The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma

De-sheng, XU; Sauter, Bernhard; Huang, Tiangui; Meseck, Marcia; Woo, Savio L. C.; Chen, Shu‐Hsia

doi:10.1038/sj.gt.3302556

Cited by 45 publications

(34 citation statements)

References 20 publications

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“…Consistent with this hypothesis, murine tumor cells engineered to express 4-1BBL exhibited enhanced immunogenicity (16), and adoptive transfer of T cells expressing 4-1BBL resulted in potent tumor rejection (17,18). Systemic administration of agonistic anti-4-1BB monoclonal antibodies enhanced tumor immunity and tumor rejection in a murine melanoma tumor model (19,20). Finally, we have previously shown that an oncolytic vaccinia virus expressing 4-1BBL had significant antitumor activity in a carcinoembryonic antigen transgenic murine carcinoma model.…”

Section: Introductionsupporting

confidence: 51%

Host Lymphodepletion Enhances the Therapeutic Activity of an Oncolytic Vaccinia Virus Expressing 4-1BB Ligand

Kim

Kim‐Schulze²,

Kim³

et al. 2009

Cancer Research

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Oncolytic viral vectors have shown promise as antitumor therapeutic agents but their effectiveness is complicated by induction of antiviral antibody responses and rapid host clearance of recombinant vectors. We developed a recombinant oncolytic vaccinia virus expressing the 4-1BBL T-cell costimulatory molecule (rV-4-1BBL) and showed modest tumor regression in the poorly immunogenic B16 murine melanoma model. To improve the therapeutic potential of this vector, we tested the antitumor activity of local intratumoral injection in the setting of host lymphodepletion, which has been shown to augment vaccination and adoptive T-cell therapy. In this model, rV-4-1BBL injection in the setting of lymphodepletion promoted MHC class I expression, reduced antiviral antibody titers, promoted viral persistence, and rescued effectormemory CD8 + T cells, significantly improving the therapeutic effectiveness of the oncolytic vector. These data suggest that vaccination with rV-4-1BBL in the setting of host nonmyeloablative lymphodepletion represents a logical strategy for improving oncolytic vaccination in melanoma, and perhaps other cancers as well. [Cancer Res 2009;69(21):8516-25]

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Section: Introductionsupporting

confidence: 51%

Host Lymphodepletion Enhances the Therapeutic Activity of an Oncolytic Vaccinia Virus Expressing 4-1BB Ligand

Kim

Kim‐Schulze²,

Kim³

et al. 2009

Cancer Research

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“…Anti-4-1BB has been also used in combination with IL-12-expressing dendritic cell (24), human telomerase reverse transcriptase gene therapy (25), dendritic cell-based vaccine (4), IL-12 gene therapy (3), and radiation (26). Soluble 4-1BB ligand in combination with IL-12 gene therapy produced potent antitumor response against hepatic colon carcinoma model (27). Induction of potent antitumor effect by the use of single-chain Fv of anti-4-1BB is another important approach (28,29).…”

Section: Cd11cmentioning

confidence: 99%

Mechanisms Involved in Synergistic Anticancer Immunity of Anti-4-1BB and Anti-CD4 Therapy

et al. 2007

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Anti-4-1BB-mediated anticancer effects were potentiated by depletion of CD4 + cells in B16F10 melanoma-bearing C57BL/6 mice. Anti-4-1BB induced the expansion and differentiation of polyclonal tumor-specific CD8 + T cells into IFN-;-producing CD11c + CD8 + T cells. The CD4 + cell depletion was responsible for facilitating immune cell infiltration into tumor tissues and removing some regulatory barriers such as T regulatory and indoleamine-2,3-dioxygenase (IDO) + dendritic cells. Both monoclonal antibodies (mAb) contributed to the efficient induction of MHC class I molecules on the tumor cells in vivo. The effectors that mediated the anti-4-1BB effect were NKG2D + KLRG1 + CD11c + CD8 + T cells that accumulated preferentially in the tumor tissues. Blocking NKG2D reduced the therapeutic effect by 20% to 26%, which may indicate that NKG2D contributes partially to tumor killing by the differentiated CD8 + T cells. Our results indicate that the combination of the two mAbs, agonistic anti-4-1BB and depleting anti-CD4, results in enhanced production of efficient tumor-killing CTLs, facilitation of their infiltration, and production of a susceptible tumor microenvironment. [Cancer Res 2007;67(18):8891-9]

