Chronic Graft Versus Host Disease (cGVHD) occurs in over 50-70% of patients undergoing hematopoietic stem-cell transplantation (HSCT) and is the leading cause of late non-relapse mortality. cGVHD typically has insidious multi-organ involvement and has been associated with a worse quality of life, functional status, and increased risk of subsequent comorbidities. The last several years have seen advances in the understanding of the disease, which provided a framework for the design of translational and clinical studies with newer agents currently at different phases which that may hopefully change the course of the disease. This review provides an overview of more commonly used and newer second line options for the management of cGVHD.
{"title":"Advances in the treatment of chronic graft-versus-host disease","authors":"Eric D. Johnson, Daniel R. Couriel","doi":"10.1002/acg2.55","DOIUrl":"10.1002/acg2.55","url":null,"abstract":"<p>Chronic Graft Versus Host Disease (cGVHD) occurs in over 50-70% of patients undergoing hematopoietic stem-cell transplantation (HSCT) and is the leading cause of late non-relapse mortality. cGVHD typically has insidious multi-organ involvement and has been associated with a worse quality of life, functional status, and increased risk of subsequent comorbidities. The last several years have seen advances in the understanding of the disease, which provided a framework for the design of translational and clinical studies with newer agents currently at different phases which that may hopefully change the course of the disease. This review provides an overview of more commonly used and newer second line options for the management of cGVHD.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.55","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45466712","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}
Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Despite this knowledge, a number of CMV-related diagnostic and therapeutic issues remain critical. No uniform guidance exists for the best strategy to monitor and prevent CMV infection and disease. In particular, we lack standard threshold values for assessing the CMV DNAemia in the monitoring of CMV infection; there is no consensus in the adoption of immunoglobulin therapy and adoptive transfer of HSCT donor-derived CMV-specific T cells. Furthermore, antiviral drugs used in the preemptive therapy are characterized by high levels of toxicity. Of interest, recent availability of new drugs will probably modify the antiviral strategy in a large proportion of patients. The uncertainty in the management of CMV infections is further complicated by the continuous evolution in the transplantation strategies and the consequent infectious risk. This paper will focus on challenging issues in the monitoring, prevention, and treatment of CMV infections in allo-HSCT populations. Assessment of pretransplant CMV status, immunological monitoring after transplant, and CMV disease prevention and therapy strategies will be discussed.
{"title":"Advances in CMV infection prevention and treatment after allo-HSCT","authors":"Corrado Girmenia","doi":"10.1002/acg2.53","DOIUrl":"10.1002/acg2.53","url":null,"abstract":"<p>Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Despite this knowledge, a number of CMV-related diagnostic and therapeutic issues remain critical. No uniform guidance exists for the best strategy to monitor and prevent CMV infection and disease. In particular, we lack standard threshold values for assessing the CMV DNAemia in the monitoring of CMV infection; there is no consensus in the adoption of immunoglobulin therapy and adoptive transfer of HSCT donor-derived CMV-specific T cells. Furthermore, antiviral drugs used in the preemptive therapy are characterized by high levels of toxicity. Of interest, recent availability of new drugs will probably modify the antiviral strategy in a large proportion of patients. The uncertainty in the management of CMV infections is further complicated by the continuous evolution in the transplantation strategies and the consequent infectious risk. This paper will focus on challenging issues in the monitoring, prevention, and treatment of CMV infections in allo-HSCT populations. Assessment of pretransplant CMV status, immunological monitoring after transplant, and CMV disease prevention and therapy strategies will be discussed.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.53","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48147921","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}
Chronic lymphocytic leukemia (CLL) has experienced a revolution over the past few decades with a marked expansion in therapeutic options and improvement in outcomes. This success can be attributed to an improved understanding of the molecular and genetic underpinnings of disease pathogenesis and the emergence of a variety of effective, well-tolerated, targeted therapies. The field is now continuing to evolve with an improved understanding of prognostic and predictive biomarkers of response, exploration of novel combination strategies with the goal of inducing deeper and more durable remissions, and the development of next-generation and immune-based agents. Here, we review the recent advances in CLL therapy as well as the novel therapeutic innovations that are likely to contribute to the rapidly evolving treatment paradigms in this disease.
