Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers.
Nov. 2016 | Hatakeyama, Hiroto; Wu, Sherry Y; Lyons, Yasmin A; Pradeep, Sunila; Wang, Wanqin; Huang, Qian; Court, Karem A; Liu, Tao; Nie, Song; Rodriguez-Aguayo, Cristian; Shen, Fangrong; Huang, Yan; Hisamatsu, Takeshi; Mitamura, Takashi; Jennings, Nicholas; Shim, Jeajun; Dorniak, Piotr L; Mangala, Lingegowda S; Petrillo, Marco; Petyuk, Vladislav A; Schepmoes, Athena A; Shukla, Anil K; Torres-Lugo, Madeline; Lee, Ju-Seog; Rodland, Karin D; Fagotti, Anna; Lopez-Berestein, Gabriel; Li, Chun; Sood, Anil K
Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers. PMID 27806300
Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers.
Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence.
Mai 2015 | Wefers, Christina; Lambert, Laurens J; Torensma, Ruurd; Hato, Stanleyson V
Ovarian cancer is a devastating disease with a high relapse rate. Due to a mostly asymptomatic early stage and lack of early diagnostic tools, the disease is usually diagnosed in a late stage. Surgery and chemotherapy with taxanes and platinum compounds are very effective in reducing tumor burden. However, relapses occur frequently and there is a lack of credible second-line options. Therefore, new treatment modalities are eagerly awaited. The presence and influx of immune cells in the ovarian cancer tumor microenvironment are correlated with survival. High numbers of infiltrating T cells correlate with improved progression free and overall survival, while the presence of regulatory T cells and expression of T cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy, especially cell-based immunotherapy could be a promising novel addition to the treatment of ovarian cancer. Here, we review the available data on the immune contexture surrounding ovarian cancer and discuss novel strategies and targets for immunotherapy in ovarian cancer. In the end the addition of immunotherapy to existing therapeutic options could lead to a great improvement in the outcome of ovarian cancer, especially when targeting cancer stem cells. PMID 25727651
Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial.
Jan. 2015 | Baek, Soyoung; Kim, Yong-Man; Kim, Sung-Bae; Kim, Choung-Soo; Kwon, Seog-Woon; Kim, YongMan; Kim, HyunSoo; Lee, Hyunah
While ovarian cancer (OvCa) responds well to surgery and conventional chemotherapy, a high recurrence rate of advanced OvCa is observed. In this phase I/II study, 10 OvCa patients with minimal residual disease were treated with autologous dendritic cells (DCs) and IL-2 to evaluate the safety and feasibility of this therapeutic strategy and to characterize the antigen-specific immune alterations induced through this treatment. Approximately 4 months after initial debulking and chemotherapy, patients received two subcutaneous doses of autologous monocyte-derived DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH) at 4-week intervals. After each DC inoculation, low-dose (200 mIU) IL-2 was introduced for 14 consecutive days as an immune adjuvant. The vaccination was well tolerated. In three out of 10 patients, the inclusion status after the initial therapy showed the maintenance of complete remission (CR) after DC vaccination for 83, 80.9 and 38.2 months without disease relapse. One patient with stable disease (SD) experienced the complete disappearance of tumor after DC vaccination, and this status was maintained for 50.8 months until tumor recurrence. In two patients with partial response (PR) was not responding to DC vaccination and their disease recurred. In the three patients with disease free long-term survival, significant immune alterations were observed, including increased natural killer (NK) activity, IFN-γ-secreting T cells, immune-stimulatory cytokine secretion and reduced immune-suppressive factor secretion after DC vaccination. Thus, in patients with NED status and increased overall survival, DC vaccination induced tumor-related immunity, potentially associated with long-term clinical responses against OvCa. PMID 24976269
[The effect of immunotherapy and hyperthermia on advanced or recurrent ovarian and uterine cancer - 229 clinical cases].
Okt. 2014 | Nakamura, Kana; Hanazawa, Sayaka; Takeda, Takashi; Sumiyoshi, Rumi; Kobayashi, Shogo; Takeda, Hiroko; Takeda, Tsutomu
We treated 116 advanced or recurrent ovarian cancer and 102 uterine cancer patients with hyperthermia and/or immunotherapy(2005/7-2013/11). Of these, 63, 31, and 8 patients had cervical cancer, endometrial cancer, and uterine sarcoma, respectively. Standard therapy showed no effect or was refused by these patients. Twenty-nine(25.0%)ovarian cancer patients experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months). The effective rate of a combination of therapies including activated lymphocyte therapy, dendritic cell therapy, and hyperthermia was 47.5%. Thirteen(12.7%)uterine cancer patients experienced a clinical benefit. The effective rates for cervical cancer, endometrial cancer, and uterine sarcoma were 7.9%, 22.5%, and 12.5%, respectively. Both hyperthermia and immunotherapy were administered to successfully treat these patients. PMID 25335722
The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer.
