Effects of Interleukin-12 on the Immune Response to a Multipeptide Vaccine for Resected Metastatic Melanoma

Lee, Peter P.; Wang, F.; Kuniyoshi, Jon; Rubio, Valerie; Stuge, Tor B.; Groshen, Susan; Gee, Conway; Lau, Roy; Jeffery, Georgia; Margolin, Kim; Marty, Verna; Weber, Jeffrey S.

doi:10.1200/jco.2001.19.18.3836

Cited by 213 publications

(105 citation statements)

References 49 publications

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“…Indeed, Weber et al (52) have recently shown that including IL-12 upon immunization of melanoma patients with peptides from gp100 and tyrosinase significantly increased the numbers of Ag-specific tetramer-positive and IFN-␥-producing cells in peripheral blood. We have obtained preliminary results suggesting that such immunization can significantly reduce growth of established, progressing tumors in a murine model.…”

Section: Discussionmentioning

confidence: 99%

Peptide Antigen Priming of Naive, But Not Memory, CD8 T Cells Requires a Third Signal That Can Be Provided by IL-12

Schmidt

Mescher

2002

The Journal of Immunology

120

127

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Challenge with peptide Ag in the absence of adjuvant results in tolerance of CD8 T cells specific for the Ag. In contrast, administration of IL-12 along with peptide results in massive clonal expansion, development of effector function, and establishment of a long-lived memory population. Using adoptive transfer of TCR-transgenic CD8 T cells, this effect of IL-12 is shown to be independent of CD4 T cells and to require costimulation provided by CD28 and possibly LFA-1. IL-12 supports responses when IL-12Rβ1-deficient mice are used as recipients for the adoptively transferred CD8 T cells, demonstrating that the IL-12 is acting directly on the T cells rather than on host APC. These results provide strong support for a three-signal model for in vivo activation of naive CD8 T cells by peptide Ag, in which the presence or absence of the third signal determines whether tolerance or activation occurs. In contrast, memory CD8 T cells are effectively activated by peptide Ag in the absence of IL-12 or adjuvant.

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Section: Discussionmentioning

confidence: 99%

Peptide Antigen Priming of Naive, But Not Memory, CD8 T Cells Requires a Third Signal That Can Be Provided by IL-12

Schmidt

Mescher

2002

The Journal of Immunology

120

127

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“…1c). However, treatment of tumor-injected SJL mice with IL-12 failed to inhibit tumor growth, perhaps due to its known toxicity (31,32). On the basis of these results, we opted not to pursue the use of IL-12 in vivo, by either ectopic gene expression or pharmaceutical agent, to inhibit tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms

Simmons

Koneru

Mohindru

et al. 2005

The Journal of Immunology

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Although T cells infiltrate many types of murine and human neoplasms, in many instances tumor-specific cytotoxicity is not observed. Strategies to stimulate CTL-mediated antitumor immunity have included in vitro stimulation and/or genetic engineering of T cells, followed by adoptive transfer into tumor-bearing hosts. In this model of B cell lymphoma in SJL/J mice, we used Tim-3+ T-bet+ Th1 cells to facilitate the development of tumor-specific CTL. Tumor-specific Th1 cell lines were polarized with IL-12 during in vitro stimulation and long term maintenance. As few as 5 million Tim-3+ T-bet+ Th1 cells enabled recipients to resist growth of malignant transplantable cells. In addition, similar numbers of Th1 cells injected into 2- to 3-mo-old mice inhibited development of the spontaneous primary lymphomas, which normally arise in 90% of aging mice. CFSE+ Th1 cells colocalized with injected tumor cells in vivo and formed conjugates with the tumor cells within follicles, whereas in nontumor-challenged recipients the CFSE+ Th1 cells localized only within the T cell zones of the spleen. These results provide evidence that adoptive immunotherapy with Tim-3+ T-bet+ tumor-specific Th1 cells can be used to induce host cytotoxic responses that inhibit the development and growth of neoplastic cells.

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“…17,18,55,62,63,65,67,68 The timing, dose, and location of IL -12 administration have been shown to have immunostimulatory, 22,44,67,68 immune -suppressive, 30,31,62 -65 and antiangiogenic 25,57 effects in different models. Therefore, its effect as a vaccine adjuvant should be carefully studied and used with caution, as it may in fact inhibit instead of potentiating vaccines.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene–modified dendritic cell vaccines

et al. 2002

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Genetic immunotherapy with tumor antigen gene -modified dendritic cells ( DC ) generates robust immunity, although antitumor protection is not complete in all models. Previous experience in a model in which C57BL / 6 mice immunized with DC transduced with adenoviral vectors expressing MART -1 demonstrated a 20 -40% complete protection to a tumor challenge with B16 melanoma cells. Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in naïve mice. In the present study, we wished to determine if the supraphysiological production of the Th1 -skewing cytokine interleukin -12 ( IL -12 ) could enhance immune activation and antitumor protection in this model. In a series of experiments immunizing mice with DC cotransduced with MART -1 and IL -12, antitumor protection and antigen -specific splenocyte cytotoxicity and interferon g production inversely correlated with the amount of IL -12 produced by DC. This adverse effect of IL -12 could not be explained by a direct cytotoxic effect of natural killer cells directed towards DC, nor the production of nitric oxide leading to down -regulation of the immune response -the two mechanisms previously recognized to explain immune -suppressive effects of IL -12 -based vaccine therapy. In conclusion, in this animal model, IL -12 production by gene -modified DC leads to a cytokine -induced dose -dependent inhibition of antigen -specific antitumor protection.

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Effects of Interleukin-12 on the Immune Response to a Multipeptide Vaccine for Resected Metastatic Melanoma

Abstract: These data suggest a significant proportion of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine and indicate that IL-12 may increase the immune response and supporting further development of IL-12 as a vaccine adjuvant.

Cited by 213 publications

References 49 publications

Peptide Antigen Priming of Naive, But Not Memory, CD8 T Cells Requires a Third Signal That Can Be Provided by IL-12

Peptide Antigen Priming of Naive, But Not Memory, CD8 T Cells Requires a Third Signal That Can Be Provided by IL-12

Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms

Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene–modified dendritic cell vaccines

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