Pub Date : 2023-04-11DOI: 10.1146/annurev-cancerbio-061421-012235
D. Salas-Benito, Trisha R. Berger, M. Maus
Chimeric antigen receptor (CAR) T cell therapy has emerged as a new opportunity for cancer treatment; however, resistance can occur due to intrinsic (T cells), extrinsic (tumors), or acquired (tumors) factors. In many cases, the knowledge of these mechanisms comes from clinical observations of patients treated with CAR T cells. In addition, the structure of the CAR molecule and the manufacturing process can impact CAR T cell efficacy. Extrinsic factors such as the mutations in the tumor cell, or cells in the tumor microenvironment, can also play a role. Tumor cells may exhibit acquired antigen loss or heterogeneity that enables resistance to CAR T cell killing; additionally, myeloid cells, T regulatory cells, and fibroblasts can exert an immunosuppressive effect and abrogate CAR T cell antitumor efficacy. We will discuss these mechanisms of resistance and the novel approaches being used to overcome them to improve the widespread use of this promising cancer therapy.
{"title":"Stalled CARs: Mechanisms of Resistance to CAR T Cell Therapies","authors":"D. Salas-Benito, Trisha R. Berger, M. Maus","doi":"10.1146/annurev-cancerbio-061421-012235","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-012235","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has emerged as a new opportunity for cancer treatment; however, resistance can occur due to intrinsic (T cells), extrinsic (tumors), or acquired (tumors) factors. In many cases, the knowledge of these mechanisms comes from clinical observations of patients treated with CAR T cells. In addition, the structure of the CAR molecule and the manufacturing process can impact CAR T cell efficacy. Extrinsic factors such as the mutations in the tumor cell, or cells in the tumor microenvironment, can also play a role. Tumor cells may exhibit acquired antigen loss or heterogeneity that enables resistance to CAR T cell killing; additionally, myeloid cells, T regulatory cells, and fibroblasts can exert an immunosuppressive effect and abrogate CAR T cell antitumor efficacy. We will discuss these mechanisms of resistance and the novel approaches being used to overcome them to improve the widespread use of this promising cancer therapy.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49390668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-25DOI: 10.1146/annurev-cancerbio-061421-013525
T. Fernando, H. Moore, M. Wongchenko, Ciara Metcalfe
Estrogen receptor (ER) α is expressed in the vast majority of breast cancers and is one of the most successfully prosecuted drug targets in oncology, with multiple classes of endocrine therapies approved for the treatment of ER+ breast cancer. These existing agents are highly active, both as single agents and as combination partners for other targeted therapies, and have significantly benefited patients. However, each of these standard-of-care (SOC) therapies has liabilities that allow for the reengagement of ER signaling as a mechanism of resistance. Data supporting the continued dependence of tumors on ER signaling following exposure to SOC agents have underpinned an extraordinary reenergizing of academic, biotechnology, and pharmaceutical groups pursuing next-generation ER-targeted therapies. The hypothesis that there remains an opportunity to bring further meaningful benefit to patients through fully optimized ER-targeted therapies is currently being investigated in the clinic. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Next-Generation Estrogen Receptor–Targeted Therapeutics","authors":"T. Fernando, H. Moore, M. Wongchenko, Ciara Metcalfe","doi":"10.1146/annurev-cancerbio-061421-013525","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-013525","url":null,"abstract":"Estrogen receptor (ER) α is expressed in the vast majority of breast cancers and is one of the most successfully prosecuted drug targets in oncology, with multiple classes of endocrine therapies approved for the treatment of ER+ breast cancer. These existing agents are highly active, both as single agents and as combination partners for other targeted therapies, and have significantly benefited patients. However, each of these standard-of-care (SOC) therapies has liabilities that allow for the reengagement of ER signaling as a mechanism of resistance. Data supporting the continued dependence of tumors on ER signaling following exposure to SOC agents have underpinned an extraordinary reenergizing of academic, biotechnology, and pharmaceutical groups pursuing next-generation ER-targeted therapies. The hypothesis that there remains an opportunity to bring further meaningful benefit to patients through fully optimized ER-targeted therapies is currently being investigated in the clinic. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46042814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-25DOI: 10.1146/annurev-cancerbio-061521-085949
Matthew D. Park, M. Belabed, Steven T. Chen, Pauline Hamon, S. Hegde, R. Mattiuz, T. Marron, M. Merad
Myeloid cells represent a dominant cellular compartment of tumor lesions and play key roles in tumor inception, progression, metastasis, and response to treatment. Mononuclear phagocytes (MNPs), which include dendritic cells and macrophages, are unique among myeloid cells, as they not only shape both the broader composition and state of the tumor microenvironment but can also specifically instruct cancer-specific, T cell–mediated tumor cell killing, making them especially attractive targets for cancer treatment. Although MNPs remain difficult to modulate therapeutically, our understanding of MNP biology in the antitumor immune response has expanded significantly, offering hope for new possibilities in cancer immunotherapy. Here, we review the recent advances in our study of the cellular identity, molecular diversity, and spatial organization of MNPs in tumors, and we discuss the importance of tailoring therapeutic strategies to incorporate these new insights into cancer treatment design. