Seminars in Oncology RSS feed: Current Issue. Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the diagnosis and management of patients with cancer. Each issue examines a single topic of clinical importance. You're guided through each cancer's biology, epidemiology, and pathophysiology, its clinical presentation and therapeutic options, and appropriate follow-up measures. This journal makes an excellent addition to every oncology practice. 2012 Topics , Volume 39 Molecular Pathogenesis of Hematologic Malignancies Jaroslaw P. Maciejewski, Torsten Haferlach Advances in the Treatment of Cutaneous Malignancies Vernon Sondak, Ronald C. DeConti, L. Frank Glass New Perspectives in Hepatocellular Carcinoma Brian Carr Cancer Vaccines Jeffrey Schlom Bone Marrow Transplantation Neal Flomenberg Prostate Cancer William Kevin Kelly http://www.seminoncol.org/?rss=yesElsevier Inc.en © 2012 Published by Elsevier Inc. All rights reserved. Seminars in Oncology0093-7754393June 2012 © 2012 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.seminoncol.org/article/PIIS0093775412000760/abstract?rss=yesCover10.1053/S0093-7754(12)00076-0Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1OFCOFChttp://www.seminoncol.org/article/PIIS0093775412000784/abstract?rss=yesMasthead10.1053/S0093-7754(12)00078-4Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1IFCIFChttp://www.seminoncol.org/article/PIIS0093775412000504/abstract?rss=yesThis issue of Seminars in Oncology is aimed at defining the current state of research, development, and clinical evaluation of therapeutic cancer vaccines. The various chapters review potential reasons for past failures, the US Food and Drug Administration (FDA) approval of Sipuleucel-T for prostate cancer therapy, promising randomized phase II and phase III results with several other therapeutic vaccines in different cancer types, and the broad range of cancer vaccines and vaccine strategies currently being evaluated in preclinical settings and in phase I and phase II trials.Introduction: Therapeutic Cancer VaccinesJeffrey Schlom, James W. Hodge10.1053/j.seminoncol.2012.02.009Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Jeffrey Schlom, PhD, and James W. Hodge, PhD, MBA, Guest Editors243244http://www.seminoncol.org/article/PIIS0093775412000450/abstract?rss=yes Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate an immune response to prostate cancer that prolongs the overall survival of men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). The clinical development program and key efficacy, safety, and immune response findings from the phase III studies are presented. The integration of sipuleucel-T into the treatment paradigm of advanced prostate cancer and future directions for research are discussed. Sipuleucel-T for the Treatment of Advanced Prostate CancerMark W. Frohlich10.1053/j.seminoncol.2012.02.004Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section I: Clinical Investigations in a Specific Cancer Type245252http://www.seminoncol.org/article/PIIS0093775412000553/abstract?rss=yes Many of the efforts toward developing vaccines against human malignancies have been frustrated by the lack of identification of a tumor-specific antigen that would allow tumor cells to be distinguished from normal cells. Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given patient's B-cell lymphoma are unique to that tumor, and can thus serve as a tumor-specific marker. When conjugated to the immune carrier keyhole limpet hemocyanin (KLH), vaccination with an idiotype protein vaccine has been able to improve length of freedom from disease relapse in patients with follicular lymphoma (FL) in a minimal residual disease (MRD) state after induction therapy, as demonstrated in a recent randomized, controlled phase III trial. In addition to predictive biomarker discovery, using residual autologous tumor and blood samples from patients vaccinated on the phase III trial, we have now developed a next generation idiotype DNA vaccine with the goal of reducing vaccine production time while maintaining efficacy. A first-in-human study is planned to evaluate its use in patients with asymptomatic phase lymphoplasmacytic lymphoma. Lymphoma Vaccine Therapy: Next Steps After a Positive, Controlled Phase III Clinical TrialSheeba K. Thomas, Larry W. Kwak10.1053/j.seminoncol.2012.02.014Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section I: Clinical Investigations in a Specific Cancer Type253262http://www.seminoncol.org/article/PIIS0093775412000528/abstract?rss=yes The inherent immunogenicity of melanoma and renal cell carcinoma (RCC) has made these tumors a focus of considerable research in vaccine development. Recent data from murine studies of immunosurveillance have highlighted the importance of both innate and adaptive immune responses in shaping a tumor's inherent susceptibility to immune surveillance and immunotherapy. Melanoma has been a useful model for the identification of tumor-associated antigens and a number of putative renal cell antigens have been described more recently. These antigens have been targeted using a variety of vaccine strategies, including protein- and peptide-based