Lentivirus-Induced Dendritic Cells (iDC) for Immune-Regenerative Therapies in Cancer and Stem Cell Transplantation

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2017 May 27

PMID 28548069

Citations 4

Authors

Renata Stripecke

Affiliations

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Abstract

Conventional dendritic cells (cDC) are differentiated professional antigen presenting cells capable of potently stimulating naïve T cells and with vast potential for immunotherapeutic applications. The manufacture of clinical-grade cDC is relatively complex and requires several days for completion. Clinical trials showed poor trafficking of cDC from subcutaneous injection sites to lymph nodes (LN), where DC can optimally stimulate naïve lymphocytes for long-lasting memory responses. We demonstrated in mouse and human systems that a single overnight lentiviral (LV) gene transfer into DC precursors for production of combination of cytokines and antigens was capable to induce autonomous self-differentiation of antigen-loaded DC and . These highly viable induced DC (iDC) effectively migrated from the injected skin to LN, where they effectively activated antigen-specific effector memory T cells. Two iDC modalities were validated in relevant animal models and are now in clinical development: Self-differentiated Myeloid-derived Antigen-presenting-cells Reactive against Tumors co-expressing GM-CSF/IL-4/TRP2 for melanoma immunotherapy in the autologous setting (SmartDCtrp2), and Self-differentiated Myeloid-derived Lentivirus-induced against human cytomegalovirus as an allogeneic matched adoptive cell after stem cell transplantation (SmyleDCpp65). The lentiviral vector design and packaging methodology has "evolved" continuously in order to simplify and optimize function and biosafety of and genetic reprogramming of iDC. Here, we address the challenges seeking for new creations of genetically programmed iDC and integrase-defective LV vaccines for immune regeneration.

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