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1.
Blood ; 131(1): 30-38, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29118005

RESUMO

There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need, because it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an "off-the-shelf" product that is easily scalable in contrast to adoptive T-cell therapies. Among these, the bispecific T-cell engager blinatumomab has emerged as the most successful BsAb to date. It consists of 2 single-chain variable fragments specific for CD19 present on B-cell malignancies and CD3 expressed on almost all T cells. Blinatumomab has shown potent antitumor activity as a single agent, particularly for acute lymphoblastic leukemia, resulting in its US Food and Drug Administration approval. However, although successful in inducing remissions, these are normally short-lived, with median response durations of <1 year. Nevertheless, the success of blinatumomab has reinvigorated the BsAb field, which is bustling with preclinical and clinical studies for not only B-cell-derived lymphoblastic leukemia and lymphoma but also acute myeloid leukemia and multiple myeloma. Here, we will review the successes and challenges of T-cell-targeted BsAbs for the immunotherapy of hematological malignancies with special focus on conducted clinical studies and strategies to improve their efficacy.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Neoplasias Hematológicas/terapia , Linfócitos T/imunologia , Animais , Neoplasias Hematológicas/imunologia , Humanos
2.
Mol Ther ; 24(9): 1615-26, 2016 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-27401038

RESUMO

Immunotherapy with CD123-specific T-cell engager proteins or with T cells expressing CD123-specific chimeric antigen receptors is actively being pursued for acute myeloid leukemia. T cells secreting bispecific engager molecules (ENG-T cells) may present a promising alternative to these approaches. To evaluate therapeutic potential, we generated T cells to secrete CD123/CD3-bispecific engager molecules. CD123-ENG T cells recognized primary acute myeloid leukemia (AML) cells and cell lines in an antigen-dependent manner as judged by cytokine production and/or tumor killing, and redirected bystander T cells to AML cells. Infusion of CD123-ENG T cells resulted in regression of AML in xenograft models conferring a significant survival advantage of treated mice in comparison to mice that received control T cells. At high effector to target ratios, CD123-ENG T cells recognized normal hematopoietic stem and progenitor cells (HSPCs) with preferential recognition of HSPCs from cord blood compared to bone marrow. We therefore introduced the CD20 suicide gene that can be targeted in vivo with rituximab into CD123-ENG T cells. The expression of CD20 did not diminish the anti-AML activity of CD123-ENG T cells, but allowed for rituximab-mediated ENG-T cell elimination. Thus, ENG-T cells coexpressing CD20 suicide and CD123 engager molecules may present a promising immunotherapeutic approach for AML.


Assuntos
Imunoterapia , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD20/genética , Antígenos CD20/metabolismo , Complexo CD3/genética , Complexo CD3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Genes Transgênicos Suicidas/genética , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunoterapia/métodos , Subunidade alfa de Receptor de Interleucina-3/genética , Leucemia Mieloide Aguda/genética , Camundongos , Retroviridae/genética , Rituximab/farmacologia , Transdução Genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Blood ; 129(1): 9-10, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28057672
4.
Front Immunol ; 13: 880108, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35615350

RESUMO

Immunotherapy with T-cells expressing bispecific T-cell engagers (ENG T-cells) is a promising approach to improve the outcomes for patients with recurrent/refractory acute myeloid leukemia (AML). However, similar to T-cells expressing chimeric antigen receptors (CARs), their antitumor activity is limited in the setting of chronic antigen stimulation. We therefore set out to explore whether transgenic expression of IL15 improves the effector function of ENG T-cells targeting CD123-positive AML. T-cells expressing CD123-specific ENG (CD123-ENG) ± IL15 were generated by retroviral transduction from peripheral blood T cells from healthy donors or patients with AML. In this study, we characterized in detail the phenotype and effector functions of ENG T-cell populations in vitro and in vivo. IL15-expressing CD123-ENG (CD123-ENG.IL15) T-cells retained their antigen-specificity and effector function in the setting of chronic antigen exposure for more 30 days of coculture with AML blasts in contrast to CD123-ENG T-cells, whose effector function rapidly eroded. Furthermore, CD123-ENG.IL15 T-cells remained in a less differentiated state as judged by a high frequency of naïve/memory stem T-cell-like cells (CD45RA+CCR7+/CD45RO-CD62L+ cells) without evidence of T-cell exhaustion. Single cell cytokine profiling using IsoPlexis revealed enhanced T-cell polyfunctionality of CD123-ENG.IL15 T-cells as judged by effector cytokine production, including, granzyme B, IFN-γ, MIP-1α, perforin, TNF-α, and TNF-ß. In vivo, CD123-ENG.IL15 T-cells exhibited superior antigen-specific anti-AML activity and T-cell persistence in both peripheral blood and tissues (BM, spleens, and livers), resulting in a significant survival advantage in one AML xenograft model and two autologous AML PDX models. In conclusion, we demonstrate here that the expansion, persistence, and anti-AML activity of CD123-ENG T-cells can be significantly improved by transgenic expression of IL15, which promotes a naïve/TSCM-like phenotype. However, we also highlight that targeting a single tumor antigen (CD123) can lead to immune escape, reinforcing the need to develop approaches to target multiple antigens. Likewise, our study demonstrates that it is feasible to evaluate autologous T cells in AML PDX models, which will be critical for future preclinical evaluations of next generation AML-redirected T-cell therapies.