Okt. 2014 | Kobayashi, Masanori; Chiba, Asako; Izawa, Hiromi; Yanagida, Eri; Okamoto, Masato; Shimodaira, Shigetaka; Yonemitsu, Yoshikazu; Shibamoto, Yuta; Suzuki, Noboru; Nagaya, Masaki; ,
Despite the increased rate of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Dendritic cell (DC)-based immunotherapy has been developed as a novel strategy for generating antitumor immunity as part of cancer treatments. The present study aimed to assess the feasibility and clinical effects of DC therapy for recurrent ovarian cancer (ROC). PMID 25298213
Ovarian cancer biology and immunotherapy.
Okt. 2014 | Latha, T Sree; Panati, Kalpana; Gowd, D Sravan Kumar; Reddy, Madhava C; Lomada, Dakshayani
Ovarian cancer is the most lethal malignancy of the female reproductive system and the fifth leading cause of cancer death in women. In the year 2012 alone, United States had 22,280 new ovarian cancer cases and 15,500 deaths were reported. About 7%-10% of ovarian cancers result from an inherited tendency to develop the disease. Ovarian cancer has the ability to escape the immune system because of its pathological interactions between cancer cells and host immune cells in the tumor microenvironment create an immunosuppressive network that promotes tumor growth, protects the tumor from immune system. The levels of immune suppressive elements like regulatory T cells, plasmacytoid dendritic cells and cytokines such as IL-10, IL-6, TNF-α, and TGF-β are elevated in the tumor microenvironment. Vascular endothelial growth factor is known to have an immune suppressing role besides its angiogenic role in the tumor microenvironment. Ovarian cancer is associated with high mortality partly due to difficulties in early diagnosis and development of metastases. These problems may overcome by developing accurate mouse models that should mimic the complexity of human ovarian cancer. Such animal models are better suited to understand pathophysiology, metastases, and also for preclinical testing of targeted molecular therapeutics. Immunotherapy is an area of active investigation and off late many clinical trials is ongoing to prevent disease progression. The main aim of dendritic cells vaccination is to stimulate tumor specific effector T cells that can reduce tumor size and induce immunological memory to prevent tumor relapse. PMID 24911597
Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies.
Mai 2014 | Coosemans, A; Vergote, I; Van Gool, S W
Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor-associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy. PMID 24784346
Dendritic cell-based immunotherapy in ovarian cancer.
Feb. 2014 | Coosemans, An; Vergote, Ignace; Van Gool, Stefaan W
Worldwide, 80% of patients with ovarian cancer die of the disease. New treatments for this aggressive disease are therefore being intensively searched. Although dendritic cell-based vaccines against gynecological malignancies are in their infancy, this immunotherapeutic approach holds much promise. Here, we present our view on an optimal dendritic cell-based immunotherapeutic strategy against ovarian cancer. PMID 24501688
Dendritic cell vaccination, immune regulation, and clinical outcomes in ovarian cancer.
Dez. 2013 | Goyne, Hannah E; Cannon, Martin J
Clinical optimism for dendritic cell vaccination against ovarian cancer has been tempered by the knowledge that tumors avail themselves of multiple mechanisms of immune evasion, thus blunting the efficacy of therapeutic vaccination. Mechanisms of immune suppression include infiltration by regulatory T cells (Treg) and myeloid suppressor cell populations, expression of co-inhibitory receptors, and expression of indoleamine 2,3-dioxygenase (IDO). Expression of both B7-H1 and IDO are associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in ovarian cancer patients. In sharp contrast, recent studies have indicated that Th17 cell infiltration in ovarian cancer correlates with improved patient outcomes and prolonged overall survival. Given that IDO plays a pivotal role in the balance between Treg and Th17 immunity, elucidation of the mechanisms that regulate IDO activity and immune suppression may lead to novel adjuvants to boost the clinical efficacy of dendritic cell vaccination against ovarian cancer and other malignancies. PMID 24302925
Immunological response after WT1 mRNA-loaded dendritic cell immunotherapy in ovarian carcinoma and carcinosarcoma.
Sep. 2013 | Coosemans, An; Vanderstraeten, Anke; Tuyaerts, Sandra; Verschuere, Tina; Moerman, Philippe; Berneman, Zwi; Vergote, Ignace; Amant, Frédéric; Van Gool, Stefaan W
Dendritic cell (DC)-based immunotherapy is an emerging new treatment option in ovarian cancer, an important cause of cancer-related mortality. PMID 24023319
A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside.
