Pub Date : 2019-07-01DOI: 10.1097/PPO.0000000000000388
Rajeev Sharma
{"title":"Glycemic Variation and Cancer Occurrence—A New Paradigm","authors":"Rajeev Sharma","doi":"10.1097/PPO.0000000000000388","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000388","url":null,"abstract":"","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"25 1","pages":"241 - 242"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75142511","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}
Pub Date : 2019-07-01DOI: 10.1097/PPO.0000000000000392
A. Tsimberidou, R. Said, L. Staudt, B. Conley, N. Takebe
Abstract Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or “actionable mutations” for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.
{"title":"Defining, Identifying, and Understanding “Exceptional Responders” in Oncology Using the Tools of Precision Medicine","authors":"A. Tsimberidou, R. Said, L. Staudt, B. Conley, N. Takebe","doi":"10.1097/PPO.0000000000000392","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000392","url":null,"abstract":"Abstract Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or “actionable mutations” for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"32 1","pages":"296 - 299"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77829897","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}
Pub Date : 2019-07-01DOI: 10.1097/PPO.0000000000000391
Meagan B. Farmer, Danielle C. Bonadies, S. Mahon, M. Baker, Sumedha Ghate, Christine Munro, Chinmayee B. Nagaraj, A. Besser, Kara Bui, Christen M Csuy, B. Kirkpatrick, A. McCarty, S. McQuaid, Jessica Sebastian, D. Sternen, L. Walsh, E. Matloff
Purpose In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. Methods An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. Results All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. Discussion As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.
目的在这个正在进行的国家病例系列中，我们记录了25个新的基因检测病例，其中检测被推荐、订购、解释或使用错误。方法通过社交媒体平台(如Facebook、Twitter、LinkedIn)向全国遗传咨询师协会(National Society of genetic Counselors)、全国遗传咨询师协会(National Society of genetic Counselors)癌症特别兴趣小组(Special Interest Group)成员、私人遗传咨询师实验室小组(private genetic counselor laboratory groups)发出提交基因检测不良事件案例的邀请。邀请函中强调的例子包括在基因检测的排序、咨询和/或解释方面的错误，并且没有限制提交涉及遗传性癌症易感性基因检测的病例。要求提供临床文件，包括家谱。接受了26例病例，并进行了专题分析。提交者被要求在稿件提交前批准其案例的代表。所有提交的病例都发生在美国，来自癌症、儿科、孕前和一般成人环境，涉及医疗级和直接面向消费者的基因检测和原始数据分析。在8个案例中，医生安排了错误的基因检测。在2例中，订购基因检测时出现了多次错误。在3例病例中，由于基因检测结果被误解或由于提供者的遗传学知识有限，患者从提供者那里得到了不正确的信息。在3例病例中，发现的致病基因变异被错误地认为完全解释了可疑的癌症家族史。在2例中，患者获得的基因检测结果不充分或没有信息。在2个案例中，检测实验室的结果解释/文件是错误的。在2个案例中，遗传咨询师重新解释了直接面向消费者进行基因检测的人的结果，并/或要求澄清医学级别的检测。随着基因检测变得越来越普遍和复杂，很明显，我们必须确保进行适当的检测，并正确解释和使用结果。由于劳动力的限制，对一些人来说，获得认证的遗传咨询师仍然是一个问题。潜在的解决方案涉及多个方面的行动:新的遗传咨询提供模式，扩大遗传咨询队伍，改善非遗传学卫生保健专业人员的遗传学和基因组学教育，解决卫生保健政策障碍，等等。遗传咨询师也将自己定位于新的角色，以帮助患者和消费者以及卫生保健提供者、系统和付款人适应新的基因检测技术和模式。这项有待完成的工作意义重大，但基因检测错误的后果也同样重要。
{"title":"Errors in Genetic Testing: The Fourth Case Series","authors":"Meagan B. Farmer, Danielle C. Bonadies, S. Mahon, M. Baker, Sumedha Ghate, Christine Munro, Chinmayee B. Nagaraj, A. Besser, Kara Bui, Christen M Csuy, B. Kirkpatrick, A. McCarty, S. McQuaid, Jessica Sebastian, D. Sternen, L. Walsh, E. Matloff","doi":"10.1097/PPO.0000000000000391","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000391","url":null,"abstract":"Purpose In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. Methods An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. Results All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. Discussion As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"36 1","pages":"231 - 236"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91304235","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}
