Lentivirally transduced dendritic cells as a tool for cancer immunotherapy

Breckpot, Karine; Dullaers, Mélissa; Bonehill, Aude; Meirvenne, Sonja Van; Heirman, Carlo; Greef, Catherine De; Bruggen, Pierre van der; Thielemans, Kris

doi:10.1002/jgm.400

Cited by 157 publications

(202 citation statements)

References 55 publications

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“…We noted, however, that after regressing some tumors grew back. OVA-transfected tumor cells can lose OVA expression over time (46,47), a trend that we also observed by RT-PCR analysis of OVA expression at days 4, 7, and 11 after tumor inoculation ( Supplementary Fig. S6); the loss of TAA expression may explain why some tumors grew back after regressing.…”

Section: Discussionsupporting

confidence: 72%

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

172

133

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The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in nontumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8 þ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436-47. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 72%

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

172

133

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“…The lentiviral vector pHR-IG was made by Dr Yoshitaka Akagi in our lab by replacement of eGFP in pHR-G (pHR'tripCMV-GFP-SIN) [33] by IRES-eGFP from pIRES2-eGFP (Promega). The IL-4 gene was cloned upstream of the IRES to generate pHR-IL4IG.…”

Section: Lentivirus Generationmentioning

confidence: 99%

“…The GFP-firefly luciferase fusion (GLF) gene was subcloned from pJW.GFP-yLuc (kindly provided by Dr MH Bachmann) into pHR2 to generate pHR2-GLF. Lentiviral particles expressing GFP, IL-4/GFP or GLF were prepared as described before [33]. Briefly, 293T cells plated in 175 cm 2 flasks, and the next day, near-confluent cells were co-transfected with 45 μg lentiviral vector together with packaging and VSV-G-expressing vectors (3:2:1 ratio) in presence of 25 μM chloroquine (Sigma).…”

Section: Lentivirus Generationmentioning

confidence: 99%

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Creusot

Yaghoubi²,

Kodama

et al. 2008

Clinical Immunology

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A deficit in IL-4 production has been previously reported in both diabetic human patients and nonobese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/ IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

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“…87 Titration assays based on vector-encoded reporter gene expression using fluorescence-activated cell sorting analysis of cells transduced with varying amounts of the virus have been widely used. 88 An important factor is the cell line used for titration, as receptors for a given glycoprotein may vary from cell line to cell line. Frequently, a cell line (such as HeLa or 293 cells) is chosen because it is considered generally permissive to infection rather than representing the natural tropism of the virus from which the glycoprotein was derived.…”

Section: Downstream Processing Of Lentiviral Vectorsmentioning

confidence: 99%

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

2007

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Lentiviral vectors have emerged as promising tools for both gene therapy and immunotherapy purposes. They exhibit several advantages over other viral systems in that they are less immunogenic and are capable of transducing a wide range of different cell types, including dendritic cells (DC). DC transduced ex vivo with a whole range of different (tumor) antigens were capable of inducing strong antigen-specific T-cell responses, both in vitro and in vivo. Recently, the administration of lentiviral vectors in vivo has gained substantial interest as an alternative method for antigenspecific immunization. This method offers a number of advantages over DC vaccines as the same lentivirus can in principle be used for all patients resulting in a significantly reduced cost and requirement for considerably less expertise for the generation and administration of lentiviral vaccines. By selectively targeting lentiviral vectors to, or restricting transgene expression in certain cell types, selectivity, safety and efficacy can be further improved. This review will focus on the use of direct administration of lentiviral vectors encoding tumor-associated antigens (TAA) for the induction of tumor-specific immune responses in vivo, with a special focus on problems related to the generation of large amounts of highly purified virus and specific targeting of antigenpresenting cells (APC).

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Lentivirally transduced dendritic cells as a tool for cancer immunotherapy

Abstract: We show that, using lentiviral vectors, efficient gene transfer in human and murine DC can be obtained and that these DC can elicit antigen-specific immune responses in vitro and in vivo. The composition of the transfer vector has a major impact on the transduction efficiency.

Cited by 157 publications

References 55 publications

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

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