Sep. 2013 | Chiang, Cheryl Lai-Lai; Kandalaft, Lana E; Tanyi, Janos; Hagemann, Andrea R; Motz, Gregory T; Svoronos, Nikolaos; Montone, Kathleen; Mantia-Smaldone, Gina M; Smith, Lori; Nisenbaum, Harvey L; Levine, Bruce L; Kalos, Michael; Czerniecki, Brian J; Torigian, Drew A; Powell, Daniel J; Mick, Rosemarie; Coukos, George
Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. PMID 23838316
A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer.
Juni 2013 | Kandalaft, Lana E; Chiang, Cheryl L; Tanyi, Janos; Motz, Greg; Balint, Klara; Mick, Rosemarie; Coukos, George
Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy. PMID 23777306
Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer.
Apr. 2013 | Kandalaft, Lana E; Powell, Daniel J; Chiang, Cheryl L; Tanyi, Janos; Kim, Sarah; Bosch, Marnix; Montone, Kathy; Mick, Rosemarie; Levine, Bruce L; Torigian, Drew A; June, Carl H; Coukos, George
Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 10(9) autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8(+) lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes. PMID 23482679
Immunotherapy in ovarian cancer.
Dez. 2012 | Mantia-Smaldone, Gina M; Corr, Bradley; Chu, Christina S
Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012. While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 y. Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer. By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer. PMID 22906947
Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review.
Nov. 2012 | Tanyi, Janos L; Chu, Christina S
After decades of extensive research, epithelial ovarian cancer still remains a lethal disease. Multiple new studies have reported that the immune system plays a critical role in the growth and spread of ovarian carcinoma. This review summarizes the development of dendritic cell (DC) vaccinations specific for ovarian cancer. So far, DC-based vaccines have induced effective antitumor responses in animal models, but only limited results from human clinical trials are available. Although DC-based immunotherapy has proven to be clinically safe and efficient at inducing tumor-specific immune responses, its clear role in the therapy of ovarian cancer still needs to be clarified. The relatively disappointing low-response rates in early clinical trials point to the need for the development of more effective and personalized DC-based anticancer vaccines. This article reviews the basic mechanisms, limitations and future directions of DC-based anti-ovarian cancer vaccine development. PMID 23148752
Pre-clinical assessment of autologous DC-based therapy in ovarian cancer patients with progressive disease.
Nov. 2012 | Hardwick, Nicola; Ledermann, Jonathan A; Aitkens, Egla; Chain, Benny
Dendritic cell-based vaccines offer promise for therapy of ovarian cancer. Previous studies have demonstrated that oxidation of several antigens, including ovarian cancer cells, using hypochlorous acid strongly enhances their immunogenicity and their uptake and presentation by dendritic cells. The response of T cells and dendritic cells to autologous tumour from patients with active disease has not previously been investigated. Monocyte-derived dendritic cells were generated from patients with active disease and activated by co-culture with oxidised tumour cells and the TLR agonist poly I:C. The dendritic cells showed an activated phenotype, but secreted high levels of TGFβ. Co-culture of the antigen-loaded dendritic cells with autologous T cells generated a population of effector T cells that showed a low level of specific lytic activity against autologous tumour, as compared to autologous mesothelium. The addition of neutralising antibody to TGFβ in DC/T cell co-cultures increased the levels of subsequent tumour killing in three samples tested. Co-culture of monocytes from healthy volunteers with the ovarian cell line SKOV-3 prior to differentiation into dendritic cells reduced the ability of dendritic cells to stimulate cytotoxic effector cells. The study suggests that co-culture of dendritic cells with oxidised tumour cells can generate effector cells able to kill autologous tumour, but that the high tumour burden in patients with active disease may compromise dendritic cell and/or T cell function. PMID 22476408
Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy.
Juni 2012 | Kleef, R; Kekic, S; Ludwig, N
We report on a 4-year progression-free survival of a 54-year-old female first diagnosed in December 2007 with advanced bilateral ovarian cancer FIGO IIIc, disseminated peritoneal carcinosis and malignant diaphragm invasion. Treatment started in January 2008 with 6 cycles of Taxol 175 mg/m(2)/carboplatin AUC 5 in 3-week intervals. Twenty-four hours following each chemotherapy session, fever-range long-duration whole-body hyperthermia (WBH) was performed at the temperature plateau of 40°C body core temperature for 6 h. Three months after completion of chemotherapy, 4 more long-duration WBH procedures were performed in monthly intervals. Importantly, long-duration WBH was paralleled with intradermal vaccination of autologous dendritic cells. No other treatment was given to the patient. Four years following the first diagnosis, the patient is still in complete remission with no evidence of disease. PMID 22679425
Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission.
Apr. 2012 | Chu, Christina S; Boyer, Jean; Schullery, Daniel S; Gimotty, Phyllis A; Gamerman, Victoria; Bender, James; Levine, Bruce L; Coukos, George; Rubin, Stephen C; Morgan, Mark A; Vonderheide, Robert H; June, Carl H
In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Immunotherapy may have potential for consolidation therapy. PMID 22021066
Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses.
