi; Tajiri, Hisao
Treatment combining dendritic cells (DCs) pulsed with three types of major histocompatibility complex (MHC) class I and II (DC/WT1-I/II)-restricted Wilms' tumor 1 (WT1) peptides with chemotherapy may stabilize disease in pancreatic cancer patients. PMID 25550602
Antigen-loaded dendritic cell migration: MR imaging in a pancreatic carcinoma model.
Dez. 2014 | Zhang, Zhuoli; Li, Weiguo; Procissi, Daniele; Li, Kangan; Sheu, Alexander Y; Gordon, Andrew C; Guo, Yang; Khazaie, Khashayarsha; Huan, Yi; Han, Guohong; Larson, Andrew C
To test the following hypotheses in a murine model of pancreatic cancer: (a) Vaccination with antigen-loaded iron-labeled dendritic cells reduces T2-weighted signal intensity at magnetic resonance (MR) imaging within peripheral draining lymph nodes ( LN lymph node s) and (b) such signal intensity reductions are associated with tumor size changes after dendritic cell vaccination. PMID 25222066
Noninvasive radiofrequency treatment effect on mitochondria in pancreatic cancer cells.
Okt. 2014 | Curley, Steven A; Palalon, Flavio; Lu, Xiaolin; Koshkina, Nadezhda V
The development of novel therapeutic approaches for cancer therapy is important, especially for tumors that have poor response or develop resistance to standard chemotherapy and radiation. We discovered that noninvasive radiofrequency (RF) fields can affect cancer cells but not normal cells, inhibit progression of tumors in mice, and enhance the anticancer effects of chemotherapy. However, it remains unclear what physiological and molecular mechanisms this treatment induces inside cells. Here, we studied the effect of RF treatment on mitochondria in human pancreatic cancer cells. PMID 24986120
Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis.
Juli 2014 | Kobayashi, Masanori; Shimodaira, Shigetaka; Nagai, Kazuhiro; Ogasawara, Masahiro; Takahashi, Hidenori; Abe, Hirofumi; Tanii, Mitsugu; Okamoto, Masato; Tsujitani, Sun-Ichi; Yusa, Seiichi; Ishidao, Takefumi; Kishimoto, Junji; Shibamoto, Yuta; Nagaya, Masaki; Yonemitsu, Yoshikazu; ,
Dendritic cell (DC)-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it difficult to compare clinical outcomes. Here, we identified factors that determined the clinical benefits by analyzing data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimens. PMID 24777613
Identification of pancreatic cancer-associated tumor antigen from HSP-enriched tumor lysate-pulsed human dendritic cells.
Juni 2014 | Kim, Han-Soo; Kang, Dukjin; Moon, Myeong Hee; Kim, Hyung Jik
Vaccine strategies utilizing dendritic cells (DCs) to elicit anti-tumor immunity are the subject of intense research. Although we have shown that DCs pulsed with heat-treated tumor lysate (HTL) induced more potent anti-tumor immunity than DCs pulsed with conventional tumor lysate (TL), the underlying molecular mechanism is unclear. In order to explore the molecular basis of this approach and to identify potential antigenic peptides from pancreatic cancer, we analyzed and compared the major histocompatibility complex (MHC) ligands derived from TL- and HTL-pulsed dendritic cells by mass spectrophotometry. PMID 24954332
Different responses of human pancreatic adenocarcinoma cell lines to oncolytic Newcastle disease virus infection.
Feb. 2014 | Buijs, P R A; van Eijck, C H J; Hofland, L J; Fouchier, R A M; van den Hoogen, B G
Newcastle disease virus (NDV) is a naturally occurring oncolytic virus with clinically proven efficacy against several human tumor types. Selective replication in and killing of tumor cells by NDV is thought to occur because of differences in innate immune responses between normal and tumor cells. In our effort to develop oncolytic virotherapy with NDV for patients with pancreatic cancer, we evaluated the responses to NDV infection and interferon (IFN) treatment of 11 different established human pancreatic adenocarcinoma cell lines (HPACs). Here we show that all HPACs were susceptible to NDV. However, this NDV infection resulted in different replication kinetics and cytotoxic effects. Better replication resulted in more cytotoxicity. No correlation was observed between defects in the IFN pathways and NDV replication or NDV-induced cytotoxicity. IFN production by HPACs after NDV infection differed substantially. Pretreatment of HPACs with IFN resulted in diminished NDV replication and decreased the cytotoxic effects in most HPACs. These findings suggest that not all HPACs have functional defects in the innate immune pathways, possibly resulting in resistance to oncolytic virus treatment. These data support the rationale for designing recombinant oncolytic NDVs with optimized virulence that should likely contain an antagonist of the IFN pathways. PMID 24384773
Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma.
