Progress in Tumor Research最新文献

{"title":"Immunotherapy of Breast Cancer.","authors":"Carmen Criscitiello,&nbsp;Giuseppe Curigliano","doi":"10.1159/000437183","DOIUrl":"https://doi.org/10.1159/000437183","url":null,"abstract":"<p><p>Cancer immunoediting is the process by which the immune system protects the host from tumor development and guides the somatic evolution of tumors by eliminating highly immunogenic tumor cells. A fundamental dogma of tumor immunology and of cancer immunosurveillance in particular is that cancer cells express antigens that differentiate them from their nontransformed counterparts. Molecular studies clearly show that these antigens were often products of mutated cellular genes, aberrantly expressed normal genes, or genes encoding viral proteins. There is a strict correlation between genetic instability and the immune landscape of a breast cancer. Mutational heterogeneity in breast cancer is associated with new cancer-associated genes and new cancer antigens. Frequencies of somatic mutations or mutational burden can be related to the immunogenicity of breast cancer. We believe that molecular subtypes of breast cancer that are triple negative, luminal B-like or HER2-positive have a high mutational burden and can be considered immunogenic. The increasing knowledge of the immune system's capacity to not only recognize and destroy cancer, but also to shape cancer immunogenicity will develop more informed attempts to control cancer via immunological approaches. To be effective in breast cancer, immunotherapies will have to increase the quality or quantity of immune effector cells, reveal additional protective tumor antigens, and/or eliminate cancer-induced immunosuppressive mechanisms. Multiple immunotherapy approaches are under investigation in patients with breast cancer. These include vaccine approaches to elicit strong specific immune responses to tumor antigens such as WT-1, HER2 and NY-ESO-1, approaches involving adoptive transfer of in vitro-expanded, naturally arising or genetically engineered tumor-specific lymphocytes, therapeutic administration of monoclonal antibodies to target and eliminate tumor cells, and approaches that inhibit or destroy the molecular or cellular mediators of cancer-induced immunosuppression, such as CTLA-4, PD-1 or Treg cells. Here we provide a concise and comprehensive review on the role and utility of promising immunotherapeutics for the treatment of patients with breast cancer. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"30-43"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000437183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34008635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Developments in Actively Personalized Cancer Vaccination with a Focus on RNA as the Drug Format.","authors":"Mustafa Diken,&nbsp;Sebastian Kreiter,&nbsp;Björn Kloke,&nbsp;Ugur Sahin","doi":"10.1159/000437184","DOIUrl":"https://doi.org/10.1159/000437184","url":null,"abstract":"<p><p>Developments in sequencing technologies have not only led to a rapid generation of genomic and transcriptional data from cancer patients, but also revealed the vast diversity of cancer-specific changes in patient tumors. Among these, mutation changes in the protein sequence can result in novel epitopes recognized by the immune system and, therefore, can be employed in the development of personalized vaccines. Thanks to its easy design and scalable GMP production, vaccines based on mRNAs coding for mutated epitopes have emerged as a reliable strategy for the exploitation of the potential of patient-specific genomic data. In this review, we provide an overview of recent developments in actively personalized vaccinations, with a special focus on the promise of mRNA vaccines. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"44-54"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000437184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34016100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapies in Early and Advanced Renal Cell Cancer.","authors":"Benjamin Kasenda,&nbsp;James Larkin,&nbsp;Martin Gore","doi":"10.1159/000436988","DOIUrl":"https://doi.org/10.1159/000436988","url":null,"abstract":"<p><p>The development of new immunomodulatory monoclonal antibodies targeting the CTLA-4 or PD-1 axis has led to a revival of research on immunotherapies in solid tumours including renal cell cancer (RCC). The initial results observed with these monoclonal antibodies in the treatment of advanced melanoma have resulted in considerable interest in this treatment strategy in all tumour types. Preliminary data of these new antibodies in advanced RCC are promising and they have good safety profiles. Response rates are low but durable tumour control has been observed in some patients. However, at the moment there is no evidence that targeting the CTLA-4 or PD-1 axis provides a substantial clinical benefit compared to established treatment with tyrosine kinase or mTOR inhibitors. There are also no reliable predictive markers. At the moment, several randomised trials have been initiated to investigate the new immunomodulatory antibodies either as single agents or in combination with anti-VEGF targeted therapy. Vaccines have continued to be investigated in advanced and adjuvant settings. No trial has so far established vaccines as a standard treatment in either situation. There are still large randomised trials ongoing investigating the potential benefit of a vaccine in combination with standard tyrosine kinase inhibitor therapy. In this chapter we will summarise selected studies on immunotherapy in advanced RCC with a focus on anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. We will also touch briefly on the adjuvant situation and tumour vaccines. