Pub Date : 2016-01-01DOI: 10.1097/PPO.0000000000000164
J. Villasboas, S. Ansell
AbstractHodgkin lymphoma (HL) is a lymphoid malignancy characterized by a reactive immune infiltrate surrounding relatively few malignant cells. In this scenario, active immune evasion seems to play a central role in allowing tumor progression. Immune checkpoint inhibitor pathways are normal mechanisms of T-cell regulation that suppress immune effector function following an antigenic challenge. Hodgkin lymphoma cells are able to escape immune surveillance by co-opting these mechanisms. The programmed cell death 1 (PD-1) pathway in particular is exploited in HL as the malignant Hodgkin and Reed-Sternberg cells express on their surface cognate ligands (PD-L1/L2) for the PD-1 receptor and thereby dampen the T-cell–mediated antitumoral response. Monoclonal antibodies that interact with and disrupt the PD-1:PD-L1/L2 axis have now been developed and tested in early-phase clinical trials in patients with advanced HL with encouraging results. The remarkable clinical activity of PD-1 inhibitors in HL highlights the importance of immune checkpoint pathways as therapeutic targets in HL. In this review, we discuss the rationale for targeting PD-1 and PD-L1 in the treatment of HL. We will evaluate the published clinical data on the different agents and highlight the safety profile of this class of agents. We discuss the available evidence on the use of biomarkers as predictors of response to checkpoint blockade and summarize the areas under active investigation in the use of PD-1/PD-L1 inhibitors for the treatment of HL.
{"title":"Checkpoint Inhibition: Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors in Hodgkin Lymphoma","authors":"J. Villasboas, S. Ansell","doi":"10.1097/PPO.0000000000000164","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000164","url":null,"abstract":"AbstractHodgkin lymphoma (HL) is a lymphoid malignancy characterized by a reactive immune infiltrate surrounding relatively few malignant cells. In this scenario, active immune evasion seems to play a central role in allowing tumor progression. Immune checkpoint inhibitor pathways are normal mechanisms of T-cell regulation that suppress immune effector function following an antigenic challenge. Hodgkin lymphoma cells are able to escape immune surveillance by co-opting these mechanisms. The programmed cell death 1 (PD-1) pathway in particular is exploited in HL as the malignant Hodgkin and Reed-Sternberg cells express on their surface cognate ligands (PD-L1/L2) for the PD-1 receptor and thereby dampen the T-cell–mediated antitumoral response. Monoclonal antibodies that interact with and disrupt the PD-1:PD-L1/L2 axis have now been developed and tested in early-phase clinical trials in patients with advanced HL with encouraging results. The remarkable clinical activity of PD-1 inhibitors in HL highlights the importance of immune checkpoint pathways as therapeutic targets in HL. In this review, we discuss the rationale for targeting PD-1 and PD-L1 in the treatment of HL. We will evaluate the published clinical data on the different agents and highlight the safety profile of this class of agents. We discuss the available evidence on the use of biomarkers as predictors of response to checkpoint blockade and summarize the areas under active investigation in the use of PD-1/PD-L1 inhibitors for the treatment of HL.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"28 1","pages":"17–22"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83533273","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 : 2016-01-01DOI: 10.1097/PPO.0000000000000172
S. Lonial
AbstractThe recent explosion of immune-based treatments for cancer has significantly impacted remission durations and overall survival for many diseases. Multiple myeloma is no exception to this trend, with several immune-based treatments including checkpoint blockade, cellular therapy, and most advanced now antibody-based treatment coming to fruition. While the use of monoclonal antibodies has been a significant interest in myeloma for some time, identifying the ideal target has been an issue. Given the dependence of plasma cells on interleukin 6 signaling for survival and proliferation, there were several trials testing both single agent and combination therapy effects of anti–interleukin 6 antibodies, which did not demonstrate significant clinical activity; however, more recent antibodies targeting receptors such as CD38 and SLAMF7 (previously known as CS1) are demonstrating significant clinical benefit. In this article, we briefly review the preclinical and clinical data surrounding these 2 important targets and the antibodies that clinically will be used as therapeutic agents in the context of multiple myeloma.