Apr. 2012 | Muenyi, Clarisse S; Pinhas, Allan R; Fan, Teresa W; Brock, Guy N; Helm, C William; States, J Christopher
Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation. PMID 22331493
A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients.
Feb. 2012 | Rahma, Osama E; Ashtar, Ed; Czystowska, Malgorzata; Szajnik, Marta E; Wieckowski, Eva; Bernstein, Sarah; Herrin, Vincent E; Shams, Mortada A; Steinberg, Seth M; Merino, Maria; Gooding, William; Visus, Carmen; Deleo, Albert B; Wolf, Judith K; Bell, Jeffrey G; Berzofsky, Jay A; Whiteside, Theresa L; Khleif, Samir N
Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. PMID 21927947
Combinatorial strategies for alleviation of tumor-associated immune suppression and therapeutic vaccination against ovarian cancer.
Juli 2011 | Goyne, Hannah; Stone, Pamela J B; Cannon, Martin J
Dendritic cell vaccination against ovarian cancer--tipping the Treg/TH17 balance to therapeutic advantage?
März 2011 | Cannon, Martin J; Goyne, Hannah; Stone, Pamela J B; Chiriva-Internati, Maurizio
The pathology of ovarian cancer is characterized by profound immunosuppression in the tumor microenvironment. Mechanisms that contribute to the immunosuppressed state include tumor infiltration by regulatory T cells (Treg), expression of B7-H1 (PDL-1), which can promote T cell anergy and apoptosis through engagement of PD-1 expressed by effector T cells, and expression of indoleamine 2,3-dioxygenase (IDO), which can also contribute to effector T cell anergy. Expression of both B7-H1 and IDO has been associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in patients with ovarian cancer. In a remarkable counterpoint to these observations, ovarian tumor infiltration with T(H)17 cells correlates with markedly improved clinical outcomes. In this Future Perspectives review, we argue that dendritic cell (DC) vaccination designed to drive tumor-antigen-specific T(H)17 T cell responses, combined with adjuvant treatments that abrogate immunosuppressive mechanisms operative in the tumor microenvironment, offers the potential for clinical benefit in the treatment of ovarian cancer. We also discuss pharmacological approaches to modulation of MAP kinase signaling for manipulation of the functional plasticity of DC, such that they may be directed to promote T(H)17 responses following DC vaccination. PMID 21271951
Ovarian cancer immunotherapy: opportunities, progresses and challenges.
März 2010 | Liu, Bei; Nash, John; Runowicz, Carolyn; Swede, Helen; Stevens, Richard; Li, Zihai
Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer. PMID 20146807
Regional abdominal hyperthermia combined with systemic chemotherapy for the treatment of patients with ovarian cancer relapse: Results of a pilot study.
Feb. 2010 | Fotopoulou, Christina; Cho, Chie Hee; Kraetschell, Robert; Gellermann, Johanna; Wust, Peter; Lichtenegger, Werner; Sehouli, Jalid
Due to the poor prognosis of patients with ovarian cancer relapse (OCR), newer strategies are warranted to improve the therapeutic index. We performed a prospective phase I/II-study of regional abdominal hyperthermia (RHT) combined with systemic chemotherapy in OCR patients in order to evaluate outcome, efficacy and tolerance. PMID 20146566
Cellular immunotherapy for ovarian cancer.
Mai 2009 | Cannon, Martin J; O'Brien, Timothy J
Ovarian cancer is frequently diagnosed at an advanced stage, and although initially responsive to surgery and chemotherapy, has a high rate of recurrence and mortality. Cellular immunotherapy may offer the prospect of treatment to prevent or delay recurrent metastatic disease. PMID 19456205
Whole-body hyperthermia (WBH) in combination with carboplatin in patients with recurrent ovarian cancer - a phase II study.
Jan. 2009 | Atmaca, Akin; Al-Batran, Salah-Eddin; Neumann, Antje; Kolassa, Yvonne; Jäger, Dirk; Knuth, Alexander; Jäger, Elke
Despite considerable progress in the front-line treatment in patient with advanced ovarian cancer, the outcome of patients with recurrent or refractory disease is still poor. Based on promising results of a pilot study, we initiated a phase II study with WBH and carboplatin in pretreated patients with advanced ovarian cancer to investigate the toxicity and efficacy of WBH in combination with carboplatin. PMID 19059635
Ovarian cancer detection and treatment: current situation and future prospects.