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"On the Biology and Therapeutic Modulation of Macrophages and Dendritic Cells in Cancer","authors":"Matthew D. Park, M. Belabed, Steven T. Chen, Pauline Hamon, S. Hegde, R. Mattiuz, T. Marron, M. Merad","doi":"10.1146/annurev-cancerbio-061521-085949","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061521-085949","url":null,"abstract":"Myeloid cells represent a dominant cellular compartment of tumor lesions and play key roles in tumor inception, progression, metastasis, and response to treatment. Mononuclear phagocytes (MNPs), which include dendritic cells and macrophages, are unique among myeloid cells, as they not only shape both the broader composition and state of the tumor microenvironment but can also specifically instruct cancer-specific, T cell–mediated tumor cell killing, making them especially attractive targets for cancer treatment. Although MNPs remain difficult to modulate therapeutically, our understanding of MNP biology in the antitumor immune response has expanded significantly, offering hope for new possibilities in cancer immunotherapy. Here, we review the recent advances in our study of the cellular identity, molecular diversity, and spatial organization of MNPs in tumors, and we discuss the importance of tailoring therapeutic strategies to incorporate these new insights into cancer treatment design. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41780411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061421-040659
K. Luckett, K. Ganesh
Organoid models have revolutionized cancer research through their ability to capture the cellular heterogeneity and spatial organization of a tumor in 3D culture. Patient-derived organoids can also mirror responses to therapy in vitro, opening the doors to personalized medicine that can direct clinical decision-making. As cancer immunotherapy has flourished and efforts to develop novel immunotherapies have increased, models that incorporate immune cells into organoid coculture to recapitulate the complexity of the tumor microenvironment faithfully are in high demand. To this end, a wide variety of organoid immune coculture methods have been developed, each differing in the source of immune cells used, types of immune cells maintained in culture, and their specific utility. This review aims to organize these methods into a framework that will aid researchers in choosing the appropriate system for their experimental needs. We also highlight several nonimmune cell types that have been successfully incorporated into organoid culture and the biology these coculture models are poised to interrogate. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Engineering the Immune Microenvironment into Organoid Models","authors":"K. Luckett, K. Ganesh","doi":"10.1146/annurev-cancerbio-061421-040659","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-040659","url":null,"abstract":"Organoid models have revolutionized cancer research through their ability to capture the cellular heterogeneity and spatial organization of a tumor in 3D culture. Patient-derived organoids can also mirror responses to therapy in vitro, opening the doors to personalized medicine that can direct clinical decision-making. As cancer immunotherapy has flourished and efforts to develop novel immunotherapies have increased, models that incorporate immune cells into organoid coculture to recapitulate the complexity of the tumor microenvironment faithfully are in high demand. To this end, a wide variety of organoid immune coculture methods have been developed, each differing in the source of immune cells used, types of immune cells maintained in culture, and their specific utility. This review aims to organize these methods into a framework that will aid researchers in choosing the appropriate system for their experimental needs. We also highlight several nonimmune cell types that have been successfully incorporated into organoid culture and the biology these coculture models are poised to interrogate. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41464314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061421-012447
A. Herms, P. Jones
Normal tissues progressively acquire mutations. Some mutations are positively selected, driving clonal expansions that may colonize the majority of a tissue by old age. In several cases mutant clonal expansion is due to biasing stem cell fate toward proliferation. However, the expansionary phase is transient and is followed by reversion toward wild-type behavior so that normal tissue integrity is retained. Here we consider the implications of these findings for carcinogenesis. We propose that to be considered a cancer driver, a mutant gene should be more prevalent in tumors than the normal lineage from which it emerged. Cancer risk is not dependent on mutational burden, but rather may reflect the relative frequency of pro- and anti-oncogenic mutants within a tissue. Understanding the basis of mutant clonal advantage over wild-type cells allows interventions to halt the expansion or even deplete oncogenic mutants from normal tissue, potentially lowering cancer risk. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Somatic Mutations in Normal Tissues: New Perspectives on Early Carcinogenesis","authors":"A. Herms, P. Jones","doi":"10.1146/annurev-cancerbio-061421-012447","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-012447","url":null,"abstract":"Normal tissues progressively acquire mutations. Some mutations are positively selected, driving clonal expansions that may colonize the majority of a tissue by old age. In several cases mutant clonal expansion is due to biasing stem cell fate toward proliferation. However, the expansionary phase is transient and is followed by reversion toward wild-type behavior so that normal tissue integrity is retained. Here we consider the implications of these findings for carcinogenesis. We propose that to be considered a cancer driver, a mutant gene should be more prevalent in tumors than the normal lineage from which it emerged. Cancer risk is not dependent on mutational burden, but rather may reflect the relative frequency of pro- and anti-oncogenic mutants within a tissue. Understanding the basis of mutant clonal advantage over wild-type cells allows interventions to halt the expansion or even deplete oncogenic mutants from normal tissue, potentially lowering cancer risk. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43731611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061421-123301