Mai 2013 | Ghansah, Tomar; Vohra, Nasreen; Kinney, Kathleen; Weber, Amy; Kodumudi, Krithika; Springett, Gregory; Sarnaik, Amod A; Pilon-Thomas, Shari
Pancreatic cancer is an extremely aggressive malignancy with a dismal prognosis. Cancer patients and tumor-bearing mice have multiple immunoregulatory subsets including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) that may limit the effectiveness of anti-tumor immunotherapies for pancreatic cancer. It is possible that modulating these subsets will enhance anti-tumor immunity. The goal of this study was to explore depletion of immunoregulatory cells to enhance dendritic cell (DC)-based cancer immunotherapy in a murine model of pancreatic cancer. Flow cytometry results showed an increase in both Tregs and MDSC in untreated pancreatic cancer-bearing mice compared with control. Elimination of Tregs alone or in combination with DC-based vaccination had no effect on pancreatic tumor growth or survival. Gemcitabine (Gem) is a chemotherapeutic drug routinely used for the treatment for pancreatic cancer patients. Treatment with Gem led to a significant decrease in MDSC percentages in the spleens of tumor-bearing mice, but did not enhance overall survival. However, combination therapy with DC vaccination followed by Gem treatment led to a significant delay in tumor growth and improved survival in pancreatic cancer-bearing mice. Increased MDSC were measured in the peripheral blood of patients with pancreatic cancer. Treatment with Gem also led to a decrease of this population in pancreatic cancer patients, suggesting that combination therapy with DC-based cancer vaccination and Gem may lead to improved treatments for patients with pancreatic cancer. PMID 23604104
Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer.
Jan. 2013 | Tschoep-Lechner, Katharina Elisabeth; Milani, Valeria; Berger, Frank; Dieterle, Nelli; Abdel-Rahman, Sultan; Salat, Christoph; Issels, Rolf-Dieter
There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC. PMID 23245336
Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer.
Okt. 2012 | Ishikawa, Takeshi; Kokura, Satoshi; Sakamoto, Naoyuki; Ando, Takashi; Imamoto, Eiko; Hattori, Takeshi; Oyamada, Hirokazu; Yoshinami, Naomi; Sakamoto, Masafumi; Kitagawa, Kazutomo; Okumura, Yoko; Yoshida, Naohisa; Kamada, Kazuhiro; Katada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Yasuda, Hiroaki; Sakagami, Junichi; Konishi, Hideyuki; Yagi, Nobuaki; Naito, Yuji; Yoshikawa, Toshikazu
Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer. PMID 22838644
Two avirulent, lentogenic strains of Newcastle disease virus are cytotoxic for some human pancreatic tumor lines in vitro.
Sep. 2012 | Walter, Robert J; Attar, Bashar M; Rafiq, Asad; Delimata, Megan; Tejaswi, Sooraj
Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Highly infectious Newcastle disease virus (NDV) strains are known to be very cytotoxic for an array of human tumor cell types in vitro and in vivo but the effects of these and avirulent NDV strains on pancreatic neoplasms are little known. PMID 22964957
Heat shock protein 27 as a prognostic and predictive biomarker in pancreatic ductal adenocarcinoma.
Juli 2012 | Schäfer, Claus; Seeliger, Hendrik; Bader, Dominik C; Assmann, Gerald; Buchner, Denise; Guo, Yang; Ziesch, Andreas; Palagyi, Andreas; Ochs, Stephanie; Laubender, Rüdiger P; Jung, Andreas; De Toni, Enrico N; Kirchner, Thomas; Göke, Burkhard; Bruns, Christiane; Gallmeier, Eike
A role of heat shock protein 27 (HSP27) as a potential biomarker has been reported in various tumour entities, but comprehensive studies in pancreatic cancer are lacking. Applying tissue microarray (TMA) analysis, we correlated HSP27 protein expression status with clinicopathologic parameters in pancreatic ductal adenocarcinoma specimens from 86 patients. Complementary, we established HSP27 overexpression and RNA-interference models to assess the impact of HSP27 on chemo- and radiosensitivity directly in pancreatic cancer cells. In the TMA study, HSP27 expression was found in 49% of tumour samples. Applying univariate analyses, a significant correlation was found between HSP27 expression and survival. In the multivariate Cox-regression model, HSP27 expression emerged as an independent prognostic factor. HSP27 expression also correlated inversely with nuclear p53 accumulation, indicating either protein interactions between HSP27 and p53 or TP53 mutation-dependent HSP27-regulation in pancreatic cancer. In the sensitivity studies, HSP27 overexpression rendered HSP27 low-expressing PL5 pancreatic cancer cells more susceptible towards treatment with gemcitabine. Vice versa, HSP27 protein depletion in HSP27 high-expressing AsPC-1 cells caused increased gemcitabine resistance. Importantly, HSP27 expression was inducible in pancreatic cancer cell lines as well as primary cells. Taken together, our study suggests a role for HSP27 as a prognostic and predictive marker in pancreatic cancer. Assessment of HSP27 expression could thus facilitate the identification of specific patient subpopulations that might benefit from individualized treatment options. Additional studies need to clarify whether modulation of HSP27 expression could represent an attractive concept to support the incorporation of hyperthermia in clinical treatment protocols for pancreatic cancer. PMID 22004109
Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma.
Feb. 2012 | Kimura, Yukino; Tsukada, Jun; Tomoda, Takeshi; Takahashi, Hidenori; Imai, Kazuhiro; Shimamura, Kanae; Sunamura, Makoto; Yonemitsu, Yoshikazu; Shimodaira, Shigetaka; Koido, Shigeo; Homma, Sadamu; Okamoto, Masato
In the current study, we have evaluated the clinical and immunological responses in patients with advanced pancreatic carcinoma who received dendritic cell (DC)-based immunotherapy in combination with gemcitabine and/or S-1. PMID 21792083
Newcastle disease virus LaSota strain kills human pancreatic cancer cells in vitro with high selectivity.