{"title":"Advances in drug-based therapies in chronic lymphocytic leukemia and future prospects","authors":"Jennifer L. Crombie, Jennifer R. Brown","doi":"10.1002/acg2.51","DOIUrl":"10.1002/acg2.51","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) has experienced a revolution over the past few decades with a marked expansion in therapeutic options and improvement in outcomes. This success can be attributed to an improved understanding of the molecular and genetic underpinnings of disease pathogenesis and the emergence of a variety of effective, well-tolerated, targeted therapies. The field is now continuing to evolve with an improved understanding of prognostic and predictive biomarkers of response, exploration of novel combination strategies with the goal of inducing deeper and more durable remissions, and the development of next-generation and immune-based agents. Here, we review the recent advances in CLL therapy as well as the novel therapeutic innovations that are likely to contribute to the rapidly evolving treatment paradigms in this disease.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.51","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48536026","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}
Haneen Shalabi, Ashley Koegel, Anusha Ponduri, Haiying Qin, Dalia Salem, Maryalice Stetler-Stevenson, Constance Yuan, Bonnie Yates, Cindy Delbrook, Mignon Loh, Terry J. Fry, Nirali N. Shah
Targeted immunotherapeutic approaches have become an attractive, novel therapy in the treatment of chemotherapy resistant or relapsed high-risk acute lymphoblastic leukemia (ALL). Many of these therapies, chimeric antigen receptor (CAR) T cells, and bispecific T-cell engagers (BiTE) in particular, rely on surface expression of the antigen for activity and efficacy. As such, antigen loss is a growing problem in this relapsed population. We present a case of relapsed, refractory B-ALL that has immunophenotypic variability in the leukemia blasts in response to the sequential targeted immunotherapies received. This case additionally describes a bolstered CAR-T cell expansion after the patient received subsequent blinatumomab therapy, suggesting a potential strategy for utilization of multiagent immunotherapies to have synergistic approaches to eradicate disease and prolong remission in patients with relapsed hematologic malignancies (Anti-CD22 chimeric receptor T cells in pediatric and young adult patients with recurrent or relapsed CD22-expressing B-cell malignancies. clinicaltrials.gov NCT02315612).
{"title":"Case report: Impact of BITE on CAR-T cell expansion","authors":"Haneen Shalabi, Ashley Koegel, Anusha Ponduri, Haiying Qin, Dalia Salem, Maryalice Stetler-Stevenson, Constance Yuan, Bonnie Yates, Cindy Delbrook, Mignon Loh, Terry J. Fry, Nirali N. Shah","doi":"10.1002/acg2.50","DOIUrl":"10.1002/acg2.50","url":null,"abstract":"<p>Targeted immunotherapeutic approaches have become an attractive, novel therapy in the treatment of chemotherapy resistant or relapsed high-risk acute lymphoblastic leukemia (ALL). Many of these therapies, chimeric antigen receptor (CAR) T cells, and bispecific T-cell engagers (BiTE) in particular, rely on surface expression of the antigen for activity and efficacy. As such, antigen loss is a growing problem in this relapsed population. We present a case of relapsed, refractory B-ALL that has immunophenotypic variability in the leukemia blasts in response to the sequential targeted immunotherapies received. This case additionally describes a bolstered CAR-T cell expansion after the patient received subsequent blinatumomab therapy, suggesting a potential strategy for utilization of multiagent immunotherapies to have synergistic approaches to eradicate disease and prolong remission in patients with relapsed hematologic malignancies (Anti-CD22 chimeric receptor T cells in pediatric and young adult patients with recurrent or relapsed CD22-expressing B-cell malignancies. clinicaltrials.gov NCT02315612).</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.50","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42960315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The role of autologous stem cell transplantation in diffuse large B-cell lymphoma","authors":"Liana Nikolaenko, Alex F. Herrera","doi":"10.1002/acg2.33","DOIUrl":"10.1002/acg2.33","url":null,"abstract":"Immunochemotherapy Sensitive? Yes No","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.33","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44803893","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}
In the latest World Health Organization classification of myeloid neoplasms, chronic myelomonocytic leukemia (CMML) exists as a separate entity under the category of myelodysplastic/myeloproliferative (MDS/MPN) overlap syndromes. Outcomes remain uniformly poor with a median overall survival of ~2 years and an inherent risk of transformation into acute myeloid leukemia (15%-20% over 5 years). Due to unique biologic characteristics such as overlapping features of myelodysplasia and myeloproliferation, and clinical diversity despite relative genomic homogeneity, CMML represents a unique model to study chronic myeloid tumor biology. Recent advances have focused on understanding the role of putative genomic abnormalities, in particular, clonal evolution of pathogenic alterations in genes regulating the epigenome (TET2), chromatin architecture (ASXL1), spliceosome complex (SRSF2, SF3B1), and cell signaling (NRAS, KRAS, CBL, JAK2). Disease prognostication has evolved from purely clinical prognostic models to those incorporating pathogenic gene variants. Therapeutic options in this disease remain dismal with only two agents approved by the United States Food and Drug Administration, namely 5-azacitidine and decitabine. Allogeneic hematopoietic stem cell transplantation remains the sole curative option in this disease; however, is associated with substantial treatment-related morbidity and mortality. Future areas of research include opportunities to further improve disease prognostication by employing novel technologies such as machine learning, incorporation of methylation and cytokine signatures, in addition to gene mutations; insights into clonal origins of this disease, and novel therapeutic strategies.