Matthew G. Jones, Dian Yang, J. Weissman
During tumor evolution, cancer cells can acquire the ability to proliferate, invade neighboring tissues, evade the immune system, and spread systemically. Tracking this process remains challenging, as many key events occur stochastically and over long times, which could be addressed by studying the phylogenetic relationships among cancer cells. Several lineage tracing approaches have been developed and employed in many tumor models and contexts, providing critical insights into tumor evolution. Recent advances in single-cell lineage tracing have greatly expanded the resolution, scale, and readout of lineage tracing toolkits. In this review, we provide an overview of static lineage tracing methods, and then focus on evolving lineage tracing technologies that enable reconstruction of tumor phylogenies at unprecedented resolution. We also discuss in vivo applications of these technologies to profile subclonal dynamics, quantify tumor plasticity, and track metastasis. Finally, we highlight outstanding questions and emerging technologies for building comprehensive cancer evolution roadmaps. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"New Tools for Lineage Tracing in Cancer In Vivo","authors":"Matthew G. Jones, Dian Yang, J. Weissman","doi":"10.1146/annurev-cancerbio-061421-123301","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-123301","url":null,"abstract":"During tumor evolution, cancer cells can acquire the ability to proliferate, invade neighboring tissues, evade the immune system, and spread systemically. Tracking this process remains challenging, as many key events occur stochastically and over long times, which could be addressed by studying the phylogenetic relationships among cancer cells. Several lineage tracing approaches have been developed and employed in many tumor models and contexts, providing critical insights into tumor evolution. Recent advances in single-cell lineage tracing have greatly expanded the resolution, scale, and readout of lineage tracing toolkits. In this review, we provide an overview of static lineage tracing methods, and then focus on evolving lineage tracing technologies that enable reconstruction of tumor phylogenies at unprecedented resolution. We also discuss in vivo applications of these technologies to profile subclonal dynamics, quantify tumor plasticity, and track metastasis. Finally, we highlight outstanding questions and emerging technologies for building comprehensive cancer evolution roadmaps. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45610572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061421-040258
Daniel J. Zabransky, M. Yarchoan, E. Jaffee
Immune checkpoint inhibitors induce significant and durable treatment responses in about 20% of all cancers, but many patients have natural resistance to current immunotherapies. The past decade of technological advances has resulted in large-scale profiling of many cancers and their tumor microenvironments, rapidly expanding our understanding of the mechanisms utilized by tumors to create immune-resistant microenvironments. In this review, we discuss key factors that create immune resistance and emerging concepts that are redefining how we view immune resistance, as well as highlight novel strategies that aim to convert immune-resistant into immune-sensitive tumors. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Strategies for Heating Up Cold Tumors to Boost Immunotherapies","authors":"Daniel J. Zabransky, M. Yarchoan, E. Jaffee","doi":"10.1146/annurev-cancerbio-061421-040258","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-040258","url":null,"abstract":"Immune checkpoint inhibitors induce significant and durable treatment responses in about 20% of all cancers, but many patients have natural resistance to current immunotherapies. The past decade of technological advances has resulted in large-scale profiling of many cancers and their tumor microenvironments, rapidly expanding our understanding of the mechanisms utilized by tumors to create immune-resistant microenvironments. In this review, we discuss key factors that create immune resistance and emerging concepts that are redefining how we view immune resistance, as well as highlight novel strategies that aim to convert immune-resistant into immune-sensitive tumors. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49187763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061521-082320
M. Raftery, A. S. Franzén, G. Pecher
Chimeric antigen receptor (CAR) T cell therapy has been a great success in CD19+ hematological diseases. Natural killer (NK) CAR cells offer an alternative to CAR T cells with an intrinsic potential for universal off-the-shelf cell therapeutics. The choice of cell type and the choice of CAR are both relevant for the feasibility, effectivity, engraftment, persistence, side effects, and safety of the cell therapy. Until recently CAR NK cells have proven difficult to develop into therapeutic products. Here, we give an overview of the source of CAR NK cells, gene transfer methods, and the manufacture of CAR NK cells for clinical application. We discuss improvements, as well as future options and problems that need to be addressed. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"CAR NK Cells: The Future is Now","authors":"M. Raftery, A. S. Franzén, G. Pecher","doi":"10.1146/annurev-cancerbio-061521-082320","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061521-082320","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has been a great success in CD19+ hematological diseases. Natural killer (NK) CAR cells offer an alternative to CAR T cells with an intrinsic potential for universal off-the-shelf cell therapeutics. The choice of cell type and the choice of CAR are both relevant for the feasibility, effectivity, engraftment, persistence, side effects, and safety of the cell therapy. Until recently CAR NK cells have proven difficult to develop into therapeutic products. Here, we give an overview of the source of CAR NK cells, gene transfer methods, and the manufacture of CAR NK cells for clinical application. We discuss improvements, as well as future options and problems that need to be addressed. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48379382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061421-020411
