Effective Immune Rejection of Advanced Metastasized Cancer

Schirrmacher,; Beckhove, Philipp; Krüger, Achim; Rocha, Marian; Umansky,; Fichtner, Kp; Hull, We; Zangemeister‐Wittke, Uwe; Griesbach, A; Jurianz, K.; Vonhoegen, P

doi:10.3892/ijo.6.3.505

Cited by 17 publications

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“…42 A further application of the bs vaccine, which is supported by the data of this study, could consist of an ex vivo activation and expansion of patient-derived T cells for later reinfusion for adoptive cellular immunotherapy. 43 Recently, it was demonstrated in an animal tumor model 44 that bsCD28 vaccine was better than a B7-transfected vaccine. It was able to induce tumor-specific T-cell responses in vitro and had immunotherapeutic effects in vivo, leading to a regression of established tumors.…”

Section: Discussionmentioning

confidence: 99%

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Haas

Herold‐Mende

Gerhards³

et al. 1999

Cancer Gene Ther

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A new, generally applicable procedure is described for the introduction of defined costimulatory molecules into human cancer cells to increase their T-cell stimulatory capacity. The procedure involves infection with Newcastle disease virus to mediate the cell surface binding of costimulatory molecules (e.g., specially designed bispecific antibodies (bsAb)). The modification is independent of tumor cell proliferation and laborious recombinant gene technology and can be applied directly to freshly isolated and ␥-irradiated patient-derived tumor cells as an autologous cancer vaccine. Following the infection of tumor cells with a nonvirulent strain of Newcastle disease virus, the cells are washed and then further modified by coincubation with bsAbs, which attach with one arm to the viral hemagglutinin-neuraminidase (HN) molecule on the infected tumor cells. The second specificity of one bsAb (bs HN ϫ CD28) is directed against CD28 to augment antitumor T-cell responses by selectively channeling positive costimulatory signals via the CD28 pathway. A second bsAb (bs HN ϫ CD3) was produced to deliver T-cell receptor-mediated signals either alone (bsCD3 vaccine) or in combination with anti-CD28 (bsCD3 vaccine plus bsCD28 vaccine). In human T-cell stimulation studies in vitro, the bsCD28 vaccine caused an up-regulation of early (CD69) and late (CD25) T-cell activation markers on CD4 and CD8 T lymphocytes from either normal healthy donors or cancer patients (autologous system) and induced tumor cytostasis in nonmodified bystander tumor cells. In addition, in combination with the bsCD3 vaccine, augmented antitumor cytotoxicity and T-cell proliferative responses were observed. This tumor vaccine modification procedure is highly specific, quick, economic, and has a broad range of clinical applications. T here is now much evidence that an antigen (Ag)-specific, T-cell-mediated immune response requires, apart from the Ag, additional costimulatory signals. 1,2 These signals are normally provided by professional Ag-presenting cells (APCs) such as dendritic cells, macrophages, and activated B lymphocytes but not, for instance, by carcinoma cells, which represent the majority of human tumors and are derived from the non-APCtype cells that form the epithelial layers. In the absence of costimulation, encounters with a tumor-associated Ag (TAA) can lead to T-cell inactivation or death rather than to proliferation and differentiation into effector cells. Modern gene therapy strategies, therefore, aim at transforming carcinoma cells into professional APCs by transfecting genes that code for T-cell costimulatory molecules, such as CD80 (B7-1), 2,3 CD86 (B7-2), and/or cytokines. 4,5 In support of this concept, some nonimmunogenic transplantable tumor cells were shown to become immunogenic after CD80, CD86, and/or cytokine gene transfection, and mice that rejected such transfectants developed systemic protective immunity against the nontransfected tumor. [2][3][4][5][6] B7 transfection, however, often does not suffice to transfer immunogen...