Jan. 2012 | Walter, Robert J; Attar, Bashar M; Rafiq, Asad; Tejaswi, Sooraj; Delimata, Megan
Pancreatic cancer is highly resistant to treatment. Previously, we showed that Newcastle disease virus (NDV) strain 73-T was highly cytotoxic to a range of tumor types in vitro and in vivo but the effects of NDV on pancreatic tumors are unknown. We determined the cytotoxicity of the lentogenic LaSota strain of NDV (NDV-LS) toward 7 different human pancreatic tumor cell lines and 4 normal human cell lines (keratinocytes, fibroblasts, pancreatic ductal cells, and vascular endothelial cells). PMID 22233946
Regional hyperthermia combined with chemoradiotherapy in primary or recurrent locally advanced pancreatic cancer : an open-label comparative cohort trial.
Okt. 2011 | Maluta, Sergio; Schaffer, Moshe; Pioli, Fabio; Dall'oglio, Stefano; Pasetto, Stefano; Schaffer, Pamela M; Weber, Bernard; Giri, Maria Grazia
To evaluate the therapeutic effect of delivering regional hyperthermia (HT) plus chemoradiotherapy (CRT) in patients suffering from locally advanced unresectable pancreatic cancer (LAPC). PMID 21932025
A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors.
Sep. 2011 | Lepisto, Andrew J; Moser, Arthur J; Zeh, Herbert; Lee, Kenneth; Bartlett, David; McKolanis, John R; Geller, Brian A; Schmotzer, Amy; Potter, Douglas P; Whiteside, Theresa; Finn, Olivera J; Ramanathan, Ramesh K
Pancreatic and biliary cancers are relatively resistant to chemotherapy and radiation and may therefore provide an opportunity for testing the potential of immunotherapy. MUC1 is an epithelial cell glycoprotein that is highly overexpressed and aberrantly glycosylated in many adenocarcinomas, including pancreatic tumors, providing a tumor specific antigen and target. We performed a Phase I/II clinical trial of a MUC1 peptide-loaded DC vaccine in 12 pancreatic and biliary cancer patients following resection of their primary tumors. The primary endpoints were vaccine toxicity and immunogenicity and the secondary endpoint was clinical outcome. The vaccine was well tolerated and no toxicity was observed. Three patients had pre-existing MUC1 antibody responses that remained stable post vaccination. MUC1-specific T cell responses were difficult to evaluate due to increases in activity of all CD8 and CD4 T cells following each vaccination. Prior to vaccination, patients entered onto this trial had a significantly higher percentage of FoxP3+CD4+ T cells compared to age matched healthy controls. The percentage of these cells also increased transiently following each injection, returning to baseline or below before the next injection. Vaccinated patients have been followed for over four years and four of the twelve patients are alive, all without evidence of recurrence. Study of the immune parameters in long-term survivors several years after vaccination may yield the sought after immune correlates of clinical responses that analysis of immune responses shortly after vaccination has not revealed. PMID 19129927
Current immunotherapeutic approaches in pancreatic cancer.
Sep. 2011 | Koido, Shigeo; Homma, Sadamu; Takahara, Akitaka; Namiki, Yoshihisa; Tsukinaga, Shintaro; Mitobe, Jimi; Odahara, Shunichi; Yukawa, Toyokazu; Matsudaira, Hiroshi; Nagatsuma, Keisuke; Uchiyama, Kan; Satoh, Kenichi; Ito, Masaki; Komita, Hideo; Arakawa, Hiroshi; Ohkusa, Toshifumi; Gong, Jianlin; Tajiri, Hisao
Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer. PMID 21922022
Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study.
Juli 2011 | Bauer, Christian; Dauer, Marc; Saraj, Samira; Schnurr, Maximilian; Bauernfeind, Franz; Sterzik, Alexander; Junkmann, Jana; Jakl, Veronika; Kiefl, Rosemarie; Oduncu, Fuat; Emmerich, Bertold; Mayr, Doris; Mussack, Thomas; Bruns, Christiane; Rüttinger, Dominik; Conrad, Claudius; Jauch, Karl-Walter; Endres, Stefan; Eigler, Andreas
Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. PMID 21547597
Hyperthermia potentiates oncolytic herpes viral killing of pancreatic cancer through a heat shock protein pathway.
Juli 2010 | Eisenberg, David P; Carpenter, Susanne G; Adusumilli, Prasad S; Chan, Mei-Ki; Hendershott, Karen J; Yu, Zhenkun; Fong, Yuman
Oncolytic herpes simplex virus-1 (HSV-1) is designed to specifically infect, replicate in, and lyse cancer cells. This study investigates a novel therapeutic regimen, combining the effects of NV1066 (a recombinant HSV-1) and hyperthermia in the treatment of pancreatic cancer. PMID 20633729
Impact of surgery and chemotherapy on cellular immunity in pancreatic carcinoma patients in view of an integration of standard cancer treatment with immunotherapy.