Nov. 2008 | Argento, Marylène; Hoffman, Pascale; Gauchez, Anne-Sophie
Between 70 and 75% of ovarian carcinomas are not discovered until they have reached an advanced stage III or later. Efforts should therefore be concentrated on earlier diagnosis. Ovarian cancer is not an entirely silent disease. Today, it is known that there are key symptoms which, depending on their frequency and intensity, can serve as warning signs to clinicians and patients. Mass screening for ovarian cancer is not currently possible because of a lack of specific markers for use in biological and imaging techniques, although new markers are now being developed. Screening every six or twelve months with the CA 125 blood test plus a transvaginal ultrasound is restricted to women at risk. Certain teams have proposed preventive bilateral adnexectomy for such women. The ovary is a complex organ subjected to a hormonal environment and affected by immune system dysfunctions. There now appears to be consensus on the influence of hormones in ovarian cancer, namely the beneficial role of pregnancy, breast feeding and in particular oral contraception, as well as the deleterious role of hormone replacement therapy (HRT). However, the two main arguments put forward, incessant ovulation and exposure to gonadotropins, do not explain all the epidemiological data. It is through a better understanding of the etiology of ovarian cancer that new therapies can be developed. The theory of cancer immune surveillance, whereby lymphocytes have a sentinel role of recognizing and constantly suppressing malignant cells, provided a starting point for research into antitumoral immunotherapy. The first trials of vaccination by direct injection of tumor antigens or "loaded" dendritic cells today offer considerable hope for patients. PMID 19031970
Immunotherapy opportunities in ovarian cancer.
Feb. 2008 | Chu, Christina S; Kim, Sarah H; June, Carl H; Coukos, George
Ovarian cancer is responsible for the majority of gynecologic cancer deaths and despite the highest standard of multimodality therapy with surgery and cytotoxic chemotherapy, long-term survival remains low. With compelling evidence that epithelial ovarian cancer is an immunogenic tumor capable of stimulating an antitumor immune response, renewed efforts to develop immune therapies to augment the efficacy of traditional therapies are underway. Current immunotherapies focus on varied modes of antitumor vaccine development, particularly with the use of dendritic cell vaccines, effective methods for adoptive T-cell transfer and combinatorial approaches with immune modulatory therapy subverting natural tolerance mechanisms or boosting effector mechanisms. Additional combinatorial approaches include the use of cytokines and/or chemotherapy with immune therapy. PMID 18279065
Vaccination with dendritic cells transfected with mRNA-encoded folate-receptor-alpha for relapsed metastatic ovarian cancer.
Apr. 2007 | Hernando, Juan José; Park, Tjoung-Won; Fischer, Hans-Peter; Zivanovic, Oliver; Braun, Michael; Pölcher, Martin; Grünn, Ursula; Leutner, Claudia; Pötzsch, Bernd; Kuhn, Walther
In vitro assessment of dendritic cells pulsed with apoptotic tumor cells as a vaccine for ovarian cancer patients.
Dez. 2006 | Tobiásová, Zuzana; Pospísilová, Dagmar; Miller, Ashley M; Minárik, Ivo; Sochorová, Klára; Spísek, Radek; Rob, Lukás; Bartůnková, Jirina
Surgery and chemotherapy are standard treatments in ovarian cancer, but patients have a high rate of relapse. Dendritic cell (DC)-based vaccines are a new treatment option for elimination of residual tumor disease. We aim to explore the feasibility and immunogenicity of DC vaccines pulsed with autologous irradiated tumor cells from ovarian cancer patients. Monocyte-derived DC were generated and pulsed with autologous tumor-derived bodies, matured and subsequently cocultured with autologous lymphocytes. The ability of DC to activate lymphocytes was evaluated by proliferation and IFN-gamma ELISPOT. Induction of tumor cell apoptosis was optimal at 24 h, and DC pulsing optimal at 4 h. Maturation of DC and proliferation of lymphocytes were achieved in 75% of patients tested. Lymphocyte IFN-gamma production increased in response to tumor antigen-pulsed DC. We show the feasibility of preparing individual DC-based vaccines in ovarian cancer patients and the potential for induction of lymphocyte responses. PMID 17059893
Preparation of apoptotic tumor cells with replication-incompetent HSV augments the efficacy of dendritic cell vaccines.
