Progress in Tumor Research最新文献

{"title":"Immune Checkpoint Inhibitors.","authors":"John B A G Haanen,&nbsp;Caroline Robert","doi":"10.1159/000437178","DOIUrl":"https://doi.org/10.1159/000437178","url":null,"abstract":"<p><p>Undoubtedly the discovery of immune checkpoints such as CTLA-4 and PD-1 has been crucial to the development of cancer immunotherapy. Although these molecules were originally discovered as molecules playing a role in T cell activation or apoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral immune tolerance. Mice deficient of the immune checkpoints CTLA-4 or PD-1 develop autoimmune-like diseases that occur early after birth and are lethal in the case of CTLA-4 deficiency, or become apparent much later in life in the case of PD-1 deficiency. Blockade of CTLA-4 and PD-1 resulted in the development of antitumor immune responses that were effective as single agents or required additional treatment depending on the preclinical model. Therefore, it was surprising that single-agent anti-CTLA-4 and anti-PD-1 are so effective anticancer treatments in humans. These therapies have revolutionized cancer immunotherapy as they showed for the first time in many years of research in metastatic melanoma, which is considered one of the most immunogenic human cancers, an improvement in overall survival, with an increasing group of patients benefitting long-term from these treatments. In this chapter we discuss the discovery of immune checkpoints, the clinical application of their inhibitors and the future directions of this highly interesting class of molecules. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"55-66"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000437178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34013831","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":"Immunotherapy of Melanoma.","authors":"Alexandra Snyder,&nbsp;Dmitriy Zamarin,&nbsp;Jedd D Wolchok","doi":"10.1159/000436998","DOIUrl":"https://doi.org/10.1159/000436998","url":null,"abstract":"<p><p>The history of immunotherapy is rooted in the treatment of melanoma and therapy with immune checkpoint-blocking agents is now a cornerstone for the treatment of metastatic melanoma. The first effective immunotherapies approved by the US Food and Drug Administration in melanoma included interleukin-2 for metastatic disease and interferon alpha in the adjuvant setting. These were followed by a group of new therapies, including checkpoint-blocking antibodies targeting cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1. Therapies intended to 'reeducate' T cells, such as tumor-infiltrating lymphocyte therapy, oncolytic viruses and tumor vaccines, have yielded promising results and are under development. Finally, the integration of the above therapies as well as development of new coinhibitory and costimulatory agents, though in early stages, appear very promising and likely represent the next phase in drug development for the treatment of metastatic melanoma. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"22-9"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000436998","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34179521","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":"T Cell Engineering.","authors":"Magdalena Pircher,&nbsp;Thomas Schirrmann,&nbsp;Ulf Petrausch","doi":"10.1159/000437180","DOIUrl":"https://doi.org/10.1159/000437180","url":null,"abstract":"<p><p>T cells are a new and promising antigen-specific therapeutic option for the treatment of malignant diseases. To achieve antigen specificity against tumor antigens, T cells can be manipulated by gene transfer to express chimeric antigen receptors (CARs). CAR-expressing T cells are called redirected T cells. CARs are composed of an extracellular antibody-derived antigen recognition domain, a transmembrane domain and a cytoplasmatic signal domain. Therefore, redirected T cells combine the exchangeable specificity of an antibody with the cytotoxic machinery of a T cell. Early clinical trials with redirected T cells targeting cluster of differentiation (CD) 19 have shown impressive results in CD19-positive hematological cancers. However, for solid cancers only limited clinical experience exists and new and innovative concepts have to be developed to overcome tumor-mediated immune suppression. Herein, we describe the general design of a CAR, the function of the different domains and the different strategies to produce redirected T cells. Furthermore, we summarize and discuss the preclinical and clinical data indicating the tremendous potential of redirected T cells to become a mainstay of cancer immunotherapy. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"110-35"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000437180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34015850","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":"Radiotherapy and Immunotherapy: Improving Cancer Treatment through Synergy.","authors":"Kobe Reynders,&nbsp;Dirk De Ruysscher","doi":"10.1159/000437185","DOIUrl":"https://doi.org/10.1159/000437185","url":null,"abstract":"<p><p>Radiotherapy is an important cornerstone in cancer treatment. Ionizing gamma-irradiation is capable of inducing DNA damage and consequential cell death in a precise and effective manner. In recent years it has become clear, however, that this is not the only relevant mechanism of action. Radiotherapy alters the immune composition of the tumor and influences upregulation of MHC I and cancer-testis antigens, inducing immunogenic cell death and supporting dendritic cell activation. Paradoxically, it also increases the relative ratio of regulatory T cells to CD4+ cells, which hampers an effective immune response. Nevertheless, the overall stimulating influence of irradiation on the immune system has been recognized and illustrated in preclinical studies as well as clinical case reports. There have been several attempts to use radiotherapy as an in situ vaccine. The basic rationale is a synergistic effect of different immune therapies like dendritic cell vaccination and CTLA-4 blockade with irradiation. Changes in the immune phenotype after radiotherapy can facilitate dendritic cell functioning. Immune therapy is also able to overcome the inhibitory pool of regulatory T cells through CTLA-4 inhibition, a weak point of radiotherapy. Although successful in preclinical models, there is still a lot of ground that needs to be covered. The optimal radiation dose is crucial, as well as timing and patient selection. Once these unknown parameters are explored, there is a lot of potential in the powerful combination of local immunization and systemic immune treatments for future novel cancer regimens. </p>","PeriodicalId":49661,"journal":{"name":"Progress in Tumor Research","volume":"42 ","pages":"67-78"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000437185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34186878","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":"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":"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}