Mai 2009 | Bellone, Graziella; Novarino, Anna; Vizio, Barbara; Brondino, Gabriele; Addeo, Alfredo; Prati, Adriana; Giacobino, Alice; Campra, Donata; Fronda, Gian Ruggero; Ciuffreda, Libero
As surgery and chemotherapy may act as adjuvants providing antitumor immunity benefits, we ran phenotypical and functional immunomonitoring in patients with resectable pancreatic adenocarcinoma and advanced metastatic disease receiving combined treatment (cisplatin, gemcitabine, 5-FU). Blood was taken before/one month after resection; before/during chemotherapy. Controls were age- and gender-matched. Circulating lymphocyte, myeloid and plasmacytoid dendritic cell (MDC and PDC) subsets were examined by flow cytometry; functional activity by mixed lymphocyte reaction (MLR) for DC allostimulation, through 4-h 51Cr-release assay for Natural Killer (NK) and lymphokine-activated-killer (LAK) cell cytotoxicity; ELISA for spontaneous/activated cytokine release by PBMC and T cells. Significant differences occurred in several parameters between pretreatment patient and control values: fewer CD8+ cells and increased apoptosis-prone CD3+/CD95+ lymphocytes, higher frequency of MDC, reduced allostimulatory activity by ex vivo-generated DC, depressed LAK activity, elevated IL-10 and IL-12p40 production; impaired IL-12p70 and IFN-gamma production by stimulated PBMC and T cells. Only IL-12p70 level was correlated with survival. One month after radical, but not palliative surgery, the percentage of T-lymphocytes coexpressing CD3/CD95 decreased significantly, the stimulatory capacity of DC increased, and LPS-induced IL-12p70 release by PBMC rose concomitantly with the anti-CD3 stimulated-IFN-gamma production by T cells. In patients with locally advanced or metastatic disease, one and/or two combined drug cycles increased percentage of CD4+ cells and LAK cell cytotoxicity and decreased PDC frequency and spontaneous/LPS-stimulated IL-10 by PBMC. Results suggest immunological changes induced by surgical resection/combined chemotherapy indicate specific precisely-timed windows of opportunity for introducing immunotherapy in pancreatic cancer, possibly improving survival in this highly lethal disease. PMID 19424589
A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer.
März 2009 | Hirooka, Yoshiki; Itoh, Akihiro; Kawashima, Hiroki; Hara, Kazuo; Nonogaki, Koji; Kasugai, Toshifumi; Ohno, Eizaburo; Ishikawa, Takuya; Matsubara, Hiroshi; Ishigami, Masatoshi; Katano, Yoshiaki; Ohmiya, Naoki; Niwa, Yasumasa; Yamamoto, Koji; Kaneko, Toru; Nieda, Mie; Yokokawa, Kiyoshi; Goto, Hidemi
Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. PMID 19276867
Countering tumor-induced immunosuppression during immunotherapy for pancreatic cancer.
Feb. 2009 | Morse, Michael A; Hall, Joseph Robert; Plate, Janet M D
Vaccines for pancreatic cancer have been challenged by a number of factors, especially the immunosuppressive microenvironment within the tumor that allows for escape from immune surveillance. PMID 19216622
[Specific immune against pancreatic cancer induced by dendritic cells pulsed with mutant K-ras peptide].
Dez. 2008 | Yang, Bo; He, Yang; Sun, Dong-lin; Zou, Yan; Qin, Xi-hu; Huang, Bo-hua
To investigate whether dendritic cells (DCs) pulsed with mutant K-ras peptide (12-Val) can induce efficiently specific anti-tumor immune response against pancreatic cancer. PMID 19062734
Biological approaches to therapy of pancreatic cancer.
Okt. 2008 | Wong, Han Hsi; Lemoine, Nicholas R
Pancreatic cancer is a lethal disease and notoriously difficult to treat. Only a small proportion is curative by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Clearly there is a need for the continual development of novel therapeutic agents to improve the current situation. Improvement of our understanding of the disease has generated a large number of studies on biological approaches targeting the molecular abnormalities of pancreatic cancer, including gene therapy and signal transduction inhibition, antiangiogenic and matrix metalloproteinase inhibition, oncolytic viral therapy and immunotherapy. This article provides a review of these approaches, both investigated in the laboratories and in subsequent clinical trials. PMID 18724071
Immunotherapy of pancreatic carcinoma.
Juni 2008 | Märten, Angela; Büchler, Markus W
Patients with carcinoma of the exocrine pancreas have an especially poor prognosis. This is a systemic disease that is insensitive to radiotherapy and often to chemotherapy. One promising treatment strategy is immunotherapy, and several phase I/II clinical trials have been conducted. Unspecific stimulation or vaccinations with peptides have generated encouraging results and data from phase II clinical trials with combination therapies are highly promising. The use of immunotherapy and combination therapies that include immunotherapy for the potential treatment of pancreatic adenocarcinoma, requires investigation in phase III randomized and controlled clinical trials in combination with appropriate immunomonitoring. PMID 18516755
Immunotherapy of pancreatic carcinoma.