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Section: Discussionmentioning

confidence: 99%

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Haas

Herold‐Mende

Gerhards³

et al. 1999

Cancer Gene Ther

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“…If systemic antitumor immunity is induced, however, it is at least partially mediated by CD8 T cells [20], We could recently demonstrate in a metastatic mouse leukemia variant (into which the bacterial lac-Z gene was introduced) that the overall load as well as the pattern of liver metastases is strongly controlled by host immune T cells [21]. In this system, CD4 T cells with helper function and CDS T cells with effector function were involved in the antitumor immune response [22], Recently, we observed ef fective immune rejection via synergistic CD4 and CD8 im mune T-cell interaction even in advanced metastasized can cer [23]. In another recent study, we could demonstrate in duction of long-term immunological protection by tumor cell vaccination in immunocompetent but not in immunoincompetent animals.…”

Section: Cytokine Gene Transfected Tumor Cell Vaccinesmentioning

confidence: 99%

Tumor Vaccine Design: Concepts, Mechanisms, and Efficacy Testing

Schirrmacher¹

1995

Int Arch Allergy Immunol

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This paper deals with the design of tumor vaccines for either prophylactic application, such as viral vaccines, or for therapeutic application in cancer patients. It discusses important aspects in the design of vaccines which come from experience in the fields of infectious diseases and autoimmunity. As examples of tumor vaccines which are presently being tested, virus-infected tumor cell vaccines and gene-transfected tumor cell vaccines are further discussed. Such live cell vaccines are compared with oncolysate vaccines or vaccines prepared from purified tumor antigens and adjuvants. Future perspectives of such approaches for biotherapy of cancer are also discussed.

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“…This favourable graft-vs-leukaemia (GvL) effect is often associated with a risk for the development of graft-vs-host (GvH) disease with significant morbidity and mortality (Mackinnon et al, 1995;Slavin et al, 1998). We have established an animal model for the investigation of GvL and GvH reactivity of tumour-immune lymphocytes (Schirrmacher et al, 1995). In situ activated tumour-reactive lymphocytes from the tumour-resistant mouse strain B10.D2 are transferred into 5 Gy irradiated late-stage ESb-MP tumour-bearing DBA/2 mice.…”

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confidence: 99%

“…This leads to complete remission of the primary tumour and to the eradication of metastases. The two strains of mice are identical at the MHC but differ in minor histocompatibility and in Mls antigens (Schirrmacher et al, 1995. The latter represent endogenous viral superantigens (vSAGs) which are encoded by mouse mammary tumour virus proviruses (Mtvs) that are integrated in murine genomes (Beutner et al, 1992).…”

mentioning

confidence: 99%

“…We previously demonstrated that Vb6 + T cells which are transferred with other splenic lymphocytes from the donor strain B10.D2 into tumour-bearing DBA/2 mice are able to break the anti-tumour tolerance and to infiltrate the metastasised organs (Schirrmacher et al, 1995). In the liver, these Vb6 + T cells form close contacts with vSAG7 expressing metastasised tumour cells (vSAG7 + ESb-MP) and with host macrophages in the vicinity of metastases (Müerköster et al, 1998).…”

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confidence: 99%

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Superantigen reactive Vβ6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells

et al. 2002

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The endogenous viral superantigen 7 in DBA/2 mice serves as a target antigen on syngeneic ESb-MP lymphoma cells for allogeneic graft-vs-leukaemia reactive cells. Allogeneic viral superantigen 7 reactive Vb6 + T cells are able to transfer graft-vsleukaemia reactivity and to kill specifically viral superantigen 7 + ESb-MP tumour cells in vitro. Here we elucidate the mechanism of this superantigen specific cell lysis. Already 10 min after co-incubation with in vitro stimulated Vb6 + T cells, viral superantigen 7 + ESb-MP tumour cells show an apoptotic phenotype (Annexin V-positivity, DNA-fragmentation). This extremely rapid type of cell death is not mediated by the death inducing ligands CD95L, TRAIL and TNF but by perforin and granzyme B. Surprisingly, neither mitochondria nor any of the known caspases appear to be involved in this type of tumour cell killing. In contrast, nitric oxide, released by activated macrophages and endothelial cells, induces in the same tumour cells another type of apoptosis which is much slower and involves mitochondria and caspase activation. A synergistic effect between the two different effector mechanisms of superantigen reactive donor cytotoxic T lymphocytes and nitric oxide releasing host macrophages and endothelial cells might explain the effective immune rejection of even advanced metastasised cancer in this graft-vs-leukaemia animal model.

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Effective Immune Rejection of Advanced Metastasized Cancer

Cited by 17 publications

References 0 publications

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Tumor Vaccine Design: Concepts, Mechanisms, and Efficacy Testing

Superantigen reactive Vβ6+ T cells induce perforin/granzyme B mediated caspase-independent apoptosis in tumour cells

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