vaccines, recombinant antigen-expressing vectors, and whole cell vaccine approaches. While evidence for clinical benefit has been disappointing to date, several current phase III clinical trials are in progress based on promising results from phase II studies. Accumulating data suggest that the tumor microenvironment and mechanisms of immunological escape by established tumors are significant barriers that must be overcome before vaccine therapy can be fully realized. This review will discuss the basis for vaccine development, describe some of the more promising vaccine strategies in development, and mention some of the tumor escape mechanisms that block effective anti-tumor immunity for melanoma and RCC. Vaccines for Melanoma and Renal Cell CarcinomaHoward L. Kaufman10.1053/j.seminoncol.2012.02.011Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section I: Clinical Investigations in a Specific Cancer Type263275http://www.seminoncol.org/article/PIIS0093775412000486/abstract?rss=yes Cancer vaccines have shown success in curing tumors in preclinical models. Accumulating evidence also supports their ability to induce immune responses in patients. In many cases, these responses correlate with improved clinical outcomes. However, cancer vaccines have not yet demonstrated their true potential in clinical trials. This is likely due to the difficulty in mounting a significant anti-tumor response in patients with advanced disease because of pre-existing tolerance mechanisms that are actively turning off immune recognition in cancer patients. This review will examine the recent progress being made in the design and implementation of whole cell cancer vaccines, one vaccine approach that simultaneously targets multiple tumor antigens to activate the immune response. These vaccines have been shown to induce antigen-specific T-cell responses. Preclinical studies evaluating these vaccines given in sequence with other agents and cancer treatment modalities support the use of immunomodulating doses of chemotherapy and radiation, as well as immune-modulating pathway–targeted monoclonal antibodies, to enhance the efficacy of cancer vaccines. Based on emerging preclinical data, clinical trials are currently exploring the use of combinatorial immune-based therapies for the treatment of cancer. Whole Cell Vaccines—Past Progress and Future StrategiesBridget P. Keenan, Elizabeth M. Jaffee10.1053/j.seminoncol.2012.02.007Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section II: Diverse Vaccine Platforms276286http://www.seminoncol.org/article/PIIS0093775412000449/abstract?rss=yes A promising cancer vaccine involves the fusion of dendritic cells (DCs) with tumor cells such that a broad array of tumor antigens are presented in the context of DC-mediated costimulation and stimulatory cytokines. In diverse animal models, vaccination with DC/tumor fusions results in protection from an otherwise lethal challenge of tumor cells and eradication of established disease. In phase I clinical studies, vaccination with DC/tumor fusions was well tolerated, and induced immunologic responses in the majority of patients and clinical responses in a subset. Vaccine efficacy may be blunted by the immunosuppressive milieu characteristic of patients with malignancy, including the increased presence of regulatory T cells, and inhibitory pathways such as the PD-1/PDL-1 pathway. A current focus of research interest lies in enhancing response to cancer vaccines, by combining vaccination with tumor cytoreduction, regulatory T-cell depletion, and blockade of critical inhibitory pathways. Dendritic/Tumor Fusion Cells as Cancer VaccinesDavid Avigan, Jacalyn Rosenblatt, Donald Kufe10.1053/j.seminoncol.2012.02.003Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section II: Diverse Vaccine Platforms287295http://www.seminoncol.org/article/PIIS0093775412000516/abstract?rss=yes We have developed an “off-the-shelf” vector-based vaccine platform containing transgenes for carcinoma-associated antigens and multiple costimulatory molecules (designated TRICOM). Two TRICOM platforms have been evaluated both preclinically and in clinical trials. PROSTVAC consists of rV, rF-PSA-TRICOM and is being used in prostate cancer therapy trials. PANVAC consists of rV, rF-CEA-MUC1-TRICOM; the expression of the two pan-carcinoma transgenes CEA and MUC-1 renders PANVAC vaccination applicable for therapeutic applications for a range of human carcinomas. Many new paradigms have emerged as a consequence of completed and ongoing TRICOM vaccine trials, including (1) clinical evidence of patient benefit may be delayed, because multiple vaccinations may be necessary to induce a sufficient anti-tumor immune response; (2) survival, and not strict adherence to RECIST criteria or time-to-progression, may be the most appropriate trial endpoint when TRICOM vaccines are used as monotherapy; (3) certain patient populations are more likely to benefit from vaccine therapy as compared to other therapeutics; and (4) TRICOM vaccines combined with standard-of-care therapeutics, either concomitantly or sequentially, are feasible because of the limited toxicity of vaccines. Clinical Evaluation