Feb. 2006 | Courrèges, M C; Benencia, F; Conejo-García, J R; Zhang, L; Coukos, G
The use of dendritic cells (DCs) loaded with apoptotic tumor cells is an attractive approach to tumor vaccination in the absence of well-characterized tumor antigens. Apoptotic tumor cells are a convenient source of polyvalent tumor antigen, but may induce only weak immunization. We tested the role of replication-incompetent recombinant herpes simplex virus (HSV) d106 lacking all immediate early genes except ICP0 in the generation of apoptotic cells for tumor vaccination, using ID8-VEGF, a syngeneic mouse model of ovarian carcinoma expressing high levels of VEGF, and TC-1, a human papillomavirus (HPV) 16 E6- and E7-transformed adenocarcinoma. HSVd106 killed tumor cells by apoptosis. Tumor cells infected by HSVd106 were engulfed more avidly by immature DCs, and induced DC maturation more efficiently than tumor cells killed by ultraviolet B (UVB) radiation. HSVd106 infection induced stronger upregulation of heat shock protein (Hsp) 70 and glucose-related protein (GRP) 94 than UVB in cells undergoing apoptosis. Immunization of mice with DCs loaded with HSVd106-killed cells elicited stronger antitumor T-cell response, including tumor-reactive interferon-gamma-secreting and cytotoxic T cells, and resulted in significantly stronger delay in tumor growth than immunization with DCs loaded with UVB-killed tumor cells. Moreover, in the TC-1 model, a protective effect of vaccination (40% tumor free animals) was observed only after immunization with DCs loaded with HSVd106-killed cells. Thus, the use of replication-incompetent HSV strains lacking immediate early genes except ICP0 offers possible advantages in the preparation of whole tumor cell antigen for DC-based tumor vaccination. PMID 16138121
Current approaches in ovarian cancer vaccines.
Feb. 2005 | Reinartz, S; Wagner, U
Much of the current approaches in the treatment of advanced ovarian cancer are directed towards prolongation of duration between primary treatment and remission. Immunotherapy is regarded as one attractive option for consolidation of initial therapeutic responses. In fact, immune reactivity against ovarian carcinoma can be induced by various immunotherapeutical approaches including antibodies, peptides or dendritic cell vaccines. This review provides an overview of recent clinical trials using various concepts of immunotherapy for the treatment of ovarian cancer. Possible reasons for limited clinical success as well as further progress to improve efficacy of current immune intervention strategies, e.g. by vaccines targeting a broader range of tumor-derived antigenic structures or activating diverse host immune functions, will be discussed. PMID 15729204
[Immunotherapy--perspectives in therapy of ovarian carcinomas].
Dez. 2004 | Zapletalová, K; Tobiasová, Z; Spísek, R; Rob, L; Bartůnková, J
To summarise recent knowledge and clinical studies of immunotherapy in the treatment of malignant ovarian epithelial tumors. PMID 15587893
Immunological treatment of ovarian cancer.
Mai 2004 | Cannon, Martin J; Santin, Alessandro D; O'Brien, Timothy J
Development of immunological treatments for ovarian cancer has not been a conspicuous success story over the past few years. Only a handful of clinical trials have reported immunological responses, and correlation with clinical benefit has been elusive. Several recent studies presented in this review, however, point to a revival of optimism for the development of novel immunotherapeutic strategies. PMID 15128013
Whole-body hyperthermia in combination with platinum-containing drugs in patients with recurrent ovarian cancer.
Apr. 2004 | Douwes, Friedrich; BogoviC, Juri; Douwes, Ortrun; Migeod, Friedrich; Grote, Christoph
Patients with advanced ovarian cancer have an enormous risk of relapse after primary therapy, and the prognosis for these patients remains bleak. Primary and acquired resistance of tumor cells to antineoplastic drugs is a major cause of the limited effectiveness of chemotherapy. The effect of whole-body hyperthermia (WBH) combined with platinum-containing chemotherapy in the treatment of recurrent ovarian cancer was examined in this study. PMID 15108039
Dendritic cell-based vaccines in breast and gynaecologic cancer.
Dez. 2003 | Hernando, Juan José; Park, Tjoung-Won; Kuhn, Walther C
Major advances in understanding the functional interactions between tumour cells and the host immune system, in particular the generation and regulation of T cell immunity, have revived interest in cancer vaccination strategies. A crucial step for mounting an anti-tumour response is the capture, processing and presentation of tumour antigens (TA) to cognate T cells by professional antigen-presenting cells (APC), followed by their activation and clonal proliferation. Dendritic cells (DC) are potent APC with the unique ability to stimulate primary immune responses. Animal models have demonstrated that TA-charged DC can activate specific cytotoxic T cells (CTL) and even regression of established tumours in cancer-bearing hosts. These findings, as well as the elaboration of methods for generating large numbers of DC ex vivo, have provided a compelling rationale for using DC as potent adjuvants to deliver TA to the immune system in order to trigger or amplify an inadequate response. The capacity of TA-pulsed DC to induce significant CTL immunity translating into occasional therapeutic benefit has been documented in several clinical settings including B cell lymphoma, myeloma, melanoma, prostate, colon, ovarian and renal cell carcinoma. In this review, we summarize key biological functions of DC and focus on recent DC-based vaccination trials of breast, ovarian and cervical cancer. PMID 14666641
TRANCE- and CD40 ligand-matured dendritic cells reveal MHC class I-restricted T cells specific for autologous tumor in late-stage ovarian cancer patients.