Mai 2008 | Märten, Angela
Patients with carcinoma of the exocrine pancreas have especially poor prognosis with a five-year survival rate of <1% and a median survival of 4-6 months. Pancreatic carcinoma is a systemic disease, insensitive to radiotherapy and mostly to chemotherapy. Accordingly, new treatment modalities are worth being investigated. One of the promising approaches is immunotherapy. Several phase I/II trials that have been published show interesting results, whereupon antibody-based strategies seem to fail and unspecific stimulation or vaccination with peptides look encouraging. Furthermore, phase II trials dealing with combination therapies are highly promising. One of them, a combination of chemoradiotherapy plus interferon-alpha is currently tested in a randomized phase III trial. As most of the trials had enrolled only limited numbers of patients and most of the trials were not conducted and/or reported according to the new standards it is difficult to draw final conclusions from the discussed trials. Immuno-monitoring was performed only in 40% of the discussed publications. In all cases immune responses were observed and correlation with the clinical outcome is discussed. Immunotherapy of pancreatic adenocarcinoma and especially combination therapies including immunotherapy is an up-and-coming approach and needs to be investigated in well conducted phase III randomized controlled trials accompanied by appropriate immuno-monitoring. PMID 18474022
Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes.
Apr. 2008 | Kondo, Hiroshi; Hazama, Shoichi; Kawaoka, Toru; Yoshino, Shigefumi; Yoshida, Shin; Tokuno, Kazuhisa; Takashima, Motonari; Ueno, Tomio; Hinoda, Yuji; Oka, Masaaki
Pancreatic cancer has a poor prognosis. The clinical efficacy of immunotherapy using both dendritic cells pulsed with MUC1 peptide (MUC1-DC) and, cytotoxic T lymphocyte (CTL) sensitized with a pancreatic cancer, YPK-1, expressing MUC1 (MUC1-CTL) was evaluated. PMID 18383873
Immunotherapeutic approaches in pancreatic cancer.
Dez. 2007 | Stieler, J
With growing understanding of the regulation of immune responses, multiple new immunotherapeutic targets have evolved. This article gives a survey over the current approaches in pancreatic cancer therapy including peptide vaccinations, unspecific immunotherapy, allogene modified tumor cell vaccines, and vector-based vaccines. Although several trials have shown detectable immune responses, such as delayed-type hypersensitivity reactions and cytokine release in enzyme-linked immunosorbent spot (ELISPOTS) assays, and some have reported prolonged survival for immune responders, immunotherapy remains experimental. However, some approaches have made it into a phase III setting. In addition, the emerging concept of tumor stem cells may lead to a new focus on immunotherapy, since these often highly chemotherapy-resistant cells are thought to be the source of recurrences. PMID 18084958
Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model.
Aug. 2007 | Bauer, C; Bauernfeind, F; Sterzik, A; Orban, M; Schnurr, M; Lehr, H A; Endres, S; Eigler, A; Dauer, M
Tumour-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by vaccination with dendritic cells (DCs). However, clinical responses to DC-based vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. It has been shown previously that gemcitabine sensitises human pancreatic carcinoma cells against CTL-mediated lysis. Here, a murine pancreatic carcinoma model was used to investigate whether combination with gemcitabine increases therapeutic efficacy of DC-based vaccination. PMID 17395611
Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma.
Aug. 2007 | Nummer, Daniel; Suri-Payer, Elisabeth; Schmitz-Winnenthal, Hubertus; Bonertz, Andreas; Galindo, Luis; Antolovich, Dalibor; Koch, Moritz; Büchler, Markus; Weitz, Jürgen; Schirrmacher, Volker; Beckhove, Philipp
Regulatory T (Treg) cells have been detected in human carcinomas and may play a role in preventing the rejection of malignant cells. PMID 17652277
[Immunotherapeutic effects of beta-elemene combined with interleukin-23 gene-modified dendritic cells on murine pancreatic carcinoma].
Sep. 2006 | Tan, Guang; Wang, Zhong-Yu; Wang, Xiao-Gang; Cheng, Lei; Yin, Shuo
Dendritic cell (DC) vaccine is a kind of treatment vaccine with clinical application potency. Functional cytokines can enhance anti-tumor immune response of dendritic cells. This study was to investigate the protective effects on murine pancreatic carcinoma by beta-elemene combined with bone marrow-derived dendritic cells (BM-DCs) modified with murine interleukin (IL)-23 gene. PMID 16965646
Dendritic cells pulsed with alpha-galactosylceramide induce anti-tumor immunity against pancreatic cancer in vivo.
Juli 2006 | Nagaraj, S; Ziske, C; Strehl, J; Messmer, D; Sauerbruch, T; Schmidt-Wolf, I G H
Ductal pancreatic adenocarcinoma is the fourth leading cause of cancer death in the Western world. Unfortunately, recent advances in diagnostics, staging and therapy have not resulted in significant improvements. Thus, new approaches are necessary to improve the outcome of patients with exocrine pancreatic cancer. We tested triggering of specific T lymphocytes in vivo by using the immunocompetent mouse strain C57BL/6. In the present study, we tried to enhance the anti-tumor effect against pancreatic carcinoma by supplementary triggering of NKT cells in vivo. We challenged Panc02 tumor-bearing mice by intratumoral vaccination with alpha-galactosylceramide (alpha-GalCer)-loaded dendritic cells (DCs). A significant expansion of IFNgamma-producing NKT cells was observed which also correlated with decrease in tumor growth in vivo. Hence, DCs loaded with alpha-GalCer could lead to a novel treatment option for patients with pancreatic cancer. PMID 16772371
[Therapeutic effects of treatment of pancreatic carcinoma by interleukin-23 and apoptotic cell antigen-modified dendritic cell vaccine: experiment with mice].