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000436988","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34010417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted cancer therapy in colon cancer.","authors":"Claus-Henning Köhne","doi":"10.1159/000356436","DOIUrl":"https://doi.org/10.1159/000356436","url":null,"abstract":"<p><p>Constant development of chemotherapy and more recently the introduction of VEGF- and epidermal growth factor receptor (EGFR)-directed agents have improved significantly the treatment of patients with colorectal cancer. In the adjuvant setting, especially for UICC stage III colon cancer patients, fluoropyrimidine in combination with oxaliplatin is usually the standard of care. With some surprise, both VEGF inhibitors (for all patients) and EGFR (for patients with KRAS exon 2 mutant tumors) have failed to improve adjuvant chemotherapy. Also, adding an EGFR antibody to FOLFOX as perioperative treatment in patients with resectable exon 2 KRAS wild-type liver metastases was not successful. However, patients with metastatic disease harboring a RAS wild-type tumor are with no doubt candidates for combination chemotherapy plus an EGFR antibody. In patients with liver-limited disease, metastases may become resectable following intensive chemotherapy (including an EGFR antibody for RAS wild-type disease), which may result in cure or significantly prolonged survival. In the case of RAS wild-type tumors, median survival in patients with unresectable metastases approaches now 3 years if EGFR antibodies are used in the first line. There is little evidence for VEGF inhibitors in patients with RAS wild-type or mutant disease in first-line chemotherapy if combination chemotherapy is considered. VEGF inhibitors, however, are very potent drugs to be combined with chemotherapy for second-line treatment.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"36-50"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000356436","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32259452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted cancer therapy in lung cancer.","authors":"Kenichi Suda,&nbsp;Tetsuya Mitsudomi","doi":"10.1159/000355902","DOIUrl":"https://doi.org/10.1159/000355902","url":null,"abstract":"<p><p>Human cancers usually evolve through multistep processes. These processes are driven by the accumulation of abundant genetic and epigenetic abnormalities. However, some lung cancers depend on a single activated oncogene by somatic mutation, termed 'driver oncogenic mutations', for their proliferation and survival. EGFR(epidermal growth factor receptor) mutations and ALK(anaplastic lymphoma kinase) rearrangement are typical examples of such driver oncogenic mutations found in lung adenocarcinomas. EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs significantly improved treatment outcomes compared with conventional cytotoxic chemotherapy in patients with lung cancers harboring EGFR mutations or ALK rearrangement, respectively. Therefore, treatment strategies for lung cancers have dramatically changed from a 'general and empiric' to a 'personalized and evidence-based' approach according to the driver oncogenic mutation. Several novel driver oncogenic mutations, which are candidates as novel targets, such as ERBB2, BRAF, ROS1, and RET, have been discovered. Despite these successes, several limitations have arisen. One example is that some lung cancers do not respond to treatments targeting driver oncogenic mutations, as exemplified in KRAS-mutated lung cancers. Another is resistance to molecular-targeted drugs. Such resistance includes de novo resistance and acquired resistance. A number of molecular mechanisms underlying such resistance have been reported. These mechanisms can be roughly divided into three categories: alteration of the targeted oncogenes themselves by secondary mutations or amplification, activation of an alternative oncogenic signaling track, and conversion of cellular characteristics. Overcoming resistance is a current area of urgent clinical research.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"62-77"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000355902","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32259454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted therapies in renal cell carcinoma.","authors":"Marc Pracht,&nbsp;Dominik Berthold","doi":"10.1159/000355906","DOIUrl":"https://doi.org/10.1159/000355906","url":null,"abstract":"<p><p>Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"98-112"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000355906","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32259457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted cancer therapy in gastrointestinal stromal tumors.","authors":"Paolo G Casali","doi":"10.1159/000355898","DOIUrl":"https://doi.org/10.1159/000355898","url":null,"abstract":"<p><p>In gastrointestinal stromal tumors (GIST), molecularly targeted therapies, starting with imatinib, are directed against an activating mutation of KIT or PDGFRA, which drives the disease. Their efficacy has brought the median survival from one to at least 5 years in the metastatic setting. Tumor response patterns may include tumor shrinkage or not, but are marked by pathologic and radiological changes in tumor tissue. Tumor sensitivity to imatinib can be precisely predicted by the mutational status. However, the metastatic disease has not been truly converted into a chronic condition since secondary resistance to imatinib remains a major limiting factor occurring after a median of 2 years at least in most patients. Further-line therapies are available, i.e. with sunitinib and regorafenib, which can prolong progression-free survival for limited time intervals. Resistance is due to secondary mutations. These give rise to a molecular heterogeneity, which represents a formidable therapeutic challenge. However, the scenario has aspects of a 'liquid resistance'. In fact, resistance may spread in a stepwise fashion throughout the tumor: focal progression may be one possible clinical presentation, and tyrosine kinase inhibitors may impact tumor growth even beyond conventional progression. In addition, sensitive and resistant clones may expand and shrink depending on the selective pressure of tyrosine kinase inhibitors, with be possible responses on rechallenge with drugs. In the adjuvant treatment of high-risk molecularly sensitive GIST, imatinib is able to substantially delay relapses, if due to occur, with a limited survival benefit, though, apparently, without impacting the cure rate.