Emerging applications of gene edited T cells for the treatment of leukemia

Georgiadis, Christos; Qasim, Waseem

doi:10.1080/17474086.2017.1350575

Cited by 12 publications

(6 citation statements)

References 20 publications

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“…Zinc finger nucleases have been established to be effective in eliminating CCR5 expression on T cells from HIV-infected individuals in order to prevent viral spread ( 102 , 103 ). Transcription activator-like effector nucleases and CRISPR/Cas9 nuclease systems have been used for TCR knockdowns as part of CAR-T cell therapy, to produce an “off the shelf” donor T cell product for the treatment of CD19 + B cell leukemias ( 104 , 105 ). Gene-editing platforms hold great promise for the effective correction of endogenous genes using corrected DNA copies as donor templates, utilizing the cell’s own DNA repair machinery.…”

Section: Current Treatment and Management Options For Xlp1mentioning

confidence: 99%

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective

et al. 2018

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X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein–Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, SH2D1A, has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease.

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Section: Current Treatment and Management Options For Xlp1mentioning

confidence: 99%

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective

et al. 2018

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“…Excitingly, genome‐editing technologies including clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9) and transcription activator‐like effector nucleases (TALEN) may further refine AML CART cell specificity, potency, and prolonged persistence, at the same time reducing “off target” effects . Preclinical studies combining CART therapy with specific kinase inhibitors: CD19 CAR T and ibrutinib in ALL, FLT3 CART with crenolanib in AML, and CD33 or CD19 CAR T cells with PI3K inhibitor LY294002 in AML and ALL, respectively, are underway .…”

Section: Cellular Therapiesmentioning

confidence: 99%

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

2019

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Acute myeloid leukemia (AML) is a disease with heterogeneous prognosis based on the clinical, cytogenetic, and molecular profile of the patient. Despite high post-induction remission rates in adult patients up to 40% of patients relapse. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective and potentially curative post-remission treatment for AML. 1 The antileukemic effect of allo-HSCT depends on the cytotoxicity of the pretransplant conditioning therapy and the posttransplant graft versus leukemia (GVL) effect. In a meta-analysis, allo-HSCT significantly improves survival in patients in first complete remission (CR) with poor-risk and intermediate-risk cytogenetic abnormalities (poor-risk: HR -0.73; 95% CI, 0.59-0.90); (intermediate-risk AML: HR, 0.83%-95% CI, 0.74-0.93). 2,3 The introduction of non-myeloablative (NMA) and reduced intensity conditioning (RIC) regimens, advances in HLA-matching, improved supportive care, and tailored graft versus host disease (GVHD) prophylaxis have allowed for a larger application of allo-HSCT to older patients and those with comorbidities. Although Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). Reduced intensity regimens, alternative graft sources, advances in HLA-matching, improved supportive care, and tailored graft versus host disease (GVHD) prophylaxis have led to a wider application of allo-HSCT to eligible patients. Unfortunately, 30-40% of patients with AML will relapse after transplant and this is the major cause of treatment failure. Careful consideration should be paid in choosing the type of graft, graft source, and conditioning regimen to minimize the risk of disease recurrence. In addition, maintenance therapy following allo-HSCT is a potential method to keep the disease in remission, especially in those with high-risk disease characteristics. Pharmacological targeted agents with low side effect profile such as tyrosine kinase inhibitors, hypomethylating agents (HMAs), HDAC inhibitors, antibody drug conjugates (ADCs), isocitrate dehydrogenase inhibitors, and hedgehog inhibitors may prevent relapse in posttransplant setting and are under investigation. Immunological therapies including donor lymphocyte infusions (DLIs), natural killer (NK) cell therapy, peptide vaccine targeting tumor antigens, and adoptive T-cell therapies all hold promises in this area as well. As targeted agents and immunotherapies continue to be developed, patients at high risk of recurrence may benefit from prophylactic maintenance therapy. Here we review the current landscape in this rapidly evolving clinical setting. K E Y W O R D S Acute myeloid leukemia, Allogeneic Transplant, Immunotherapy, Posttransplant relapse, Targeted agents

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“…In addition to the aforementioned bispecific antigen-targeting approaches to maximize AML specificity, use of genome-editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) and transcription activator-like effector nucleases (TALEN), or checkpoint inhibitors may further fine-tune AML CAR T-cell precision, potency, and persistence. 28,[95][96][97] Combining CAR T cells with relevant kinase inhibitors may also decrease potential immunotherapeutic resistance leading to leukemia relapse. This concept has been recently successfully demonstrated in preclinical studies of CD19 CAR T cells and ibrutinib in ALL, FLT3 CAR T cells with the FLT3 inhibitor crenolanib in AML, and CD33 or CD19 CAR T cells with the PI3K inhibitor LY294002 in AML and ALL, respectively.…”

Section: Resultsmentioning

confidence: 99%

Acute myeloid leukemia chimeric antigen receptor T-cell immunotherapy: how far up the road have we traveled?

Tasian

2018

Therapeutic Advances in Hematology

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Chemotherapy resistance and relapse remain significant sources of mortality for children and adults with acute myeloid leukemia (AML). Further intensification of conventional cytotoxic chemotherapy is likely not feasible due to the severity of acute and long-term side effects upon normal tissues commonly induced by these drugs. Successful development and implementation of new precision medicine treatment approaches for patients with AML, which may improve leukemia remission and diminish toxicity, is thus a major priority. Tumor antigen-redirected chimeric antigen receptor (CAR) T-cell immunotherapies have induced remarkable responses in patients with relapsed or chemorefractory B-lymphoblastic leukemia, and similar strategies are now under early clinical study in adults with relapsed/refractory AML. However, potential on target/off tumor toxicity of AML CAR T-cell immunotherapies, notably aplasia of normal myeloid cells, may limit broader implementation of such approaches. Careful selection of optimal target antigens, consideration of toxicity mitigation strategies, and development of methodologies to circumvent potential CAR T-cell resistance are essential for successful implementation of cellular immunotherapies for patients with high-risk AML.

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Emerging applications of gene edited T cells for the treatment of leukemia

Cited by 12 publications

References 20 publications

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

Acute myeloid leukemia chimeric antigen receptor T-cell immunotherapy: how far up the road have we traveled?

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