Juni 2006 | Tan, Guang; Wang, Zhong-Yu; Yin, Shuo
To investigate the therapeutic effects on pancreatic carcinoma by dendritic cells (DCs) transfected with interleukin (IL)-23 and acquiring apoptotic cell antigen. PMID 16759530
Efficacy of immuno-cell therapy in patients with advanced pancreatic cancer.
Nov. 2005 | Kaneko, Toru; Goto, Shigenori; Kato, Akira; Akeyama, Akiteru; Tomonaga, Masamichi; Fujimoto, Katsunada; Miyamoto, Yoju; Eriguchi, Masazumi; Egawa, Koji
Patients with advanced pancreatic carcinoma have a risk of relapse after primary therapy, and the prognosis for these patients remains bleak. The effect of immuno-cell therapy in advanced pancreatic carcinoma, with or without other standard therapies, was examined. PMID 16302730
Chemosensitization of pancreatic carcinoma cells to enhance T cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells.
Juli 2005 | Dauer, Marc; Herten, Jan; Bauer, Christian; Renner, Frederik; Schad, Katharina; Schnurr, Max; Endres, Stefan; Eigler, Andreas
Dendritic cells (DCs) can induce cytotoxic T-cell (CTL) responses against tumor antigens in vitro and in vivo, yet few cancer patients experience tumor regression after DC-based vaccination. Combination with other treatment modalities, such as radiation or pharmacologic anticancer agents, may reduce tumor cell resistance against immune responses. The authors tested whether treatment with gemcitabine or cyclooxygenase-2 (COX-2) inhibitors increases the sensitivity of pancreatic carcinoma cells to CTL-mediated killing. Monocyte-derived DCs of HLA-A2+ donors were loaded with lysate from the HLA-A2+ pancreatic carcinoma cell line Panc-1 and co-cultured with autologous CD3+ T cells. ELISPOT and cytotoxicity assays performed after two rounds of in vitro stimulation confirmed induction of a tumor-specific CTL response. Changes in the magnitude and the effector mechanism of the CTL response were analyzed after treatment of Panc-1 cells with gemcitabine and COX-2 inhibitors. Compared with gemcitabine, COX-2 inhibitors more effectively sensitized Panc-1 cells to CTL-mediated killing and showed less inhibition of T-cell activation by DCs in vitro. Using anti-CD95 blocking antibody, the authors showed that the increase in CTL-mediated tumor cell killing observed after treatment with COX-2 inhibitors is dependent on CD95/CD95 ligand interaction. Increased apoptosis of Panc-1 cells treated with COX-2 inhibitor was also observed after incubation with agonistic anti-CD95 antibody. Sensitization of cancer cells to CD95-dependent killing by CTLs represents a novel mechanism of action for COX-2 inhibitors and provides a rationale for their concomitant use with immunotherapeutic strategies such as DC-based vaccination. PMID 16000951
Dendritic cells pulsed with pancreatic cancer total tumor RNA generate specific antipancreatic cancer T cells.
März 2004 | Kalady, Matthew F; Onaitis, Mark W; Emani, Sirisha; Abdul-Wahab, Zeinab; Pruitt, Scott K; Tyler, Douglas S
RNA-based dendritic cell immunotherapy with the use of total tumor RNA provides the potential to generate a polyclonal immune response to multiple known and unknown tumor antigens without HLA restriction. Our study evaluated this approach as potential immunotherapy for patients with pancreatic cancer. Dendritic cells were generated using adherent monocytes isolated from peripheral blood of patients with pancreatic cancer and evaluated phenotypically by flow cytometry to determine whether dendritic cells could be generated from the blood of patients with pancreatic cancer. Immature dendritic cells were transfected with mRNA encoding full-length carcinoembryonic antigen (CEA) or pancreatic cancer total tumor messenger RNA, and then matured. Matured dendritic cell phenotypes were also analyzed by flow cytometry. Transfected, matured dendritic cells were used to stimulate autologous T cells, and the resultant antigen-specific effector T cells were analyzed by interferon-gamma Elispot assay. Immature dendritic cells with characteristic phenotypic markers CD40, CD80, and CD86 were successfully isolated from the blood of patients with pancreatic cancer. Incubation with maturation agents increased expression of CD80 and CD83, demonstrating the induction of a mature antigen-presenting phenotype. Dendritic cells transfected with a pancreatic cancer-associated antigen (CEA) generated antigen-specific T cells (P<0.05). Dendritic cells transfected with autologous total tumor pancreatic cancer RNA generated T cells that specifically recognized HLA-matched pancreatic cancer cell lines (P<0.05 compared to control cell lines). Dendritic cells from patients with pancreatic cancer maintain the ability to translate and process transfected RNA and serve as mature antigen-presenting cells. These RNA-transfected dendritic cells from pancreatic cancer patients successfully generate specific T cells against the pancreatic cancer-associated antigen CEA as well as T cells that specifically recognize pancreatic cancer cells. These data suggest that total tumor RNA-pulsed dendritic cells may have potential as an adjuvant immunotherapy for patients with pancreatic cancer. PMID 15036193
The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer.