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"51-61"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000355898","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32259453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted cancer therapy in melanoma.","authors":"Emanuela Romano,&nbsp;Olivier Michielin","doi":"10.1159/000355903","DOIUrl":"https://doi.org/10.1159/000355903","url":null,"abstract":"<p><p>The treatment of stage IV melanoma has witnessed a very impressive pace of innovation in recent years, to a point where the management of these patients has very little in common to what was standard practice 5 years ago. If the gain in overall survival, the high response rates or the induction of a significant fraction of long survivors are all very exciting news for our patients and their families, the path that led to these discoveries is as important. Rather than empirical, the development of these new strategies has been extremely rational, based on state-of-the-art basic biology and immunology, exemplary translational research and, finally, hypothesis-driven targeted trials that led to rapid approval. In this review, we will cover all the new targeted therapies that have emerged as the results of these translational programs, focusing mainly on signaling pathway- and immune checkpoint-targeted therapies. Taken collectively, these new developments set the bar for a new paradigm in future translational and clinical research in both melanoma as well as other tumor types.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"78-88"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000355903","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32259455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted cancer therapy in breast cancer.","authors":"Giuseppe Curigliano,&nbsp;Carmen Criscitiello","doi":"10.1159/000355896","DOIUrl":"https://doi.org/10.1159/000355896","url":null,"abstract":"<p><p>Breast cancer is not a single disease. Specific biological processes and distinct genetic pathways are associated with prognosis and sensitivity to chemotherapy and targeted agents in different subtypes of breast cancers. As a consequence, breast cancer can be classified by molecular events. A primary challenge for future drug development in breast cancer will be to distinguish genes and pathways that 'drive' cancer proliferation (drivers) from genes and pathways that have no role in the development of cancer (passengers). The identification of functional pathways that are enriched for mutated genes will select subpopulation of patients likely to be sensitive to biology-driven targeted agents. The selection of driver pathways in resistant tumors will permit to discover a biology-driven platform for new drug development to overcome resistance. We are moving in the era of stratified and personalized therapy. Personalized cancer therapy is based on the precept that detailed molecular characterization of the patient's tumor and its microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. However, there are numerous challenges we need to overcome before delivering on the promise of personalized cancer therapy. These include tumor heterogeneity and molecular evolution, costs and potential morbidity of biopsies, lack of effective drugs against most genomic aberrations, technical limitations of molecular tests, and reimbursement and regulatory hurdles. Critically, successes and limitations surrounding personalized cancer therapy must be tempered with realistic expectations, which, today, encompass increased survival times for only a portion of patients.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"15-35"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000355896","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32258502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successes and limitations of targeted cancer therapy in ovarian cancer.","authors":"Giovanna Damia,&nbsp;Cristiana Sessa","doi":"10.1159/000355905","DOIUrl":"https://doi.org/10.1159/000355905","url":null,"abstract":"<p><p>In ovarian cancer, the clinical development of anticancer agents targeting DNA repair has been associated with significant results because of the elucidation of the different types of damages and repair systems, including PARP. The discovery of the BRCA mutation and its role in ovarian cancer and the clinical application of the concept of synthetic lethality have been the rationale for the successful testing of PARP inhibitors in BRCA mutated ovarian cancer patients. The recent knowledge of the molecular features of low grade ovarian cancer and the application of the concept of synthetic lethality also in this well-defined pathological entity have prompted the clinical evaluation of a combination of PI3K/MEK inhibitors, the first results of which have been already reported.</p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"41 ","pages":"89-97"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000355905","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32259456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}