of TRICOM Vector Therapeutic Cancer VaccinesRavi A. Madan, Marijo Bilusic, Christopher Heery, Jeffrey Schlom, James L. Gulley10.1053/j.seminoncol.2012.02.010Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section II: Diverse Vaccine Platforms296304http://www.seminoncol.org/article/PIIS0093775412000541/abstract?rss=yes Although cellular immunotherapy based on autolgous dendritic cells (DCs) targeting antigens expressed by metastatic cancer has demonstrated clinical efficacy, the logistical challenges in generating an individualized cell product create an imperative to develop alternatives to DC-based cancer vaccines. Particularly attractive alternatives include in situ delivery of antigen and activation signals to resident antigen-presenting cells (APCs), which can be achieved by novel fusion molecules targeting the mannose receptor and by recombinant viral vectors expressing the antigen of interest and capable of infecting DCs. A particular challenge in the use of viral vectors is the well-appreciated clinical obstacles to their efficacy, specifically vector-specific neutralizing immune responses. Because heterologous prime and boost strategies have been demonstrated to be particularly potent, we developed two novel recombinant vectors based on alphaviral replicon particles and a next-generation adenovirus encoding an antigen commonly overexpressed in many human cancers, carcinoembryonic antigen (CEA). The rationale for developing these vectors, their unique characteristics, the preclinical studies and early clinical experience with each, and opportunities to enhance their effectiveness will be reviewed. The potential of each of these potent recombinant vectors to efficiently generate clinically active anti-tumor immune response alone, or in combination, will be discussed. Novel Recombinant Alphaviral and Adenoviral Vectors for Cancer ImmunotherapyTakuya Osada, Michael A. Morse, Amy Hobeika, H. Kim Lyerly10.1053/j.seminoncol.2012.02.013Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section II: Diverse Vaccine Platforms305310http://www.seminoncol.org/article/PIIS0093775412000498/abstract?rss=yes Active immunotherapy targeting dendritic cells (DCs) has shown great promise in preclinical models and in human clinical trials for the treatment of malignant disease. Sipuleucel-T (Provenge, Dendreon, Seattle, WA), which consists of antigen-loaded dendritic cells (DCs), recently became the first targeted therapeutic cancer vaccine to be approved by the US Food and Drug Administration (FDA). However, ex vivo therapies such as Provenge have practical limitations and elicit an immune response with limited scope. By contrast, live-attenuated Listeria monocytogenes (Lm) naturally targets DCs in vivo and stimulates both innate and adaptive cellular immunity. Lm-based vaccines engineered to express cancer antigens have demonstrated striking efficacy in several animal models and have resulted in encouraging anecdotal survival benefit in early human clinical trials. Two different Lm-based vaccine platforms have advanced into phase II clinical trials in cervical and pancreatic cancer. Future Lm-based clinical vaccine candidates are expected to feature polyvalent antigen expression and to be used in combination with other immunotherapies or conventional therapies such as radiotherapy and chemotherapy to augment efficacy. Clinical Development of Listeria monocytogenes–Based ImmunotherapiesDung T. Le, Thomas W. Dubensky, Dirk G. Brockstedt10.1053/j.seminoncol.2012.02.008Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section II: Diverse Vaccine Platforms311322http://www.seminoncol.org/article/PIIS0093775412000474/abstract?rss=yes Therapeutic cancer vaccines are a unique treatment modality in that they initiate a dynamic process of activating the host immune system, which can then be exploited by concurrent or subsequent therapies. The addition of immunotherapy to standard-of-care cancer therapies has shown evidence of efficacy in preclinical models and in the clinical setting. This review examines the preclinical and clinical interactions between vaccine-mediated tumor-specific immune responses and local radiation, systemic chemotherapy, or select small molecule inhibitors, as well as the potential synergy between these modalities. The Tipping Point for Combination Therapy: Cancer Vaccines With Radiation, Chemotherapy, or Targeted Small Molecule InhibitorsJames W. Hodge, Andressa Ardiani, Benedetto Farsaci, Anna R. Kwilas, Sofia R. Gameiro10.1053/j.seminoncol.2012.02.006Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section III: Novel Vaccines and Vaccine Strategies323339http://www.seminoncol.org/article/PIIS009377541200053X/abstract?rss=yes Many immunotherapeutic agents in phase II cancer studies have given optimistic results, which were not confirmed in larger randomized studies. Here we explore the evidence that, contrary to previous opinion, many chemotherapeutic agents and other classes of drugs may enhance the response to therapeutic vaccines by reducing inflammation and/or by inhibiting regulatory T lymphocytes or myeloid-derived suppressor cells. In addition, some of these agents, such as