{"title":"Monoclonal Antibodies for the Treatment of Myeloma: Targeting SLAMF7 and CD38","authors":"S. Lonial","doi":"10.1097/PPO.0000000000000172","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000172","url":null,"abstract":"AbstractThe recent explosion of immune-based treatments for cancer has significantly impacted remission durations and overall survival for many diseases. Multiple myeloma is no exception to this trend, with several immune-based treatments including checkpoint blockade, cellular therapy, and most advanced now antibody-based treatment coming to fruition. While the use of monoclonal antibodies has been a significant interest in myeloma for some time, identifying the ideal target has been an issue. Given the dependence of plasma cells on interleukin 6 signaling for survival and proliferation, there were several trials testing both single agent and combination therapy effects of anti–interleukin 6 antibodies, which did not demonstrate significant clinical activity; however, more recent antibodies targeting receptors such as CD38 and SLAMF7 (previously known as CS1) are demonstrating significant clinical benefit. In this article, we briefly review the preclinical and clinical data surrounding these 2 important targets and the antibodies that clinically will be used as therapeutic agents in the context of multiple myeloma.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"29 1","pages":"3–6"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83337618","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 : 2016-01-01DOI: 10.1097/PPO.0000000000000166
S. Nagle, A. Garfall, E. Stadtmauer
AbstractRelapsed and refractory hematologic malignancies have a very poor prognosis. Chimeric antigen receptor T cells are emerging as a powerful therapy in this setting. Early clinical trials of genetically modified T cells for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have shown high complete response rates in patients with few therapeutic options. Exploration is ongoing for other hematologic malignancies including multiple myeloma, acute myeloid leukemia, and Hodgkin lymphoma (HL). At the same time, the design and production of chimeric antigen receptor T cells are being advanced so that this therapy can be more widely utilized. Cytokine release syndrome and neurotoxicity are common, but they are treatable and fully reversible. This review will review available data as well as future developments and challenges in the field.
{"title":"The Promise of Chimeric Antigen Receptor Engineered T Cells in the Treatment of Hematologic Malignancies","authors":"S. Nagle, A. Garfall, E. Stadtmauer","doi":"10.1097/PPO.0000000000000166","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000166","url":null,"abstract":"AbstractRelapsed and refractory hematologic malignancies have a very poor prognosis. Chimeric antigen receptor T cells are emerging as a powerful therapy in this setting. Early clinical trials of genetically modified T cells for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have shown high complete response rates in patients with few therapeutic options. Exploration is ongoing for other hematologic malignancies including multiple myeloma, acute myeloid leukemia, and Hodgkin lymphoma (HL). At the same time, the design and production of chimeric antigen receptor T cells are being advanced so that this therapy can be more widely utilized. Cytokine release syndrome and neurotoxicity are common, but they are treatable and fully reversible. This review will review available data as well as future developments and challenges in the field.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"13 1","pages":"27–33"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81806973","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 : 2016-01-01DOI: 10.1097/PPO.0000000000000169
S. Cerquozzi, N. Farhadfar, A. Tefferi
AbstractMyelofibrosis (MF) is a myeloproliferative neoplasm that presents either as a primary disease or evolves secondarily from polycythemia vera or essential thrombocythemia to post–polycythemia vera MF or post–essential thrombocythemia MF, respectively. Myelofibrosis is characterized by stem cell–derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis, constitutional symptoms, cachexia, leukemic progression, and shortened survival. Therapeutic options for patients with MF have been limited to the use of cytoreductive agents, predominantly hydroxyurea; splenectomy and splenic irradiation for treatment of splenomegaly; and management of anemia with transfusions, erythropoiesis-stimulating agents, androgens, and immunomodulatory agents along with steroids. The only curative option is allogeneic stem cell transplantation (ASCT), which is associated with high morbidity and mortality risks. Recently, JAK (Janus kinase) inhibitor therapies have become available and proven to be palliative in primary MF patients with hydroxyurea-refractory splenomegaly and severe constitutional symptoms. The purpose of this article is to review the clinical features of MF; discuss different treatment strategies, including ASCT; and discuss the potential danger and benefit of using JAK inhibitors prior to ASCT.