Apr. 2003 | Schlienger, Katia; Chu, Christina S; Woo, Edward Y; Rivers, Patricia M; Toll, Alanna J; Hudson, Brian; Maus, Marcela V; Riley, James L; Choi, Yongwon; Coukos, George; Kaiser, Larry R; Rubin, Stephen C; Levine, Bruce L; Carroll, Richard G; June, Carl H
The use of mature dendritic cells (DCs) presenting tumor-associated antigens (TAAs) to trigger tumor-specific T cells in vivo or in vitro represents a promising approach for cancer immunotherapy. We hypothesized that tumor antigens, mostly unidentified, are present on ovarian tumor cells and that mature DCs could be used to generate tumor-specific responses in unprimed patients. We also sought to measure preexisting antitumor immunity in patients with advanced ovarian cancer. PMID 12684428
Dendritic cells in vaccination therapies of malignant diseases.
Sep. 2002 | Brossart, Peter; Brossart M D, Peter
Dendritic cells (DC) are the most potent APC with the unique capacity to initiate primary immune responses. For clinical use DC can be generated in vitro from CD34+ peripheral blood progenitor cells or monocytes. Vaccination of patients with cancer using DC was shown to be effective for B-cell lymphoma, renal cell carcinoma (RCC), prostate cancer and malignant melanoma. We provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DC pulsed with HER-2/neu- or MUC1-derived peptides. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTL) could be detected in the peripheral blood using both intracellular IFN-gamma staining and Cr-release assays. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after seven immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Currently we are analyzing the effect of T-helper epitopes and IL-2 on the CTL induction using peptide pulsed DC. In this ongoing trial one patient with metastatic RCC developed a partial remission of the metastatic sites was induced after the first four vaccinations with MUC1 peptides pulsed DC, that was ongoing after the next cycles containing IL-2. Vaccine-induced peptide-specific T-cell responses in vivo were detected in the PBMNC of this patient and in peptide-specific DTH reactions. This studies demonstrate that peptide pulsed DC can be effective in cancer patients and induce significant clinical and immunological responses. PMID 12350054
Novel target antigens for dendritic cell-based immunotherapy against ovarian cancer.
Juli 2002 | Cannon, Martin J; O'Brien, Timothy J; Underwood, L Joey; Crew, Mark D; Bondurant, Kristina L; Santin, Alessandro D
Identification of tumor-specific target antigens has been a major hurdle for the treatment of malignant disease by vaccination or immunotherapy. A second challenge has been the induction of therapeutically effective immune responses to these 'self' antigens. The recent recognition of dendritic cells as powerful antigen-presenting cells capable of inducing primary T-cell responses in vitro and in vivo--in combination with identification of tumor-specific antigens--has generated widespread interest in dendritic cell-based immunotherapy against a wide variety of tumors. In this review, a series of recently identified novel ovarian tumor antigens is discussed, and the potential for therapeutic dendritic cell vaccination targeted against these antigens is assessed. PMID 12113075
Novel immunotherapeutic strategies in gynecologic oncology. Dendritic cell-based immunotherapy for ovarian cancer.
Mai 2002 | Santin, A D; Bellone, S; Underwood, L J; O'Brien, T J; Ravaggi, A; Pecorelli, S; Cannon, M J
The recognition of tumor antigen loaded dendritic cells as one of the most promising approaches to induce a tumor specific immune response in vivo has recently generated widespread interest in the use of these natural adjuvants for the therapy of human malignancies refractory to standard treatment modalities. However, many cancer patients may not benefit from current strategies of cancer vaccination because an effective tumor antigen associated with their cancer has not yet been identified or because sufficient amounts of tumor tissue cannot be obtained for antigen preparation. The recent identification and cloning of a group of preferentially expressed serine proteases as novel ovarian tumor-associated antigens may offer the opportunity to test in a large group of patients the potential of DC-based immunotherapy. In this review, we describe these ovarian tumor antigens and assess the potential for therapeutic DC vaccination for the treatment of chemotherapy-resistant ovarian cancer. PMID 12032451
Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial.
März 2002 | Hernando, Juan José; Park, Tjoung-Won; Kübler, Kirsten; Offergeld, Ruth; Schlebusch, Harald; Bauknecht, Thomas
Dendritic cell (DC)-based therapy has proven to be effective in patients with malignant lymphoma, melanoma, and renal and prostate carcinoma. In this phase I clinical trial, we have shown that patients with advanced gynaecological malignancies can be effectively vaccinated with DC pulsed with keyhole limpet haemocyanin (KLH) and autologous tumour antigens. Two patients with uterine sarcoma and six subjects with ovarian carcinoma received three to 23 intracutaneous injections of antigen-pulsed DC at 10-day or 4-week intervals. Three patients showed stable disease lasting 25 to 45 weeks, and five experienced tumour progression within the first 14 weeks. KLH- and tumour lysate-specific delayed-type hypersensitivity (DTH) reactions were observed in six and one patient, respectively. Lymphoproliferative responses to KLH and to tumour lysate stimulation were recorded in six patients and in two patients respectively. Tumour antigen-stimulated interferon-gamma (IFN-gamma) secretion by peripheral blood mononuclear cells (PBMC) in one patient was consistent with a T(H) type 1 cytokine bias. The treatment was safe, well tolerated, immunologically active and except for local cutaneous hypersensitivity devoid of significant adverse effects. PMID 11845259
Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer.