{"title":"Advances in chronic myelomonocytic leukemia and future prospects: Lessons learned from precision genomics","authors":"Abhishek A. Mangaonkar, Mrinal M. Patnaik","doi":"10.1002/acg2.48","DOIUrl":"10.1002/acg2.48","url":null,"abstract":"<p>In the latest World Health Organization classification of myeloid neoplasms, chronic myelomonocytic leukemia (CMML) exists as a separate entity under the category of myelodysplastic/myeloproliferative (MDS/MPN) overlap syndromes. Outcomes remain uniformly poor with a median overall survival of ~2 years and an inherent risk of transformation into acute myeloid leukemia (15%-20% over 5 years). Due to unique biologic characteristics such as overlapping features of myelodysplasia and myeloproliferation, and clinical diversity despite relative genomic homogeneity, CMML represents a unique model to study chronic myeloid tumor biology. Recent advances have focused on understanding the role of putative genomic abnormalities, in particular, clonal evolution of pathogenic alterations in genes regulating the epigenome (<i>TET2</i>), chromatin architecture (<i>ASXL1</i>), spliceosome complex (<i>SRSF2, SF3B1</i>), and cell signaling (<i>NRAS, KRAS, CBL, JAK2</i>). Disease prognostication has evolved from purely clinical prognostic models to those incorporating pathogenic gene variants. Therapeutic options in this disease remain dismal with only two agents approved by the United States Food and Drug Administration, namely 5-azacitidine and decitabine. Allogeneic hematopoietic stem cell transplantation remains the sole curative option in this disease; however, is associated with substantial treatment-related morbidity and mortality. Future areas of research include opportunities to further improve disease prognostication by employing novel technologies such as machine learning, incorporation of methylation and cytokine signatures, in addition to gene mutations; insights into clonal origins of this disease, and novel therapeutic strategies.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.48","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47985794","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}
Multiple myeloma (MM) is a malignant disease of plasma cells that is also characterized by immune dysregulation. There are several factors that contribute to an immunosuppressive milieu that allows tumor progression, including alterations in natural killer (NK) cells such as a decreased expression of activating receptors. NK cells play an important role in immunosurveillance against cancer. The mainstays of myeloma therapy, such as proteasome inhibitors and immunomodulatory drugs, up-regulate the expression of activating receptors (NKG2D, DNAM-1) on NK cells thereby augmenting their activity against malignant plasma cells. Cellular therapy incorporating NK cells in both the transplant and nontransplant setting offers exciting opportunities for the future. Chimeric antigen receptor (CAR)-transduced-NK cells and bispecific antibodies utilizing NK cells have already been explored in other hematologic malignancies and hold great potential against myeloma. Future clinical studies will help in clarifying the issues related to dose, frequency, long-term safety, and efficacy of NK cell therapy in multiple myeloma.