{"title":"Treatment of Myelofibrosis: A Moving Target","authors":"S. Cerquozzi, N. Farhadfar, A. Tefferi","doi":"10.1097/PPO.0000000000000169","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000169","url":null,"abstract":"AbstractMyelofibrosis (MF) is a myeloproliferative neoplasm that presents either as a primary disease or evolves secondarily from polycythemia vera or essential thrombocythemia to post–polycythemia vera MF or post–essential thrombocythemia MF, respectively. Myelofibrosis is characterized by stem cell–derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis, constitutional symptoms, cachexia, leukemic progression, and shortened survival. Therapeutic options for patients with MF have been limited to the use of cytoreductive agents, predominantly hydroxyurea; splenectomy and splenic irradiation for treatment of splenomegaly; and management of anemia with transfusions, erythropoiesis-stimulating agents, androgens, and immunomodulatory agents along with steroids. The only curative option is allogeneic stem cell transplantation (ASCT), which is associated with high morbidity and mortality risks. Recently, JAK (Janus kinase) inhibitor therapies have become available and proven to be palliative in primary MF patients with hydroxyurea-refractory splenomegaly and severe constitutional symptoms. The purpose of this article is to review the clinical features of MF; discuss different treatment strategies, including ASCT; and discuss the potential danger and benefit of using JAK inhibitors prior to ASCT.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"26 1","pages":"51–61"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82269784","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 : 2016-01-01DOI: 10.1097/PPO.0000000000000171
V. Ramakrishnan, Shaji K. Kumar
AbstractMultiple myeloma (MM) cells are characterized by genomic alternations that lead to increased cell proliferation and resistance to therapeutic interventions. Up-regulation of cyclins is a characteristic finding in a significant proportion of myeloma patients, mediated through a variety of mechanisms including chromosomal translocations. Cyclins and the cyclin-dependent kinases (CDKs) play a critical role in the cell proliferation seen in MM, especially in the high-risk disease. Given this, CDK inhibitors have been evaluated in this disease, and studies so far have led to a mixed picture. Recent studies with targeted CDK inhibitors have shown early promise, and trials of these drugs in combination with other myeloma drugs are ongoing. The malignant plasma cells in MM are highly dependent on the microenvironment for their growth and survival. Multiple signaling pathways have been found to mediate the interactions between the microenvironment and the plasma cells, whether mediated through cytokines or adhesion molecules. The PIM kinase pathway appears to play a major role in the myeloma cell survival, and PIM kinase inhibitors have shown efficacy in the laboratory, and a recent clinical trial also demonstrates important clinical activity.
{"title":"Inhibitors of the Cyclin-Dependent Kinase and PIM Kinase Pathways in the Treatment of Myeloma","authors":"V. Ramakrishnan, Shaji K. Kumar","doi":"10.1097/PPO.0000000000000171","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000171","url":null,"abstract":"AbstractMultiple myeloma (MM) cells are characterized by genomic alternations that lead to increased cell proliferation and resistance to therapeutic interventions. Up-regulation of cyclins is a characteristic finding in a significant proportion of myeloma patients, mediated through a variety of mechanisms including chromosomal translocations. Cyclins and the cyclin-dependent kinases (CDKs) play a critical role in the cell proliferation seen in MM, especially in the high-risk disease. Given this, CDK inhibitors have been evaluated in this disease, and studies so far have led to a mixed picture. Recent studies with targeted CDK inhibitors have shown early promise, and trials of these drugs in combination with other myeloma drugs are ongoing. The malignant plasma cells in MM are highly dependent on the microenvironment for their growth and survival. Multiple signaling pathways have been found to mediate the interactions between the microenvironment and the plasma cells, whether mediated through cytokines or adhesion molecules. The PIM kinase pathway appears to play a major role in the myeloma cell survival, and PIM kinase inhibitors have shown efficacy in the laboratory, and a recent clinical trial also demonstrates important clinical activity.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"24 1","pages":"7–11"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89753600","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 : 2015-11-01DOI: 10.1097/PPO.0000000000000155
M. Maus, D. Powell
Abstract The durable remission of B-cell leukemia and lymphoma following chimeric antigen receptor (CAR) T-cell therapy has brought this new form of adoptive immunotherapy to center stage with the expectation that CAR T-cell therapy may provide similar efficacy in other hematologic and solid cancers. Herein, we review recent advances in the areas of CAR design that improve CAR T-cell proliferation, engraftment, and efficacy, as well as clinical application strategies that are designed to improve clinical efficacy while reducing the risk of toxicity and broaden patient access to this promising form of cancer immunotherapy.
