Monocytes reprogrammed with lentiviral vectors co-expressing GM-CSF, IFN-α2 and antigens for personalized immune therapy of acute leukemia pre- or post-stem ... View Full Text


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Article Info

DATE

2019-10-18

AUTHORS

Julia K. Bialek-Waldmann, Michael Heuser, Arnold Ganser, Renata Stripecke

ABSTRACT

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and overall survival remains poor. Chemotherapy is the standard of care for intensive induction therapy. Patients who achieve a complete remission require post-remission therapies to prevent relapse. There is no standard of care for patients with minimal residual disease (MRD), and stem cell transplantation is a salvage therapy. Considering the AML genetic heterogeneity and the leukemia immune-suppressive properties, novel cellular immune therapies to effectively harness immunological responses to prevent relapse are needed. We developed a novel modality of immune therapy consisting of monocytes reprogrammed with lentiviral vectors expressing GM-CSF, IFN-α and antigens. Preclinical studies in humanized mice showed that the reprogrammed monocytes self-differentiated into highly viable induced dendritic cells (iDCs) in vivo which migrated effectively to lymph nodes, producing remarkable effects in the de novo regeneration of T and B cell responses. For the first-in-man clinical trial, the patient’s monocytes will be transduced with an integrase-defective tricistronic lentiviral vector expressing GM-CSF, IFN-α and a truncated WT1 antigen. For transplanted patients, pre-clinical development of iDCs co-expressing cytomegalovirus antigens is ongoing. To simplify the product chain for a de-centralized supply model, we are currently exploring a closed automated system for a short two-day manufacturing of iDCs. A phase I clinical trial study is in preparation for immune therapy of AML patients with MRD. The proposed cell therapy can fill an important gap in the current and foreseeable future immunotherapies of AML. More... »

PAGES

1891-1899

References to SciGraph publications

  • 2017-03-21. Harnessing the Immune System Against Leukemia: Monoclonal Antibodies and Checkpoint Strategies for AML in IMMUNOTHERAPY
  • 2017-07-25. Reconstructing the immune system with lentiviral vectors in VIRUS GENES
  • 2015-05-28. Lentivirus-induced ‘Smart’ dendritic cells: Pharmacodynamics and GMP-compliant production for immunotherapy against TRP2-positive melanoma in GENE THERAPY
  • 2016-09-22. PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies in LEUKEMIA
  • 2015-07-22. Generation of lentivirus-induced dendritic cells under GMP-compliant conditions for adaptive immune reconstitution against cytomegalovirus after stem cell transplantation in JOURNAL OF TRANSLATIONAL MEDICINE
  • 2008-09. T-cell activation by dendritic cells in the lymph node: lessons from the movies in NATURE REVIEWS IMMUNOLOGY
  • 2002-08-30. Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses in LEUKEMIA
  • 2017-01-16. Precision oncology for acute myeloid leukemia using a knowledge bank approach in NATURE GENETICS
  • 2013-04-25. Monitoring dendritic cell and cytokine biomarkers during remission prior to relapse in patients with FLT3-ITD acute myeloid leukemia in ANNALS OF HEMATOLOGY
  • 2014-09-04. New generation dendritic cell vaccine for immunotherapy of acute myeloid leukemia in CANCER IMMUNOLOGY, IMMUNOTHERAPY
  • 2011-04-26. Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication in ANNALS OF HEMATOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00262-019-02406-9

    DOI

    http://dx.doi.org/10.1007/s00262-019-02406-9

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31628525


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