the immunomodulatory drugs, may produce marked costimulatory activities as in the case of lenalidomide, which also has marked anti-inflammatory properties. With the first approval for a vaccine-based therapy for prostate cancer, we propose that many more vaccines will be able to achieve approval, especially when combined with the optimal chemotherapy and/or immunomodulatory drug schedule. The Potential Beneficial Effects of Drugs on the Immune Response to VaccinationWai M. Liu, Angus G. Dalgleish10.1053/j.seminoncol.2012.02.012Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section III: Novel Vaccines and Vaccine Strategies340347http://www.seminoncol.org/article/PIIS0093775412000437/abstract?rss=yes Cancers so much resemble self that they prove difficult for the immune system to eliminate, and those that have already escaped natural immunosurveillance have gotten past the natural immune barriers to malignancy. A successful therapeutic cancer vaccine must overcome these escape mechanisms. Our laboratory has focused on a multistep “push-pull” approach in which we combine strategies to overcome each of the mechanisms of escape. If tumor epitopes are insufficiently immunogenic, we increase their immunogenicity by epitope enhancement, improving their binding affinity to major histocompatibility complex (MHC) molecules. If the anti-tumor response is too weak or of the wrong phenotype, we use cytokines, costimulatory molecules, Toll-like receptor ligands, and other molecular adjuvants to increase not only the quantity of the response but also its quality, to push the response in the right direction. Finally, the tumor invokes multiple immunosuppressive mechanisms to defend itself, so we need to overcome those as well, including blocking or depleting regulatory cells or inhibiting regulatory molecules, to pull the response by removing the brakes. Some of these strategies individually have now been translated into human clinical trials in cancer patients. Combinations of these in a push-pull approach are promising for the successful immunotherapy of cancer. Strategies to Use Immune Modulators in Therapeutic Vaccines Against CancerJay A. Berzofsky, Masaki Terabe, Lauren V. Wood10.1053/j.seminoncol.2012.02.002Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section III: Novel Vaccines and Vaccine Strategies348357http://www.seminoncol.org/article/PIIS0093775412000462/abstract?rss=yes The epithelial-mesenchymal transition (EMT) is thought to be a critical step along the metastasis of carcinomas. In addition to gaining motility and invasiveness, tumor cells that undergo EMT also acquire increased resistance to many traditional cancer treatment modalities, including chemotherapy and radiation. As such, EMT has become an attractive, potentially targetable process for therapeutic interventions against tumor metastasis. The process of EMT is driven by a group of transcription factors designated as EMT transcription factors, such as Snail, Slug, Twist, and the recently identified T-box family member, Brachyury. In an attempt to determine which of these drivers of EMT is more amenable to targeted therapies and, in particular, T-cell–mediated immunotherapeutic approaches, we have examined their relative expression levels in a range of human and murine normal tissues, cancer cell lines, and human tumor biopsies. Our results demonstrated that Brachyury is a molecule with a highly restricted human tumor expression pattern. We also demonstrated that Brachyury is immunogenic and that Brachyury-specific CD8+ T cells expanded in vitro are able to lyse Brachyury-positive tumor cells. We thus propose Brachyury as an attractive target for vaccination strategies designed to specifically target tumor cells undergoing EMT. Cancer Vaccines Targeting the Epithelial-Mesenchymal Transition: Tissue Distribution of Brachyury and Other Drivers of the Mesenchymal-Like Phenotype of CarcinomasDuane H. Hamilton, Mary T. Litzinger, Romaine I. Fernando, Bruce Huang, Claudia Palena10.1053/j.seminoncol.2012.02.005Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Section III: Novel Vaccines and Vaccine Strategies358366http://www.seminoncol.org/article/PIIS0093775412000759/abstract?rss=yes At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com. I look forward to a lively discussion.Mucinous Colloid Carcinoma of the Colon Metastatic to the BreastMichael C. Yoder, Joseph P. Bannon, Edith P. Mitchell, Gloria J. Morris10.1053/j.seminoncol.2012.04.001Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1Current Clinical Practice--Available Onlinee1e7http://www.seminoncol.org/article/PIIS0093775412000796/abstract?rss=yesEditorial Board10.1053/S0093-7754(12)00079-6Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1FrontmatterA3A3http://www.seminoncol.org/article/PIIS0093775412000802/abstract?rss=yesContents10.1053/S0093-7754(12)00080-2Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1FrontmatterA5A6http://www.seminoncol.org/article/PIIS0093775412000814/abstract?rss=yesFuture and Previous Issues10.1053/S0093-7754(12)00081-4Seminars in Oncology 39, 3 (2012)2012-06-01Seminars in Oncology2012-06-01393S0093-7754(11)X0013-1FrontmatterA8A8