{"title":"The therapeutic role of natural killer cells in multiple myeloma","authors":"Ghulam Rehman Mohyuddin, Muzaffar H. Qazilbash","doi":"10.1002/acg2.49","DOIUrl":"10.1002/acg2.49","url":null,"abstract":"<p>Multiple myeloma (MM) is a malignant disease of plasma cells that is also characterized by immune dysregulation. There are several factors that contribute to an immunosuppressive milieu that allows tumor progression, including alterations in natural killer (NK) cells such as a decreased expression of activating receptors. NK cells play an important role in immunosurveillance against cancer. The mainstays of myeloma therapy, such as proteasome inhibitors and immunomodulatory drugs, up-regulate the expression of activating receptors (NKG2D, DNAM-1) on NK cells thereby augmenting their activity against malignant plasma cells. Cellular therapy incorporating NK cells in both the transplant and nontransplant setting offers exciting opportunities for the future. Chimeric antigen receptor (CAR)-transduced-NK cells and bispecific antibodies utilizing NK cells have already been explored in other hematologic malignancies and hold great potential against myeloma. Future clinical studies will help in clarifying the issues related to dose, frequency, long-term safety, and efficacy of NK cell therapy in multiple myeloma.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.49","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45254730","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}
The above paper1 was published in Volume 1 Issue 3 of Advances in Cell and Gene Therapy. The authors have identified an error in the Introduction which they would like to amend.
In the final paragraph of page 1, the first sentence “The most common toxicity of CAR therapy is Cytokine Release….” should read “The most common toxicity of CAR therapy is Cytokine Release Syndrome (CRS),8,19,20 which manifests on a spectrum from mild fever to severe multi-organ dysfunction requiring intensive care.”
{"title":"Corrigendum: Dawn of chimeric antigen receptor T cell therapy in non-Hodgkin Lymphoma","authors":"Karlo Perica, M. Lia Palomba, Renier J. Brentjens","doi":"10.1002/acg2.44","DOIUrl":"10.1002/acg2.44","url":null,"abstract":"<p>The above paper<sup>1</sup> was published in Volume 1 Issue 3 of <i>Advances in Cell and Gene Therapy</i>. The authors have identified an error in the Introduction which they would like to amend.</p><p>In the final paragraph of page 1, the first sentence “The most common toxicity of CAR therapy is Cytokine Release….” should read “The most common toxicity of CAR therapy is Cytokine Release Syndrome (CRS),<sup>8,19,20</sup> which manifests on a spectrum from mild fever to severe multi-organ dysfunction requiring intensive care.”</p><p>The authors apologize for the error.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.44","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45948715","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}
Naimisha Marneni, Navneet S. Majhail, Timothy D. Gilligan, Moshe C. Ornstein
Testicular cancer is the most common solid organ malignancy affecting males between 15 and 35 years of age with an annual incidence of approximately 9300 in the United States.1 Germ cell tumors (GCTs) are the most common type of testicular cancer and are broadly categorized as seminomatous (SGCTs) and nonseminomatous germ cell tumors (NSGCTs). Therapeutic advances and utmost sensitivity to cisplatinbased combination chemotherapy make it one of the most curable solid neoplasms, even in the presence of metastatic disease with a 5year survival rate of approximately 95%.1 The standard chemotherapy regimen of bleomycin, etoposide, and cisplatin (BEP) cures a significant proportion of patients. However, despite these advances, a subset of patients have refractory disease or develop disease recurrence requiring salvage chemotherapy. Salvage chemotherapy options include conventionaldose chemotherapy (CDCT) with cisplatin and ifosfamide plus paclitaxel (TIP) or vinblastine (VeIP) or etoposide (VIP), or highdose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/HSCT).2-4 HDCT with HSCT has been available as a therapeutic option since 1986 and has provided cure to selected patients even as a third line regimen.5 We provide data for and our approach to the utilization of HDCT with HSCT in advanced GCTs.