E. Schmidt, Linda Z Sun, A. Palmer, Cong Chen
The principle of independent drug action proposes that responses to drug combinations result from responses to one or the other of two combining agents, but not both. Explorations of biological pathway interactions in signal transduction and immunobiology as synergy have not been connected to mathematical demonstrations of above–independent action activity, which would define pharmacologic synergy. We review independent action as the explanation for cancer drug combinations and find no evidence for pharmacologic synergy. Rather, a measure of correlation of response ( ρ) when positive can explain below–independent action results, and negative correlation can explain above–independent action results. Anticorrelated responses may be a mathematical demonstration of collateral sensitivity, which can achieve above–independent action activity. Inappropriate use of biological concepts of synergy may be contributing to high failure rates for immuno-oncology clinical trials, indicating a need for more rigorous applications of independent action to the development of cancer drug combination therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Rationales for Combining Therapies to Treat Cancer: Independent Action, Response Correlation, and Collateral Sensitivity Versus Synergy","authors":"E. Schmidt, Linda Z Sun, A. Palmer, Cong Chen","doi":"10.1146/annurev-cancerbio-061421-020411","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-020411","url":null,"abstract":"The principle of independent drug action proposes that responses to drug combinations result from responses to one or the other of two combining agents, but not both. Explorations of biological pathway interactions in signal transduction and immunobiology as synergy have not been connected to mathematical demonstrations of above–independent action activity, which would define pharmacologic synergy. We review independent action as the explanation for cancer drug combinations and find no evidence for pharmacologic synergy. Rather, a measure of correlation of response ( ρ) when positive can explain below–independent action results, and negative correlation can explain above–independent action results. Anticorrelated responses may be a mathematical demonstration of collateral sensitivity, which can achieve above–independent action activity. Inappropriate use of biological concepts of synergy may be contributing to high failure rates for immuno-oncology clinical trials, indicating a need for more rigorous applications of independent action to the development of cancer drug combination therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43195728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-17DOI: 10.1146/annurev-cancerbio-061421-042605
Chirag H. Patel, J. Powell
With the significant successes of immune checkpoint blockade and adoptive cellular therapy, immunotherapy has now become an established treatment option to effectively treat cancer. However, the full potential of this treatment modality has yet to be realized, as there are many additional mechanisms whereby tumors continue to evade immune destruction. To this end, metabolic reprogramming by cancer cells serves not only to promote their own growth but also to create an immunosuppressive tumor microenvironment. The tumor metabolic microenvironment not only inhibits antitumor effector function but also supports the differentiation and function of suppressive immune cells. In this review, we delineate the major metabolic programs of cancer cells and immune cells. Furthermore, we discuss the role of so-called metabolic checkpoints that promote immune evasion and tumor growth. Finally, we review current and potential future strategies to target metabolism in order to not simply inhibit tumor growth but also enhance antitumor immune responses. Such strategies have the great potential to enhance the breadth and depth of immunotherapy for cancer by targeting metabolic checkpoints. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
{"title":"Immune Cell Metabolism and Immuno-Oncology","authors":"Chirag H. Patel, J. Powell","doi":"10.1146/annurev-cancerbio-061421-042605","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-061421-042605","url":null,"abstract":"With the significant successes of immune checkpoint blockade and adoptive cellular therapy, immunotherapy has now become an established treatment option to effectively treat cancer. However, the full potential of this treatment modality has yet to be realized, as there are many additional mechanisms whereby tumors continue to evade immune destruction. To this end, metabolic reprogramming by cancer cells serves not only to promote their own growth but also to create an immunosuppressive tumor microenvironment. The tumor metabolic microenvironment not only inhibits antitumor effector function but also supports the differentiation and function of suppressive immune cells. In this review, we delineate the major metabolic programs of cancer cells and immune cells. Furthermore, we discuss the role of so-called metabolic checkpoints that promote immune evasion and tumor growth. Finally, we review current and potential future strategies to target metabolism in order to not simply inhibit tumor growth but also enhance antitumor immune responses. Such strategies have the great potential to enhance the breadth and depth of immunotherapy for cancer by targeting metabolic checkpoints. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2023-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43120908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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