Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration

Hara, Isao; Nagai, Hiroshi; Miyake, Hideaki; Yamanaka, Kazuki; Hara, Shoji; Micallef, Mark; Kurimoto, Masashi; Gohji, Kazuo; Arakawa, Soichi; Ichihashi, Masamitsu; Kamidono, Sadao

doi:10.1038/sj.cgt.7700083

Cited by 44 publications

(35 citation statements)

References 29 publications

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“…Tumor cells were washed once with PBS and then incubated with 50 g of MMC per 10 7 cells for 1 h at 37°C (14), after which they were washed four times with PBS before use in vivo (as vaccines) or in vitro (to stimulate T cell responses).…”

Section: Methodsmentioning

confidence: 99%

Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137

Yang

Raycraft

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Section: Methodsmentioning

confidence: 99%

Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137

Yang

Raycraft

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Single-cell suspensions of spleen cells were prepared by gently pressing spleen cells through a sterile stainless steel 60-gauge mesh screen into cold RPMI 1640 supplemented with 10% heat-inactivated FBS and L-glutamine. RENCA and L1C2 (i.e., syngeneic tumor control) BALB/c tumor cells were used as stimulator cells, and were pretreated with mitomycin C (MMC) using a modification as previously described (36). Briefly, trypsinized RENCA and L1C2 tumor cells were incubated with 50 g/ml MMC at 37°C for 30 min followed by washing to remove MMC.…”

Section: Tumor-specific Lymphocyte Proliferation Assaymentioning

confidence: 99%

“…To perform this study, we isolated mononuclear cells from the spleen of the RENCA tumor-bearing animals that were treated with systemic IL-2 alone, intratumor CXCL9 alone, a combination of systemic IL-2 and CXCL9, or control-treated groups and performed mixing experiments with MMC-pretreated RENCA cells or syngeneic BALB/c L1C2 lung cancer cells pretreated with MMC using a modification as previously described (36). MMC has been shown to be able to completely block the proliferation of RENCA cells and L1C2 cells (36).…”

Section: Combined Systemic Il-2 and Intratumor Cxcl9 Therapy Induced mentioning

confidence: 99%

CXCR3/CXCR3 Ligand Biological Axis Impairs RENCA Tumor Growth by a Mechanism of Immunoangiostasis

Pan¹,

Burdick²,

Belperio³

et al. 2006

The Journal of Immunology

115

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RATIONALE Metastatic renal cell carcinoma (RCC) responds poorly to chemo‐ or radiation therapy but responds to systemic immunotherapy, albeit with low response rate. We hypothesized that the CXCR3/CXCR3 ligand biological axis could be optimized to attenuate RCC by first priming with systemic IL‐2 followed by enhancing the intratumor CXCR3 ligand levels to establish optimal CXCR3 ligand chemotactic gradient. METHODS We examined the CXCR3 ligand gradient in a murine RCC (RENCA) model and studied the anti‐tumor effect of various strategies in CXCR3−/− or CXCR3+/+ mice bearing RENCA. RESULTS Systemic IL‐2 induced the expression of CXCR3 on circulating mononuclear cells but impaired the CXCR3 ligand chemotactic gradient from plasma to tumor. IL‐2 failed to inhibit tumor growth and angiogenesis in CXCR3−/− mice. Combined systemic IL‐2 with an intratumor CXCR3 ligand led to significantly greater reduction in tumor growth and angiogenesis, increased tumor necrosis, and increased infiltration of CXCR3+ mononuclear cells, as compared to either strategy alone. These enhanced effects were associated with increased tumor‐specific immune response. CONCLUSIONS These data suggest that combined systemic IL‐2 and intratumor CXCR3 ligand is more efficacious than either strategy alone for reducing tumor‐associated angiogenesis and augmenting tumor‐associated immunity‐the concept of immunoangiostasis. FUNDED BY: NIH Grants CA87879, P50CA90388, HL66027, and P50HL67665.

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“…22,23 The therapeutic benefit of RENCA-H6 vaccine seems to be more pronounced when compared with other vaccines or molecular therapies analyzed in preclinical settings in analogical tumor models. 21,24,25 For example, Hara et al 24 showed that vaccination of (five times in 3-day intervals) with irradiated RENCA-wt (control) or RENCA-H6 cells. Fourteen days later viable cells were suspended in Matrigel and implanted s.c. into naive and immunized mice distally from the vaccination site.…”

Section: Discussionmentioning

confidence: 99%

“…21,24,47 Indeed, in mice immunized with RENCA-H6 vaccine subcutaneous RENCA tumors were densely infiltrated by activated CD4 þ and CD8 þ T lymphocytes. In our previous studies in a murine model of malignant melanoma we have shown that vaccination with H6-modified cells induced Th1 and Tc1 immune responses characterized by the presence of antigenspecific, IFNg-secreting CD4 þ and CD8 þ T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer

et al. 2010

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Although Renal Cell Cancer (RCC) is known to be immunogenic, clinical efficacy of various immunotherapeutic approaches remains unsatisfactory. Novel targeted therapies showing cytostatic rather than cytotoxic activity are unable to cure RCC patients. In our studies, we evaluated the therapeutic efficacy of whole-cell vaccine based on irradiated murine RENCA cells genetically modified to secrete designer cytokine-Hyper-IL6 (H6)-comprising IL-6 and soluble IL-6 receptor. An orthotopic RCC model based on a subcapsular implantation of RENCA cells into kidneys of Balb/C mice was employed. The efficacy of RENCA-H6 vaccine was compared with control vaccine (RENCA-wt) in relation to naive (non-immunized) animals. Three sets of vaccination experiments were carried out in a (i) protective, (ii) palliative and (iii) adjuvant (following nephrectomy) setting. The influence of vaccination on survival of RCC-bearing animals was analyzed. Specificity of vaccine-induced immune response was studied using model antigen-GFP. RCC-bearing animals immunized with RENCA-H6 vaccine showed prolonged survival compared with other groups. In palliative and adjuvant settings the survival RENCA-H6-immunized animals exceeded 75%. Administration of RENCA-H6 inhibited formation and recruitment of Treg cells (CD4 þ CD25 þ Foxp3 þ ) and increased maturation of DCs. RENCA tumors in RENCA-H6-vaccinated animals contained large populations of NK cells and activated CD4 þ , CD8 þ T cells. In addition, in mice vaccinated with RENCA-H6 cells large population of CD4 þ and CD8 þ memory cells (CD62Llow) were detected. In the orthotopic RCC model, RENCA-H6 vaccine showed high therapeutic potential, which resulted from modulation of numerous immunological mechanisms.

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Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration

Cited by 44 publications

References 29 publications

Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137

Melanoma cells transfected to express CD83 induce antitumor immunity that can be increased by also engaging CD137

CXCR3/CXCR3 Ligand Biological Axis Impairs RENCA Tumor Growth by a Mechanism of Immunoangiostasis

Gene-modified tumor vaccine secreting a designer cytokine Hyper-Interleukin-6 is an effective therapy in mice bearing orthotopic renal cell cancer

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