{"title":"High-dose chemotherapy and autologous transplantation for testicular germ cell tumors","authors":"Naimisha Marneni, Navneet S. Majhail, Timothy D. Gilligan, Moshe C. Ornstein","doi":"10.1002/acg2.47","DOIUrl":"10.1002/acg2.47","url":null,"abstract":"Testicular cancer is the most common solid organ malignancy affecting males between 15 and 35 years of age with an annual incidence of approximately 9300 in the United States.1 Germ cell tumors (GCTs) are the most common type of testicular cancer and are broadly categorized as seminomatous (SGCTs) and nonseminomatous germ cell tumors (NSGCTs). Therapeutic advances and utmost sensitivity to cisplatinbased combination chemotherapy make it one of the most curable solid neoplasms, even in the presence of metastatic disease with a 5year survival rate of approximately 95%.1 The standard chemotherapy regimen of bleomycin, etoposide, and cisplatin (BEP) cures a significant proportion of patients. However, despite these advances, a subset of patients have refractory disease or develop disease recurrence requiring salvage chemotherapy. Salvage chemotherapy options include conventionaldose chemotherapy (CDCT) with cisplatin and ifosfamide plus paclitaxel (TIP) or vinblastine (VeIP) or etoposide (VIP), or highdose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/HSCT).2-4 HDCT with HSCT has been available as a therapeutic option since 1986 and has provided cure to selected patients even as a third line regimen.5 We provide data for and our approach to the utilization of HDCT with HSCT in advanced GCTs.","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.47","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42083015","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}
Aimee C. Talleur, Jean-Yves Métais, Ying Li, Robert E. Throm, Heather Tillman, Barbara Rooney, Ardiana Moustaki, Wing Leung
Adoptive cell therapy (ACT) has emerged as an effective treatment for some cancers. However, allogeneic cell applications are in part limited by the risk of alloreactive T-cell subsets causing graft-versus-host-disease (GVHD). We therefore hypothesized that the use of CD27-depleted cells (containing natural killer [NK] cells and effector memory T-cells; without naïve or central memory T-cells) would offer protection from pathogens and GVHD, while also providing anticancer activity when genetically engineered with a chimeric antigen receptor (CAR). In this work, cell phenotypes were evaluated using flow cytometry. In vitro immunologic memory and alloreactivity were tested using lymphocyte proliferation assays. In vivo GVHD potential was assessed using NOD scid gamma (NSG) mice. Anticancer activity of CAR-transduced CD27-depleted cells was tested in vitro via a cytotoxicity assay and in vivo using NSG mice. Our results confirmed that the CD27-depleted cell fraction was enriched for NK cells, effector memory CD4pos T cells and terminal effector memory CD8pos T cells. CD27-depleted cells had strong immunologic response against common pathogens in vitro, and less GVHD potential in vitro and in vivo. CD27-depleted cells could be transduced with a CAR vector produced by stable cell lines, and demonstrated significant antileukemic activity in vitro and in vivo. These findings suggest that CD27-depletion is a promising approach to using allogeneic cells in ACT, potentially providing infection and cancer control simultaneously but having low risk of causing GVHD.
{"title":"Allogeneic CD27-depleted cells in adoptive cell therapy","authors":"Aimee C. Talleur, Jean-Yves Métais, Ying Li, Robert E. Throm, Heather Tillman, Barbara Rooney, Ardiana Moustaki, Wing Leung","doi":"10.1002/acg2.45","DOIUrl":"10.1002/acg2.45","url":null,"abstract":"<p>Adoptive cell therapy (ACT) has emerged as an effective treatment for some cancers. However, allogeneic cell applications are in part limited by the risk of alloreactive T-cell subsets causing graft-versus-host-disease (GVHD). We therefore hypothesized that the use of CD27-depleted cells (containing natural killer [NK] cells and effector memory T-cells; without naïve or central memory T-cells) would offer protection from pathogens and GVHD, while also providing anticancer activity when genetically engineered with a chimeric antigen receptor (CAR). In this work, cell phenotypes were evaluated using flow cytometry. In vitro immunologic memory and alloreactivity were tested using lymphocyte proliferation assays. In vivo GVHD potential was assessed using NOD scid gamma (NSG) mice. Anticancer activity of CAR-transduced CD27-depleted cells was tested in vitro via a cytotoxicity assay and in vivo using NSG mice. Our results confirmed that the CD27-depleted cell fraction was enriched for NK cells, effector memory CD4<sup>pos</sup> T cells and terminal effector memory CD8<sup>pos</sup> T cells. CD27-depleted cells had strong immunologic response against common pathogens in vitro, and less GVHD potential in vitro and in vivo. CD27-depleted cells could be transduced with a CAR vector produced by stable cell lines, and demonstrated significant antileukemic activity in vitro and in vivo. These findings suggest that CD27-depletion is a promising approach to using allogeneic cells in ACT, potentially providing infection and cancer control simultaneously but having low risk of causing GVHD.</p>","PeriodicalId":72084,"journal":{"name":"Advances in cell and gene therapy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/acg2.45","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45419654","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}