März 2003 | Morse, Michael A; Nair, Smita K; Boczkowski, David; Tyler, Douglas; Hurwitz, Herbert I; Proia, Alan; Clay, Timothy M; Schlom, Jeffrey; Gilboa, Eli; Lyerly, H Kim
Resected pancreatic cancer has a high risk of recurrence and mortality despite the the use of chemoradiotherapy. Because pancreatic cancers express tumor antigens such as carcinoembryonic antigen (CEA), it may be possible to immunize patients to induce tumor antigen-specific immune responses. We hypothesize that high-frequency tumor antigen-specific immune responses will reduce recurrence and increase survival. Autologous dendritic cells (DCs) loaded with tumor antigens are particularly potent at inducing tumor antigen-specific immune responses. PMID 12630764
In vivo induction of dendritic cell-mediated cytotoxicity against allogeneic pancreatic carcinoma cells.
Feb. 2003 | Stift, Anton; Friedl, Josef; Dubsky, Peter; Bachleitner-Hofmann, Thomas; Benkoe, Thomas; Brostjan, Christine; Jakesz, Raimund; Gnant, Michael
The objective of this study was to assess the toxicity and immunological response induced by autologous dendritic cells (DCs) pulsed with allogeneic tumor lysate in a pancreatic cancer patient. The lack of available tumor peptides in pancreatic cancer strongly supports the idea to use allogeneic tumor cells as a source of antigens. The patient suffering from a stage IV pancreatic cancer received 1-2x10(7) autologous monocyte-derived DCs in three-week intervals injected into a groin lymph node. Monocytes from peripheral blood were isolated by magnetic bead selection. For the first ten vaccinations DCs were loaded with autologous tumor cell lysate obtained during surgical exploration. After consumption of the autologous lysate, equal numbers of DCs were pulsed with lysate of the tumor cell line AsPc-1 and BxPc-3 for a further five vaccinations. Peripheral mononuclear cells (PMNCs) were harvested after the seventh and compared with PMNCs obtained after the fourteenth vaccination for immunological response. Delayed type hypersensitivity reactivity to DCs pulsed with autologous and allogeneic tumor lysate was also assessed. The patient received a total of fifteen vaccinations. There was no toxicity or evidence of autoimmunity observed. Delayed type hypersensitivity was found to be positive for the autologous as well as the allogeneic tumor lysate pulsed DCs. in vitro cytotoxicity assays demonstrated a dramatic increase of the PMNC killing capacity against the pancreatic cancer cell lines AsPc-1 and BxPc-3 after the fourteenth compared to the seventh vaccination. CT scans revealed a stable disease for six months. The administration of autologous DCs pulsed with allogeneic tumor lysate is non-toxic and suitable for inducing an immunological anti-tumor response. Even though this study was confined to a single patient, the data might open a door for novel immunotherapeutical strategies. PMID 12579320
[Is total body hyperthermia plus chemotherapy useful in pancreas carcinoma?].
Aug. 2002 | Ziske, C; Sauerbruch, T
Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines.
Aug. 2001 | Schnurr, M; Galambos, P; Scholz, C; Then, F; Dauer, M; Endres, S; Eigler, A
Dendritic cells (DCs) are potent antigen-presenting cells and play a pivotal role in T cell-mediated immunity. DCs have been shown to induce strong antitumor immune responses in vitro and in vivo, and their efficacy is being investigated in clinical trials. Compared with vaccination strategies directed against a single tumor antigen, tumor-cell lysate as the source of antigen offers the potential advantage of inducing a broad T-cell response against multiple known, as well as unknown, tumor-associated antigens expressed by the individual tumor. We used pancreatic carcinoma cell lines to develop an in vitro model for monitoring T-cell responses induced by lysate-pulsed DCs. Monocyte-derived DCs of HLA-A2(+) donors were pulsed with lysate generated from the HLA-A2(+) pancreatic carcinoma cell line Panc-1. In some experiments, the immunogenic protein keyhole limpet hemocyanin (KLH) was added to the lysate. Subsequently, the antigen-loaded DCs were activated with tumor necrosis factor-alpha and prostaglandin E(2). Autologous mononuclear cells were cocultured with DCs in the presence of low-dose interleukin (IL)-2 and IL-7 and were restimulated weekly with new DCs. High levels of IL-12 and IFN-gamma could be detected in the supernatants, indicating a T-helper type 1-type immune response. This cytokine profile was associated with the expression of the activation marker CD69 on both T helper and CTLs and with an antigen-induced proliferative T-cell response. After 4 weeks, CTL-mediated cytotoxicity was assessed. Tumor cell lysis was specific for Panc-1 tumor cells and was MHC class I-restricted. Cytokine secretion, CD69 expression of T cells, and antigen-induced T-cell proliferation correlated with the cytotoxic activity and were more pronounced when KLH was added to the lysate. This is the first study to show that T cells specific for pancreatic carcinoma cells can be generated in vitro by lysate-pulsed DCs and that the T-cell response can be enhanced by KLH. This in vitro model can be applied to compare different strategies in the development of DC-based tumor vaccines. PMID 11522639
Increase in the immunostimulatory effect of dendritic cells by pulsing with serum derived from pancreatic and colorectal cancer patients.