Feb. 2002 | Santin, A D; Bellone, S; Ravaggi, A; Roman, J J; Pecorelli, S; Parham, G P; Cannon, M J
Uterine serous papillary carcinoma is a highly aggressive variant of endometrial cancer histologically similar to high grade ovarian cancer. Unlike ovarian cancer, however, it is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and an extremely poor prognosis. In this study, we demonstrate that tumour lysate-pulsed autologous dendritic cells can elicit a specific CD8(+) cytotoxic T lymphocyte response against autologous tumour target cells in three patients with uterine serous papillary cancer. CTL from patients 1 and 2 expressed strong cytolytic activity against autologous tumour cells, did not lyse autologous lymphoblasts or autologous EBV-transformed cell lines, and were variably cytotoxic against the NK-sensitive cell line K-562. Patient 3 CD8(+) T cells expressed a modest but reproducible cytotoxicity against autologous tumour cells only at the time of the first priming. Further priming attempts with PBL collected from patient 3 after tumour progression in the lumboaortic lymph nodes were unsuccessful. Cytotoxicity against autologous tumour cells could be significantly inhibited by anti-HLA class I (W6/32) and anti-LFA-1 MAbs. Highly cytotoxic CD8(+) T cells from patients 1 and 2 showed a heterogeneous CD56 expression while CD56 was not expressed by non-cytotoxic CD8(+) T cells from patient 3. Using two colour flow cytometric analysis of intracellular cytokine expression at the single cell level, a striking dominance of IFN-gamma expressors was detectable in CTL populations of patients 1 and 2 while in patient 3 a dominant population of CD8(+) T cells expressing IL-4 and IL-10 was consistently detected. Taken together, these data demonstrate that tumour lysate-pulsed DC can be an effective tool in inducing uterine serous papillary cancer-specific CD8(+) CTL able to kill autologous tumour cells in vitro. However, high levels of tumour specific tolerance in some patients may impose a significant barrier to therapeutic vaccination. These results may have important implications for the treatment in the adjuvant setting of uterine serous papillary cancer patients with active or adoptive immunotherapy. PMID 11857027
Dendritic cells in cancer vaccines.
Nov. 2001 | Brossart, P; Wirths, S; Brugger, W; Kanz, L
Dendritic cells (DC) are recognized as the most potent antigen-presenting cells with the ability to stimulate naive resting T cells and to initiate primary immune responses. Encouraging results in vaccination studies in animal models and the development of protocols to generate sufficient numbers of human DC for clinical application have led to attempts to verify the feasibility and efficacy of this approach in patients in the context of Phase I/II vaccination trials. This review aims to present a concise overview of the current knowledge in DC development and biology and describes the recent data of the first published DC-based vaccination studies. These preliminary trials indicate that immunotherapies utilizing DC-presenting tumor-associated antigens can safely be administered to patients with cancer and induce significant immunologic and clinical responses. PMID 11698120
Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells.
Dez. 2000 | Brossart, P; Wirths, S; Stuhler, G; Reichardt, V L; Kanz, L; Brugger, W
Vaccination of patients with cancer using dendritic cells (DCs) was shown to be effective for B-cell lymphoma and malignant melanoma. Here we provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DCs pulsed with HER-2/neu- or MUC1-derived peptides. Ten patients were included in this pilot study. The DC vaccinations were well tolerated with no side effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood using both intracellular IFN-gamma staining and (51)Cr-release assays. The major CTL response in vivo was induced with the HER-2/neu-derived E75 and the MUC1-derived M1.2 peptide, which lasted for more than 6 months, suggesting that these peptides might be immunodominant. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after 7 immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Our results show that vaccination of DCs pulsed with a single tumor antigen may induce immunologic responses in patients with breast and ovarian cancer. This study may be relevant to the design of future clinical trials of other peptide-based vaccines. PMID 11049990
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
Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer.
Juli 1997 | Ahlert, T; Sauerbrei, W; Bastert, G; Ruhland, S; Bartik, B; Simiantonaki, N; Schumacher, J; Häcker, B; Schumacher, M; Schirrmacher, V
We investigated quality and efficacy criteria of an autologous, physically and immunologically purified, Newcastle disease virus (NDV)-modified, irradiated tumor-cell vaccine (ATV-NDV) by analyzing three independent cohorts (a through c) of patients vaccinated between 1991 and 1995. PMID 9193327