Assuntos
Interleucina-15 , Subunidade alfa de Receptor de Interleucina-3 , Leucemia Mieloide Aguda , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva/métodos , Interleucina-15/genética , Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-3/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Linfócitos T/metabolismo
5.
Oncoimmunology ; 10(1): 2000109, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858726

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy combines antigen-specific properties of monoclonal antibodies with the lytic capacity of T cells. An effective and safe CAR-T cell therapy strategy relies on identifying an antigen that has high expression and is tumor specific. This strategy has been successfully used to treat patients with CD19+ B-cell acute lymphoblastic leukemia (B-ALL). Finding a suitable target antigen for other cancers such as acute myeloid leukemia (AML) has proven challenging, as the majority of currently targeted AML antigens are also expressed on hematopoietic progenitor cells (HPCs) or mature myeloid cells. Herein, we developed a computational method to perform a data transformation to enable the comparison of publicly available gene expression data across different datasets or assay platforms. The resulting transformed expression values (TEVs) were used in our antigen prediction algorithm to assess suitable tumor-associated antigens (TAAs) that could be targeted with CAR-T cells. We validated this method by identifying B-ALL antigens with known clinical effectiveness, such as CD19 and CD22. Our algorithm predicted TAAs being currently explored preclinically and in clinical CAR-T AML therapy trials, as well as novel TAAs in pediatric megakaryoblastic AML. Thus, this analytical approach presents a promising new strategy to mine diverse datasets for identifying TAAs suitable for immunotherapy.


Assuntos
Receptores de Antígenos Quiméricos , Antígenos CD19/genética , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva , Linfócitos T
6.
Sci Transl Med ; 13(620): eabh0272, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34788079

RESUMO

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell's multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or second-generation CARs universally preserved the cells' ability to proliferate and mount an antitumor response during prolonged tumor exposure. The increased functionality of the exhaustion-resistant DNMT3A knockout CAR T cells was coupled to an up-regulation of interleukin-10, and genome-wide DNA methylation profiling defined an atlas of genes targeted for epigenetic silencing. This atlas provides a molecular definition of CAR T cell exhaustion, which includes many transcriptional regulators that limit the "stemness" of immune cells, including CD28, CCR7, TCF7, and LEF1. Last, we demonstrate that this epigenetically regulated multipotency program is firmly coupled to the clinical outcome of prior CAR T cell therapies. These data document the critical role epigenetic mechanisms play in limiting the fate potential of human T cells and provide a road map for leveraging this information for improving CAR T cell efficacy.


Assuntos
Imunoterapia Adotiva , Neoplasias , Antígenos CD28 , Epigênese Genética , Humanos , Neoplasias/terapia , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Children (Basel) ; 7(2)2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32079207

RESUMO

Outcomes for pediatric patients with acute myeloid leukemia (AML) remain poor, highlighting the need for improved targeted therapies. Building on the success of CD19-directed immune therapy for acute lymphocytic leukemia (ALL), efforts are ongoing to develop similar strategies for AML. Identifying target antigens for AML is challenging because of the high expression overlap in hematopoietic cells and normal tissues. Despite this, CD123 and CD33 antigen targeted therapies, among others, have emerged as promising candidates. In this review we focus on AML-specific T cell engaging bispecific antibodies and chimeric antigen receptor (CAR) T cells. We review antigens being explored for T cell-based immunotherapy in AML, describe the landscape of clinical trials upcoming for bispecific antibodies and CAR T cells, and highlight strategies to overcome additional challenges facing translation of T cell-based immunotherapy for AML.