Pub Date : 2019-07-01DOI: 10.1097/PPO.0000000000000383
A. Mittra, J. Moscow
Abstract The last 2 decades have seen a rapid advance of the precision oncology paradigm—from its early singular successes to becoming the prevailing model of cancer therapy. As the treatment of cancer moves away from traditional chemotherapy, so too will oncology clinical trials have to move away from the traditional model of phase I to phase III progression of drug development. Achieving this goal of individualized care will involve a concerted effort by the entire cancer care community to fundamentally change the design and implementation of oncology clinical trials. We envision that the next 2 decades will be a period of evolution in precision oncology clinical trials through scientific and technologic advances, transformation of clinical trial infrastructure, and changes in the kind of evidence required for regulatory approval.
{"title":"Future Approaches to Precision Oncology–Based Clinical Trials","authors":"A. Mittra, J. Moscow","doi":"10.1097/PPO.0000000000000383","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000383","url":null,"abstract":"Abstract The last 2 decades have seen a rapid advance of the precision oncology paradigm—from its early singular successes to becoming the prevailing model of cancer therapy. As the treatment of cancer moves away from traditional chemotherapy, so too will oncology clinical trials have to move away from the traditional model of phase I to phase III progression of drug development. Achieving this goal of individualized care will involve a concerted effort by the entire cancer care community to fundamentally change the design and implementation of oncology clinical trials. We envision that the next 2 decades will be a period of evolution in precision oncology clinical trials through scientific and technologic advances, transformation of clinical trial infrastructure, and changes in the kind of evidence required for regulatory approval.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"6 1","pages":"300 - 304"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80542980","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}
Pub Date : 2019-07-01DOI: 10.1097/PPO.0000000000000394
James H Doroshow
{"title":"Introduction by the Guest Editor: Oncologic Precision Medicine and the Use of Basket and Umbrella Clinical Trials.","authors":"James H Doroshow","doi":"10.1097/PPO.0000000000000394","DOIUrl":"10.1097/PPO.0000000000000394","url":null,"abstract":"","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"1 1","pages":"243-244"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83773029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-07-01DOI: 10.1097/PPO.0000000000000389
Alice P Chen, Mariam Eljanne, Lyndsay Harris, Shakuntala Malik, Nita L Seibel
With advances in genetic testing and its common usage, the field of precision medicine has exploded in the field of oncology. The National Cancer Institute is uniquely positioned to lead in this area of research through its wide network of investigators, partnerships with pharmaceutical companies in drug development, and laboratory capabilities. It has developed a portfolio of trials as part of a Precision Medicine Initiative that uses various basket/umbrella designs to increase the understanding of treatment of cancer through genetic selection and targeted therapies. This article describes these trials, ALCHEMIST, LungMAP, NCI/NRG ALK Trial, MPACT, NCI-MATCH, and pediatric MATCH, and their contributions to the area of precision medicine.