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“…Consistent with this, synergistic effects of IL-12 with 4-1BB on antitumor CD8 ϩ T-cell responses have been recognized by others in mouse models. 43,44 TGF-␤1 ubiquitously exists in the body. We found that effects of IL-4 on generation of NKG2D Ϫ 4-1BB Ϫ CD8 ϩ T cells became more apparent in the presence of TGF-␤1.…”

Section: Discussionmentioning

confidence: 99%

4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells

Kim

Han

Broxmeyer

2008

Blood

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IntroductionCD8 ϩ T cells are important for immune defense against cancers. 1 Costimulation is a critical process not only for initiating activation of naive T cells but also for differentiating primed cells into effector T cells. T-cell activation and differentiation are tightly regulated by suppressive cytokines such as TGF-␤1 and regulatory T cells. 2,3 T cell immune responses may reflect a balance between costimulating and suppressing immune reactions. To achieve CD8 ϩ T cell-mediated immune responses, costimulatory effects have to be dominant over immune suppression in response to antigens.NKG2D, a C-type lectin-like molecule for CD8 ϩ T cells, is a potent costimulatory molecules for promoting immunosurveillance of tumor and infected cells. 4,5 In humans, NKG2D is present on most natural killer (NK) cells, CD8 ϩ T cells, and ␥␦T cells. 4,6 Human NKG2D interacts with MHC class I chain-related proteins A and B (MICA and MICB). MIC molecules are not detected on most healthy tissues, but are induced by stress such as heat shock, viral infection, or malignant transformation. 7,8 Atypically high MICA expression on healthy tissues is linked to immunopathology of diabetes, rheumatoid arthritis, and celiac disease, suggesting involvement of NKG2D in autoimmune pathogenesis. [9][10][11][12] Similarly, NKG2D ligands (NKG2DL) expressed on tumor cells increase antitumor reactions of tumor-infiltrating cytotoxic T lymphocytes (CTLs) in vivo. 8,[13][14][15] This indicates that NKG2D and its ligand are involved in promoting various immune responses. Paradoxically, persistent expression of MICA results in impaired NK and CD8 ϩ T-cell immune responses. [16][17][18] This negative effect of MICA is mainly due to pronounced down-modulation of NKG2D. 17,19 Consistent with this, tumor-infiltrating and systemic NK cells and CD8 ϩ T-cells in cancer patients with MICA ϩ or MICB ϩ tumors are often functionally compromised. 20 In addition, MIC proteins released in the serum as a soluble form (sMIC) from some types of tumors impair NKG2D function by down-regulating NKG2D surface expression on NK and CD8 ϩ T cells. 17,[19][20][21] Transforming growth factor-␤1 (TGF-␤1) is a central molecule responsible for tumor immune escape by down-modulating NKG2D in CD8 ϩ T and NK cells. 22 Consistent with this, systemic NKG2D down-modulation is pronounced in subjects with malignancies associated with expression of TGF-␤1. 17,20,23 We previously demonstrated that 4-1BB, a specific costimulatory receptor primarily for previously primed CD8 ϩ T cells, is a unique costimulatory molecule that reverses TGF-␤1-mediated inhibition of CD8 ϩ T-cell responses. 24 4-1BB, a member of the tumor necrosis factor receptor family that includes CD40, CD27, CD30, and OX-40, is involved in enhancement of CD8 ϩ T cell-mediated responses to tumor, allografts and virus. 25 A major role of 4-1BB is to promote long-term survival and to facilitate development of effector and memory CD8 ϩ T cells. 26 The ligand for 4-1BB is expressed on activated dendritic cells (DCs), B cell...

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The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma

Cited by 45 publications

References 20 publications

Host Lymphodepletion Enhances the Therapeutic Activity of an Oncolytic Vaccinia Virus Expressing 4-1BB Ligand

Host Lymphodepletion Enhances the Therapeutic Activity of an Oncolytic Vaccinia Virus Expressing 4-1BB Ligand

Mechanisms Involved in Synergistic Anticancer Immunity of Anti-4-1BB and Anti-CD4 Therapy

4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells

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