Lentivirus-Induced Dendritic Cells for Immunization Against High-Risk WT1⁺ Acute Myeloid Leukemia

Abstract

Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain

Dendritic Cell–Mediated Immune Humanization of Mice: Implications for Allogeneic and Xenogeneic Stem Cell Transplantation

“…We have previously demonstrated several properties of murine (23,24) and human (15,25) lentivirus-induced DC that can autonomously differentiate in vivo. Among those, one particular characteristic that drastically differentiates them from conventional DCs (cultured in the presence of recombinant cytokines) is their extended longevity in vivo for several weeks after s.c. injection.…”

“…Development of relevant in vivo syngeneic and humanized mouse models to predict potency and risks of genetically modified cell therapies is an ongoing focus of our laboratory (15,(23)(24)(25)44). For donor-derived SmyleDC to be used in the context of allogeneic stem cell transplantation, one of the upmost important immunotoxicity risks is the development of acute or chronic GvHD.…”

Dendritic Cell Therapies for Hematologic Malignancies

“…Combining vaccination with immunomodulatory drugs such as lenalidomide or immune checkpoint blockade is being explored 91, 92. Future research efforts in this realm are also likely to include exploration of combinations of DC-tumor vaccination with various novel immunotherapy strategies, including chimeric antigen receptor (CAR) T lymphocyte therapy, 93 myeloid-derived suppressor cell (MDSC) inhibitors, 94 and therapies that deplete Tregs, 95 as well as lentviral or retroviral gene therapy techniques for improved induction of anti-tumor immune response 96, 97…”

WT1 shRNA delivery using transferrin-conjugated PEG liposomes in an in vivo model of melanoma

“…One of the limitations of gene therapy is tumor-specific delivery. The use of viral vectors is a good method for delivering genetic material in vitro (46)(47)(48); this strategy is limited by the host immune response in vivo (55)(56)(57).…”