Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells

Abstract

Active cancer immunotherapy relies on functional tumor-specific effector T lymphocytes for tumor elimination. Dendritic cells (DCs), as most potent antigen-presenting cells, have been popularly employed in clinical and experimental tumor treatments. We have previously demonstrated that lentiviral vector-mediated transgene delivery to DC progenitors, including bone marrow cells and hematopoietic stem cells, followed by transplantation supports systemic generation of great numbers of tumor antigenpresenting DCs. These DCs subsequently stimulate marked and systemic immune activation. Here, we examined whether this level of immune activation is sufficient to overcome tumor-induced tolerogenic environment for treating an established aggressive epithelial tumor. We showed that a combination treatment of granulocyte macrophage-colony stimulating factor and cytosinephosphate-guanine-containing oligonucleotide stimulated large numbers of tumor antigen-presenting DCs in situ from transgenemodified stem cells. Moreover, these in situ generated and activated DCs markedly stimulated activation of antigen-specific CD4 and CD8 T cells by augmenting their numbers, as well as function, even in a tumor-bearing tolerogenic environment. This leads to significant improvement in the therapeutic efficacy of established pulmonary metastases. This study suggests that lentiviral vectormodified stem cells as DC progenitors may be used as an effective therapeutic regimen for treating metastatic epithelial tumors.

Bone Marrow Stem Cells Expressing Keratinocyte Growth Factor via an Inducible Lentivirus Protects against Bleomycin-Induced Pulmonary Fibrosis

“…Recently Zhang et al, have been able to treat pulmonary metastatic tumors in mice using lentiviral-vector transduced HSCs [57]. However, there are no reports in primary lung disease models of using bone marrow transplantation of lentivirus-transduced HSCs.…”

Stem Cells and Cell Therapies in Lung Biology and Lung Diseases

“…These cells function, in part, by providing a supportive stroma for the cancers and/or by participating in tumor vascularization (145)(146)(147)(148)(149)(150)(151)(152)(153)(154)(155)(156)(157)(158)(159). In contrast, MSCs and EPCs have been demonstrated to home to areas of tumor development, and engineered EPCs and MSCs, as well as Hematopoietic Stem Cells (HSCs), have been used to suppress tumor growth in mouse tumor models of primary lung cancers, metastatic lung cancers, and of other cancers metastatic to the lung (148,(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177)(178)(179). Cell based treatment may thus be useful in lung cancer therapeutics.…”

“…Although the frequency of MSCs in the adult bone marrow is low (less than 0.1%), once isolated from bone marrow or from other tissues, MSCs can be expanded ex vivo, which makes it possible to manufacture these cells for potential therapeutic purposes. MSCs can also be relatively easily transduced or genetically manipulated to deliver or to secrete selected disease-modifying molecules (148,(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177)(178)(179)(388)(389)(390). Overall, these properties of MSCs make them an attractive potential therapeutic tool as vectors for delivery of disease-specific treatment substances or as immunomodulatory agents.…”

Stem Cells and Regenerative Medicine in Lung Biology and Diseases

“…[137][138][139][140] In contrast, MSCs and EPCs have been demonstrated to home to areas of tumor development and EPCs and MSCs engineered to secrete antitumor agents have been utilized to suppress tumor growth in mouse tumor models of primary lung cancers, metastatic lung cancers, and of other cancers metastatic to the lung. [141][142][143][144][145][146][147][148][149][150][151][152][153] Cellbased therapies may thus be useful in lung cancer therapeutics.…”