{"title":"Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity","authors":"M. Maus, D. Powell","doi":"10.1097/PPO.0000000000000155","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000155","url":null,"abstract":"Abstract The durable remission of B-cell leukemia and lymphoma following chimeric antigen receptor (CAR) T-cell therapy has brought this new form of adoptive immunotherapy to center stage with the expectation that CAR T-cell therapy may provide similar efficacy in other hematologic and solid cancers. Herein, we review recent advances in the areas of CAR design that improve CAR T-cell proliferation, engraftment, and efficacy, as well as clinical application strategies that are designed to improve clinical efficacy while reducing the risk of toxicity and broaden patient access to this promising form of cancer immunotherapy.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"29 1","pages":"475–479"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82054310","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 : 2015-11-01DOI: 10.1097/PPO.0000000000000162
L. Radvanyi
Abstract Autologous adoptive T-cell therapies have made tremendous strides over the last few years with excitement currently being generated by technologies that can reprogram T-cell specificities toward any desired antigen including chimeric antigen receptors and recombinant T-cell receptors. Time will tell whether these new genetically engineered T-cell technologies will be effective as advertised, especially in solid tumors, considering the limited availability of specific antigens and the difficulty in managing the unpredictable on-target, off-tissue toxicities. However, a form of T-cell therapy that has been utilized in patients more than any other and has left a lasting mark in the field is tumor-infiltrating lymphocytes (TILs). Tumor-infiltrating lymphocyte therapy has consistently yielded durable clinical responses in selected patients with metastatic melanoma and is now being increasingly applied to treat other solid tumors, including head and neck squamous cell carcinoma, cervical cancer, breast cancer, and lung cancer. Despite its long history in the clinic and key developments over the last few decades that have augmented response rates and have made TIL manufacturing more streamlined, a number of key outstanding conceptual questions remain to be answered in the TIL therapy field. In this review, we address critical questions, including the mechanism of action of TILs and active T-cell subsets, the current need for lymphoablative preconditioning, predictive biomarkers, the role of combination therapy such as checkpoint blockade, new excitement over the recognition of mutated antigens (the “mutanome”) by TILs, and issues in developing TILs for nonmelanoma indications. In each case, we will critically discuss the main issues and concerns and how they can affect the eventual positioning of TIL therapy in the mainstream of cancer care.
{"title":"Tumor-Infiltrating Lymphocyte Therapy: Addressing Prevailing Questions","authors":"L. Radvanyi","doi":"10.1097/PPO.0000000000000162","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000162","url":null,"abstract":"Abstract Autologous adoptive T-cell therapies have made tremendous strides over the last few years with excitement currently being generated by technologies that can reprogram T-cell specificities toward any desired antigen including chimeric antigen receptors and recombinant T-cell receptors. Time will tell whether these new genetically engineered T-cell technologies will be effective as advertised, especially in solid tumors, considering the limited availability of specific antigens and the difficulty in managing the unpredictable on-target, off-tissue toxicities. However, a form of T-cell therapy that has been utilized in patients more than any other and has left a lasting mark in the field is tumor-infiltrating lymphocytes (TILs). Tumor-infiltrating lymphocyte therapy has consistently yielded durable clinical responses in selected patients with metastatic melanoma and is now being increasingly applied to treat other solid tumors, including head and neck squamous cell carcinoma, cervical cancer, breast cancer, and lung cancer. Despite its long history in the clinic and key developments over the last few decades that have augmented response rates and have made TIL manufacturing more streamlined, a number of key outstanding conceptual questions remain to be answered in the TIL therapy field. In this review, we address critical questions, including the mechanism of action of TILs and active T-cell subsets, the current need for lymphoablative preconditioning, predictive biomarkers, the role of combination therapy such as checkpoint blockade, new excitement over the recognition of mutated antigens (the “mutanome”) by TILs, and issues in developing TILs for nonmelanoma indications. In each case, we will critically discuss the main issues and concerns and how they can affect the eventual positioning of TIL therapy in the mainstream of cancer care.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"1068 1","pages":"450–464"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82650619","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 : 2015-11-01DOI: 10.1097/PPO.0000000000000158