8.
Mol Ther Methods Clin Dev ; 18: 571-581, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32775492

RESUMO

Chimeric antigen receptor (CAR) T cells targeting CD123, an acute myeloid leukemia (AML) antigen, hold the promise of improving outcomes for patients with refractory/recurrent disease. We generated five lentiviral vectors encoding CD20, which may serve as a target for CAR T cell depletion, and 2nd or 3rd generation CD123-CARs since the benefit of two costimulatory domains is model dependent. Four CARs were based on the CD123-specific single-chain variable fragment (scFv) 26292 (292) and one CAR on the CD123-specific scFv 26716 (716), respectively. We designed CARs with different hinge/transmembrane (H/TM) domains and costimulatory domains, in combination with the zeta (z) signaling domain: 292.CD8aH/TM.41BBz (8.41BBz), 292.CD8aH/TM.CD28z (8.28z), 716.CD8aH/TM.CD28z (716.8.28z), 292.CD28H/TM. CD28z (28.28z), and 292.CD28H/TM.CD28.41BBz (28.28.41BBz). Transduction efficiency, expansion, phenotype, and target cell recognition of the generated CD123-CAR T cells did not significantly differ. CAR constructs were eliminated for the following reasons: (1) 8.41BBz CARs induced significant baseline signaling, (2) 716.8.28z CAR T cells had decreased anti-AML activity, and (3) CD28.41BBz CAR T cells had no improved effector function in comparison to CD28z CAR T cells. We selected the 28.28z CAR since CAR expression on the cell surface of transduced T cells was higher in comparison to 8.28z CARs. The clinical study (NCT04318678) evaluating 28.28z CAR T cells is now open for patient accrual.

9.
Expert Opin Biol Ther ; 18(1): 51-63, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28945115

RESUMO

INTRODUCTION: Achieving better disease control in patients diagnosed with acute myeloid leukemia (AML) has proven challenging. Overall survival has been impacted by addressing treatment related mortality with focused supportive care measures. Despite this improvement, it remains difficult to induce durable leukemia remissions despite aggressive chemotherapeutic regimens. The addition of hematopoietic stem cell transplants (HSCT) has allowed further treatment intensification and provided the benefit of graft-versus-leukemia (GVL) effect. However, HSCT carries the risk of transplant related morbidities, particularly GVHD, and anti-tumor responsiveness is still suboptimal. Thus, there is a need for alternate therapies. Immunotherapy has the potential to address this need. Areas covered: Expert opinion: The elusiveness of an ideal surface antigen target together with an immunosuppressive leukemic microenvironment add to the already difficult challenge in developing AML-targeted immunotherapies. Though many hurdles remain, recent translational discovery and progressive clinical advances anticipate exciting future developments. AREAS COVERED: This review highlights promises and challenges to immune-based therapies for AML. It aims to summarize immunotherapeutic strategies trialed in AML patients to date, inclusive of: antibodies, vaccines, and cellular therapy. It emphasizes those being used in the pediatric population, but also includes adult clinical trials and translational science that may ultimately extend to pediatric patients.


Assuntos
Imunoterapia , Leucemia Mieloide Aguda/terapia , Anticorpos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos , Transplante de Células-Tronco Hematopoéticas , Humanos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Linfócitos T/imunologia , Vacinas/imunologia
10.
Cancer Immunol Res ; 5(10): 860-870, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28821531

RESUMO

T cells expressing CD19-specific chimeric antigen receptors (CARs) with endodomains that encode a signaling domain derived from CD3ζ and CD28 or 41BB have potent antitumor activity in early-phase clinical studies for B-cell malignancies. Besides CD19-specific CARs, other approaches are actively being pursued to redirect T cells to CD19, including recombinant bispecific T-cell engager (BiTE) proteins or T cells genetically modified to express BiTEs [engager (ENG) T cells]. As BiTEs provide no costimulation, we investigated here if provision of costimulation through CD28 and 41BB enhances the effector function of CD19-ENG T cells. CD19-ENG T cells expressing CD80 and 41BBL on their cell surface (CD19-ENG.41BBL/CD80 T cells) were generated by retroviral transduction. CD19-ENG.41BBL/CD80 T cells retained their antigen specificity and had superior effector function compared with both unmodified T cells and CD19-ENG T cells expressing either CD80, 41BBL, or no costimulatory molecule, as judged by cytokine (IFNγ and IL2) production, T-cell proliferation, and their ability to sequentially kill target cells. In vivo, CD19-ENG.41BBL/CD80 T cells had superior antileukemia activity in the BV173 xenograft model, resulting in a survival advantage in comparison to CD19-ENG T cells. Thus, provision of costimulation is critical for the effector function of ENG T cells. Cancer Immunol Res; 5(10); 860-70. ©2017 AACR.


