Interleukin-12 (IL-12) gene therapy of leukemia: Immune and anti-leukemic effects of IL-12-transduced hematopoietic progenitor cells

Gautam, Subhash C.; Xu, Yong; Dumaguin, M; Janakiraman, Nalini; Chapman, Robert A.

doi:10.1038/sj.cgt.7700201

Cited by 11 publications

(14 citation statements)

References 13 publications

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“…IL-12 has several distinctive functions, such as inducing Th1 response, enhancing the generation of allospecific CD8 T cells, augmenting the proliferation of activating T and natural killer (NK) cells, and inducing the production and stabilization of IFN-g (1). Both recombinant IL-12 protein therapy and IL-12 gene therapy induce a significant inhibitory effect on the primary tumors or metastatic tumors in various tumor models and human clinical trial (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). IL-12 gene therapy has resulted in less toxicity than recombinant IL-12 protein therapy as tested in the RENCA tumor model (15).…”

Section: Introductionmentioning

confidence: 99%

Stat1 Deficiency in the Host Enhances Interleukin-12–Mediated Tumor Regression

et al. 2006

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Signal transducer and activator of transcription 1 (Stat1) is considered a key transcription factor that inhibits tumorigenesis, and Stat1 activation in the host is required for interleukin-12 (IL-12)-mediated generation of CTL activity. Using syngeneic Stat1À/À C3H mice bearing SCCVII tumors in this study, we discovered opposite results. Stat1 deficiency in the host significantly enhances IL-12-mediated tumor regression, resulting in tumor eradication from 60% of SCCVII tumor-bearing mice and significant inhibition of tumor growth when compared with control treatment (P < 0.01). This effect is independent of both Stat1-activating cytokine IFN-; and Stat1-downstream effector molecule FasL because neither neutralization of IFN-; nor knocking out of FasL enhances or inhibits IL-12-mediated tumor regression. IL-12 induces a high intensity of tumor-specific CTL activity in Stat1-deficient mice (P < 0.01), increases the CD8 T-cell density in tumor bearing Stat1À/À mice, and induces a T-celldependent tumor regression. The increased CTL activity and the high-intensity infiltration of T cells into the tumors in IL-12-treated Stat1À/À mice are likely due to the longer survival than the same cells from wild-type mice. Together, the data show that inhibition of Stat1 expression in the host enhances tumor-local IL-12 gene therapy for regressing tumors. This conclusion provides a new concept for designing an effective treatment strategy. (Cancer Res 2006; 66(8): 4461-7)

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Section: Introductionmentioning

confidence: 99%

Stat1 Deficiency in the Host Enhances Interleukin-12–Mediated Tumor Regression

et al. 2006

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“…All the mechanisms above appear to underlie the well-known anti-tumor effects of IL-12. In fact, systemic administration of IL-12 has been shown to significantly suppress the growth of a variety of established murine tumors and prolong the survival of tumor-bearing mice (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-12 Gene Modification Exerts Anti-Tumor Effects on Murine Mammary Sarcoma Cell Line in vivo

et al. 2008

Cell Mol Immunol

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“…We have previously shown that IL-12 cDNAs can be stably expressed in myeloid progenitor cells to secrete IL-12 and injection of transduced cells into mice induces the production of IFN-␥ and activation of NK cells (33). Since IL-12 secreting progenitor cells were found to induce IFN-␥ production in vivo, a primary mediator of IL-12-related toxicities, we examined the toxic side effects of IL-12 gene therapy with myeloid progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 97%

“…Previously, we have demonstrated that iv administration of 32DIL-12 cells to the mice induces the production of IFN-␥ and activation of NK cells in vivo (33). IFN-␥ and NK cells were found to suppress the proliferation and lyse 32Dp210 leukemia cells, respectively (33). The induction of IFN-␥ production by 32DIL-12 cells corroborates the previously reported effect of IL-12 favoring the differentiation of Th1 helper cells and secretion of IFN-␥, TNF-␣, and IL-2 that promote the development of cell-mediated immune responses (12,14).…”

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confidence: 98%

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