Jan. 2001 | Märten, A; Ziske, C; Schöttker, B; Renoth, S; Weineck, S; Buttgereit, P; Schakowski, F; Klingmüller, D; Scheffold, C; von Rücker, A; Sauerbruch, T; Schmidt-Wolf, I G
Both we and others have observed a relative resistance of solid tumor cells to immunological effector cells in vitro, which may be one reason for the clinical phenomenon of resistance of patients with pancreatic carcinoma or other solid tumors to immunological therapeutic approaches. Dendritic cells (DC) are professional antigen-presenting cells which can process and present tumor-associated antigens such as CA 19-9. Here we tested DC pulsed with serum containing CA 19-9 for their capacity to stimulate immunological effector cells against pancreatic carcinoma cells. Coculture of immunological effector cells with DC led to a significant increase in cytotoxic activity as measured by a lactic dehydrogenase release assay. Most interestingly, cytotoxic activity against tumor cells was further increased using DC pulsed with patient-derived CA 19-9 containing serum. Similar results have been obtained using either autologous or allogeneic serum from patients with pancreas carcinoma. The effect of serum on the cytotoxicity of effector cells increased in a dose-dependent manner. Interestingly, heat inactivation led to a significant loss of immunostimulatory capacity of the serum. Cytotoxicity was partially inhibited by using an antibody directed against CA 19-9 on the surface of the target cells. Best results were obtained when adding CA 19-9 protein to CA 19-9 containing serum for pulsing of DC. In conclusion, DC pulsed with CA 19-9 containing serum increased the cytotoxic activity of immunological effector cells against pancreatic cancer cells. DC pulsed with CA 19-9 containing serum with or without additional exogenous CA 19-9 protein may have an impact on immunotherapeutic protocols for patients with CA 19-9 secreting tumors. PMID 11008718
Increase of the immunostimulatory effect of dendritic cells by pulsing with CA 19-9 protein.
Nov. 2000 | Märten, A; Schöttker, B; Ziske, C; Weineck, S; Buttgereit, P; Huhn, D; Sauerbruch, T; Schmidt-Wolf, I G
Previously, a relative resistance of solid tumor cells to immunologic effector cells was shown in vitro. This resistance could be one reason for the clinical phenomenon of resistance of patients with colon carcinoma or other solid tumors to immunologic therapeutic approaches. In this study, dendritic cells (DCs) pulsed with CA 19-9 protein were tested for their immunostimulatory capacity of immunologic effector cells against cells derived from colon and pancreatic carcinoma. Dendritic cell cultures coexpressed CMRF-44 and CD1a, markers typical of DCs, in 31.5% +/- 5.3% after 13 days of culture. Coculture of NK-like T lymphocytes with DCs led to a significant increase in cytotoxic activity, as measured using a lactate dehydrogenase release assay. Cytotoxic activity could be further increased using DCs pulsed with CA 19-9 protein. The effect of CA 19-9 on increasing the cytotoxic effect of NK-like T lymphocytes was dose dependent. Similarly, cocultivation of DCs with NK-like T cells derived from patients with metastatic pancreatic cancer and elevated CA 19-9 serum levels led to a significant increase in cytotoxic activity. In conclusion, DCs pulsed with CA 19-9 protein can increase the cytotoxic activity of immunologic effector cells against colon carcinoma and pancreatic cancer cells. Dendritic cells pulsed with CA 19-9 protein may have an important effect on immunotherapeutic protocols for patients with cancer. PMID 10916756
A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen.
Sep. 1999 | Morse, M A; Deng, Y; Coleman, D; Hull, S; Kitrell-Fisher, E; Nair, S; Schlom, J; Ryback, M E; Lyerly, H K
Dendritic cells (DCs), antigen-presenting cells capable of priming naive T cells to specific antigens in an HLA-restricted fashion, have been demonstrated to induce protective T cell-mediated immunity in tumor-bearing animals. We performed this study to test the safety, feasibility, and clinical response of immunizations with in vitro-generated DCs, loaded with an HLA-A2-restricted peptide fragment of the tumor antigen carcinoembryonic antigen (CEA), for the treatment of patients with advanced CEA-expressing malignancies. Cell preparations enriched for autologous DCs were generated from the patients' plastic adherent peripheral blood mononuclear cells in serum-free media supplemented with granulocyte macrophage colony-stimulating factor and interleukin-4. Within the cell preparation, 66% of the cells expressed the phenotype typical for DCs (CD86high, HLA-DRhigh, and CD14low). The DCs were loaded with the CEA peptide CAP-1 and cryopreserved. Groups of three to six patients received four weekly or biweekly i.v. infusions of the CAP-1-loaded DC in escalating dose levels of 1 x 10(7), 3 x 10(7), and 1 x 10(8) cells/dose. A subset of the patients in the last group also received intradermal injections of 1 x 10(6) DCs. There were no toxicities directly referable to the treatments. One patient had a minor response, and one had stable disease. Skin punch biopsy at DC injection sites demonstrated pleomorphic infiltrates in the three patients evaluated. We conclude that it is feasible and safe to generate and administer large numbers of previously cryopreserved DCs loaded with CAP-1 peptide to patients with advanced malignancies. PMID 10389916