{"title":"National Cancer Institute Basket/Umbrella Clinical Trials: MATCH, LungMAP, and Beyond.","authors":"Alice P Chen, Mariam Eljanne, Lyndsay Harris, Shakuntala Malik, Nita L Seibel","doi":"10.1097/PPO.0000000000000389","DOIUrl":"10.1097/PPO.0000000000000389","url":null,"abstract":"<p><p>With advances in genetic testing and its common usage, the field of precision medicine has exploded in the field of oncology. The National Cancer Institute is uniquely positioned to lead in this area of research through its wide network of investigators, partnerships with pharmaceutical companies in drug development, and laboratory capabilities. It has developed a portfolio of trials as part of a Precision Medicine Initiative that uses various basket/umbrella designs to increase the understanding of treatment of cancer through genetic selection and targeted therapies. This article describes these trials, ALCHEMIST, LungMAP, NCI/NRG ALK Trial, MPACT, NCI-MATCH, and pediatric MATCH, and their contributions to the area of precision medicine.</p>","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"1 1","pages":"272-281"},"PeriodicalIF":0.0,"publicationDate":"2019-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77739097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01DOI: 10.1097/PPO.0000000000000246
S. Hu-Lieskovan, A. Ribas
Abstract The discovery of immune checkpoints and subsequent clinical development of checkpoint inhibitors have revolutionized the field of oncology. The durability of the antitumor immune responses has raised the hope for long-term patient survival and potential cure; however, currently, only a minority of patients respond. Combination strategies to help increase antigen release and T-cell priming, promote T-cell activation and homing, and improve the tumor immune microenvironment, all guided by predictive biomarkers, can help overcome the tumor immune-evasive mechanisms and maximize efficacy to ultimately benefit the majority of patients. Great challenges remain because of the complex underlying biology, unpredictable toxicity, and accurate assessment of response. Carefully designed clinical trials guided by translational studies of paired biopsies will be key to develop reliable predictive biomarkers to choose which patients would most likely benefit from each strategy.
{"title":"New Combination Strategies Using Programmed Cell Death 1/Programmed Cell Death Ligand 1 Checkpoint Inhibitors as a Backbone","authors":"S. Hu-Lieskovan, A. Ribas","doi":"10.1097/PPO.0000000000000246","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000246","url":null,"abstract":"Abstract The discovery of immune checkpoints and subsequent clinical development of checkpoint inhibitors have revolutionized the field of oncology. The durability of the antitumor immune responses has raised the hope for long-term patient survival and potential cure; however, currently, only a minority of patients respond. Combination strategies to help increase antigen release and T-cell priming, promote T-cell activation and homing, and improve the tumor immune microenvironment, all guided by predictive biomarkers, can help overcome the tumor immune-evasive mechanisms and maximize efficacy to ultimately benefit the majority of patients. Great challenges remain because of the complex underlying biology, unpredictable toxicity, and accurate assessment of response. Carefully designed clinical trials guided by translational studies of paired biopsies will be key to develop reliable predictive biomarkers to choose which patients would most likely benefit from each strategy.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"14 1","pages":"10–22"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88467348","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}
Pub Date : 2017-01-01DOI: 10.1097/PPO.0000000000000245
S. Christiansen, Shaheer Khan, G. Gibney
Abstract In recent years, the field of oncology has witnessed many breakthroughs in the treatment of advanced malignancies, particularly in patients with advanced melanoma. Targeted and immune checkpoint therapies have emerged as the primary treatment strategies for these patients. Molecular profiling of melanoma is incorporated into routine practice to identify potential therapeutic targets, and patients are offered either a targeted or immune checkpoint inhibitor therapy approach. Both strategies have limitations where not all patients experience durable responses. Preclinical data have demonstrated the ability of targeted therapy to enhance activity of effector T cells, reduce immunosuppressive cytokine production, and increase tumor cell antigen presentation, which can augment antitumor immunity. In vivo models have shown synergy with improved tumor control when targeted and immune checkpoint agents are combined. Therefore, combination strategies with targeted and immune checkpoint therapy may improve patient outcomes. Early clinical data with anti–programmed cell-death protein 1/programmed cell-death ligand 1 agents in combination with targeted inhibitors appear to have acceptable toxicity rates and the potential for enhanced antitumor activity. This review explores the current status of preclinical and clinical development for these combination approaches in patients with advanced melanoma.