C. Yee, G. Lizée, A. Schueneman
Abstract Adoptive cellular therapy represents a robust means of augmenting the tumor-reactive effector population in patients with cancer by adoptive transfer of ex vivo expanded T cells. Three approaches have been developed to achieve this goal: the use of tumor-infiltrating lymphocytes or tumor-infiltrating lymphocytess extracted from patient biopsy material; the redirected engineering of lymphocytes using vectors expressing a chimeric antigen receptor and T-cell receptor; and third, the isolation and expansion of often low-frequency endogenous T cells (ETCs) reactive to tumor antigens from the peripheral blood of patients. This last form of adoptive transfer of T cells, known as ETC therapy, requires specialized methods to isolate and expand from peripheral blood the very low-frequency tumor-reactive T cells, methods that have been developed over the last 2 decades, to the point where such an approach may be broadly applicable not only for the treatment of melanoma but also for that of other solid tumor malignancies. One compelling feature of ETC is the ability to rapidly deploy clinical trials following identification of a tumor-associated target epitope, a feature that may be exploited to develop personalized antigen-specific T-cell therapy for patients with almost any solid tumor. With a well-validated antigen discovery pipeline in place, clinical studies combining ETC with agents that modulate the immune microenvironment can be developed that will transform ETC into a feasible treatment modality.
{"title":"Endogenous T-Cell Therapy: Clinical Experience","authors":"C. Yee, G. Lizée, A. Schueneman","doi":"10.1097/PPO.0000000000000158","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000158","url":null,"abstract":"Abstract Adoptive cellular therapy represents a robust means of augmenting the tumor-reactive effector population in patients with cancer by adoptive transfer of ex vivo expanded T cells. Three approaches have been developed to achieve this goal: the use of tumor-infiltrating lymphocytes or tumor-infiltrating lymphocytess extracted from patient biopsy material; the redirected engineering of lymphocytes using vectors expressing a chimeric antigen receptor and T-cell receptor; and third, the isolation and expansion of often low-frequency endogenous T cells (ETCs) reactive to tumor antigens from the peripheral blood of patients. This last form of adoptive transfer of T cells, known as ETC therapy, requires specialized methods to isolate and expand from peripheral blood the very low-frequency tumor-reactive T cells, methods that have been developed over the last 2 decades, to the point where such an approach may be broadly applicable not only for the treatment of melanoma but also for that of other solid tumor malignancies. One compelling feature of ETC is the ability to rapidly deploy clinical trials following identification of a tumor-associated target epitope, a feature that may be exploited to develop personalized antigen-specific T-cell therapy for patients with almost any solid tumor. With a well-validated antigen discovery pipeline in place, clinical studies combining ETC with agents that modulate the immune microenvironment can be developed that will transform ETC into a feasible treatment modality.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"53 1","pages":"492–500"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73572228","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 : 2015-11-01DOI: 10.1097/PPO.0000000000000161
Bibiana I. Ferreira, R. Hill, W. Link
Abstract All drugs have molecular targets; however, this does not mean that they are targeted therapeutics. Only by the interaction with a disease-specific molecule can the drug be classified as a targeted therapeutic. This is often not clearly defined and might refer to several different therapeutic modalities such as genomically targeted therapy, immune checkpoint therapy, or pharmacokinetic targeting. To develop a precise concept of targeted therapy, it is crucial to understand how drugs were discovered and how our rapidly expanding knowledge concerning disease mechanism is driving a fundamental conceptual change in modern drug discovery and development. In combination with the increasingly detailed analysis of disease at an individual patient level, we believe that it is very timely to consider the past and current approaches involved in the development of new medicines and to discuss the paradigm shift in and basic concepts associated with targeted therapies and personalized medicine.