Assuntos
Antígenos CD28/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Expressão Gênica , Ordem dos Genes , Vetores Genéticos/genética , Humanos , Ativação Linfocitária/genética , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Retroviridae/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Ther Oncolytics ; 6: 69-79, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28856237

RESUMO

The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)+ HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL). Coculture of GPC3+ cells, GPC3-ENG MSCs, and T cells resulted in T cell activation, as judged by interferon γ (IFNγ) production and killing of tumor cells by T cells. Modification of GPC3-ENG MSCs with CD80 and 41BBL was required for antigen-dependent interleukin-2 (IL-2) production by T cells and resulted in faster tumor cell killing by redirected T cells. In vivo, GPC3-ENG MSCs ± costimulatory molecules had antitumor activity in the HUH7 HCC xenograft model, resulting in a survival advantage. In conclusion, MSCs genetically modified to express GPC3-ENG ± costimulatory molecules redirect T cells to GPC3+ tumor cells and have potent antitumor activity. Thus, further preclinical exploration of our modified approach to GPC3-targeted immunotherapy for HCC is warranted.

12.
Sci Rep ; 6: 27130, 2016 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-27255991

RESUMO

T cells expressing chimeric antigen receptors (CARs) or the infusion of bispecific T-cell engagers (BITEs) have shown antitumor activity in humans for CD19-positive malignancies. While BITEs redirect the large reservoir of resident T cells to tumors, CAR T cells rely on significant in vivo expansion to exert antitumor activity. We have shown that it is feasible to modify T cells to secrete solid tumor antigen-specific BITEs, enabling T cells to redirect resident T cells to tumor cells. To adapt this approach to CD19-positive malignancies we now generated T cells expressing secretable, CD19-specific BITEs (CD19-ENG T cells). CD19-ENG T cells recognized tumor cells in an antigen-dependent manner as judged by cytokine production and tumor killing, and redirected bystander T cells to tumor cells. Infusion of CD19-ENG T cells resulted in regression of leukemia or lymphoma in xenograft models and a survival advantage in comparison to control mice. Genetically modified T cells expressing engager molecules may present a promising addition to current CD19-targeted immunotherapies.


Assuntos
Antígenos CD19/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Anticorpos de Cadeia Única/genética , Linfócitos T/transplante , Células A549 , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Humanos , Imunoterapia , Células K562 , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Anticorpos de Cadeia Única/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Pediatrics ; 127(2): e480-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21242225

RESUMO

BACKGROUND: Acute chest syndrome (ACS) is a leading cause of hospitalization and death of children with sickle cell disease (SCD). An evidence-based ACS/SCD guideline was established to standardize care throughout the institution in February 2008. However, by the summer of 2009 use of the guideline was inconsistent, and did not seem to have an impact on length of stay. As a result, an implementation program was developed. OBJECTIVE: This quality-improvement project evaluated the influence of the development and implementation of a clinical practice guideline for children with SCD with ACS or at risk for ACS on clinical outcomes. METHODS: Clinical outcomes of 139 patients with SCD were evaluated before and after the development of the implementation program. Outcomes included average length of stay, number of exchange transfusions, average cost per SCD admission, and documentation of the clinical respiratory score and pulmonary interventions. RESULTS: Average length of stay decreased from 5.8 days before implementation of the guideline to 4.1 days after implementation (P = .033). No patients required an exchange transfusion. Average cost per SCD admission decreased from $30 359 before guideline implementation to $22 368. Documentation of the clinical respiratory score increased from 31.0% before implementation to 75.5%, which is an improvement of 44.5% (P < .001). Documentation of incentive spirometry and positive expiratory pressure increased from 23.3% before implementation to 50.4%, which is an improvement of 27.1% (P < .001). CONCLUSIONS: Implementation of a guideline for children with SCD with ACS or at risk for ACS improved outcomes for patients with SCD.


Assuntos
Síndrome Torácica Aguda/terapia , Anemia Falciforme/terapia , Assistência ao Paciente/normas , Guias de Prática Clínica como Assunto/normas , Melhoria de Qualidade/normas , Síndrome Torácica Aguda/etiologia , Adolescente , Anemia Falciforme/complicações , Criança , Pré-Escolar , Humanos , Lactente , Assistência ao Paciente/métodos , Projetos Piloto , Melhoria de Qualidade/tendências , Estudos Retrospectivos
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