{"title":"Targeted Therapies in Combination With Immune Therapies for the Treatment of Metastatic Melanoma","authors":"S. Christiansen, Shaheer Khan, G. Gibney","doi":"10.1097/PPO.0000000000000245","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000245","url":null,"abstract":"Abstract In recent years, the field of oncology has witnessed many breakthroughs in the treatment of advanced malignancies, particularly in patients with advanced melanoma. Targeted and immune checkpoint therapies have emerged as the primary treatment strategies for these patients. Molecular profiling of melanoma is incorporated into routine practice to identify potential therapeutic targets, and patients are offered either a targeted or immune checkpoint inhibitor therapy approach. Both strategies have limitations where not all patients experience durable responses. Preclinical data have demonstrated the ability of targeted therapy to enhance activity of effector T cells, reduce immunosuppressive cytokine production, and increase tumor cell antigen presentation, which can augment antitumor immunity. In vivo models have shown synergy with improved tumor control when targeted and immune checkpoint agents are combined. Therefore, combination strategies with targeted and immune checkpoint therapy may improve patient outcomes. Early clinical data with anti–programmed cell-death protein 1/programmed cell-death ligand 1 agents in combination with targeted inhibitors appear to have acceptable toxicity rates and the potential for enhanced antitumor activity. This review explores the current status of preclinical and clinical development for these combination approaches in patients with advanced melanoma.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"6 1","pages":"59–62"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72754871","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}
Pub Date : 2017-01-01DOI: 10.1097/PPO.0000000000000241
I. Giuroiu, J. Weber
Abstract The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.
{"title":"Novel Checkpoints and Cosignaling Molecules in Cancer Immunotherapy","authors":"I. Giuroiu, J. Weber","doi":"10.1097/PPO.0000000000000241","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000241","url":null,"abstract":"Abstract The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"40 1","pages":"23–31"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77854928","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}
Pub Date : 2017-01-01DOI: 10.1097/PPO.0000000000000243
B. Izar, M. Regan, D. McDermott
Abstract Immunotherapies and targeted therapies for the treatment of metastatic or advanced melanoma produce unique patterns of antitumor response. Conventional outcome measures, such as median progression-free and overall survival, may not be ideally suited to identify all patients who derive a benefit from such therapies. Therefore, the introduction of additional endpoint measures, such as milestone comparisons, may be necessary to characterize the potential benefit of such treatment approaches. Immune checkpoint inhibitors induce durable responses in a portion of patients that may continue after treatment cessation. Measuring the associated treatment-free interval, treatment-free survival, and associated patient-reported outcomes could provide important information when implemented in prospective clinical trials. In this article, we discuss the limitations of current endpoint measures and the potential advantage of using novel endpoints and how these might be used in designing clinical trials to address critical unanswered questions for patients with metastatic melanoma.
{"title":"Clinical Trial Design and Endpoints for Stage IV Melanoma in the Modern Era","authors":"B. Izar, M. Regan, D. McDermott","doi":"10.1097/PPO.0000000000000243","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000243","url":null,"abstract":"Abstract Immunotherapies and targeted therapies for the treatment of metastatic or advanced melanoma produce unique patterns of antitumor response. Conventional outcome measures, such as median progression-free and overall survival, may not be ideally suited to identify all patients who derive a benefit from such therapies. Therefore, the introduction of additional endpoint measures, such as milestone comparisons, may be necessary to characterize the potential benefit of such treatment approaches. Immune checkpoint inhibitors induce durable responses in a portion of patients that may continue after treatment cessation. Measuring the associated treatment-free interval, treatment-free survival, and associated patient-reported outcomes could provide important information when implemented in prospective clinical trials. In this article, we discuss the limitations of current endpoint measures and the potential advantage of using novel endpoints and how these might be used in designing clinical trials to address critical unanswered questions for patients with metastatic melanoma.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"31 1","pages":"63–67"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73387469","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}
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