{"title":"Special Review: Caught in the Crosshairs: Targeted Drugs and Personalized Medicine","authors":"Bibiana I. Ferreira, R. Hill, W. Link","doi":"10.1097/PPO.0000000000000161","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000161","url":null,"abstract":"Abstract All drugs have molecular targets; however, this does not mean that they are targeted therapeutics. Only by the interaction with a disease-specific molecule can the drug be classified as a targeted therapeutic. This is often not clearly defined and might refer to several different therapeutic modalities such as genomically targeted therapy, immune checkpoint therapy, or pharmacokinetic targeting. To develop a precise concept of targeted therapy, it is crucial to understand how drugs were discovered and how our rapidly expanding knowledge concerning disease mechanism is driving a fundamental conceptual change in modern drug discovery and development. In combination with the increasingly detailed analysis of disease at an individual patient level, we believe that it is very timely to consider the past and current approaches involved in the development of new medicines and to discuss the paradigm shift in and basic concepts associated with targeted therapies and personalized medicine.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"61 1","pages":"441–447"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89935514","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 : 2015-11-01DOI: 10.1097/PPO.0000000000000159
K. Noonan, I. Borrello
Abstract The clinical results achieved with immunotherapy in the past few years have now firmly established it within the cancer armamentarium. Our group has explored a novel approach to adoptive T-cell therapy utilizing marrow-infiltrating lymphocytes (MILs) initially developed with the concept of utilizing a population of T cells with a higher endogenous tumor specificity. Marrow-infiltrating lymphocytes are antigen-experienced T cells that home to and remain in the bone marrow (BM) because of the unique biology of the BM microenvironment. Marrow-infiltrating lymphocytes can easily be obtained from the BM and can be expanded to demonstrate enhanced antigen specificity. Current clinical trials utilize MILs for patients with myeloma as well as patients with relapsed disease following an allogeneic transplant. Ongoing preclinical work is currently evaluating MILs for use in solid cancers as well as pediatric cancers. The examination of a MIL as a source cell for chimeric antigen receptor T or transgenic cell receptor is also in the preclinical stages. Until now, for both chimeric antigen receptor T-cell therapy and transgenic cell receptor T-cell therapy, the target cell of choice has included peripheral blood. The unique antigen-experienced properties of MILs may make them the ideal source of cell for gene modification strategies. Therefore, MILs are a distinctive set of T cells that have been shaped by the unique BM microenvironment and may play a future role as a novel immunotherapy for hematologic malignancies.
{"title":"Marrow Infiltrating Lymphocytes: Their Role in Adoptive Immunotherapy","authors":"K. Noonan, I. Borrello","doi":"10.1097/PPO.0000000000000159","DOIUrl":"https://doi.org/10.1097/PPO.0000000000000159","url":null,"abstract":"Abstract The clinical results achieved with immunotherapy in the past few years have now firmly established it within the cancer armamentarium. Our group has explored a novel approach to adoptive T-cell therapy utilizing marrow-infiltrating lymphocytes (MILs) initially developed with the concept of utilizing a population of T cells with a higher endogenous tumor specificity. Marrow-infiltrating lymphocytes are antigen-experienced T cells that home to and remain in the bone marrow (BM) because of the unique biology of the BM microenvironment. Marrow-infiltrating lymphocytes can easily be obtained from the BM and can be expanded to demonstrate enhanced antigen specificity. Current clinical trials utilize MILs for patients with myeloma as well as patients with relapsed disease following an allogeneic transplant. Ongoing preclinical work is currently evaluating MILs for use in solid cancers as well as pediatric cancers. The examination of a MIL as a source cell for chimeric antigen receptor T or transgenic cell receptor is also in the preclinical stages. Until now, for both chimeric antigen receptor T-cell therapy and transgenic cell receptor T-cell therapy, the target cell of choice has included peripheral blood. The unique antigen-experienced properties of MILs may make them the ideal source of cell for gene modification strategies. Therefore, MILs are a distinctive set of T cells that have been shaped by the unique BM microenvironment and may play a future role as a novel immunotherapy for hematologic malignancies.","PeriodicalId":22430,"journal":{"name":"The Cancer Journal","volume":"1 1","pages":"501–505"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87307321","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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