Antibody-targeted superantigens are potent inducers of tumor-infiltrating T lymphocytes in vivo.

Dohlsten, Mikael; Hansson, Johan; Ohlsson, Lennart; Litton, Mark J.; Kalland, Terje

doi:10.1073/pnas.92.21.9791

Cited by 59 publications

(48 citation statements)

References 16 publications

(8 reference statements)

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“…Targeting of superantigens has previously been described for colon cancer therapy (Dohlsten et al, 1994(Dohlsten et al, , 1995b. This therapy leads to infiltration of T-cells in the tumour tissue (Dohlsten et al, 1995a, Litton et al, 1996. Superantigen therapy stimulates both CD4+ and CD8+ T-cells (Dohlsten et al, 1995a) that have potent cytotoxic properties to directly kill target cells, but secondary effects such as cytokine secretion and recruitment of other effector cells may be of even higher importance for successful therapy.…”

Section: Discussionmentioning

confidence: 99%

“…This therapy leads to infiltration of T-cells in the tumour tissue (Dohlsten et al, 1995a, Litton et al, 1996. Superantigen therapy stimulates both CD4+ and CD8+ T-cells (Dohlsten et al, 1995a) that have potent cytotoxic properties to directly kill target cells, but secondary effects such as cytokine secretion and recruitment of other effector cells may be of even higher importance for successful therapy. These secondary events are important to kill sub-populations of cancer cells not expressing the antigen.…”

Section: Discussionmentioning

confidence: 99%

“…To potentiate the effects of monoclonal antibodies, the use of fusions with superantigens, which are of bacterial or viral origin and activate T cells by linking the T cell receptor to MHC class II on antigen presenting cells (reviewed by Johnson et al, 1992), have previously been described by us (Dohlsten et al, 1994;Brodin et al, 1998). Thereby, large amounts of cytotoxic and cytokine producing T-cells can be targeted to destroy and initiate a powerful T cell attack against tumour cells in vivo (Dohlsten et al, 1994(Dohlsten et al, , 1995a. Most studies of antibody targeted superantigens, e.g.…”

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Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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Summary Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA D227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a K d of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA D227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA D227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10 -10 M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA D227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA D227A . Thus, 5T4FabV13-SEA D227A has highly attractive properties for therapy of human NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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“…SAg have, in contrast to conventional peptide antigens, a unique capacity of activating both subsets of Tcells (Herrmann et al, 1990;Dohlsten et al, 1990). In fact, it has been demonstrated previously that both CD4 + and CD8 + T-cells are recruited to the tumour area in response to antibody-targeted SAg tumour therapy (Dohlsten et al, 1995a;Litton et al, 1996Litton et al, , 1997Rosendahl et al, 1998a). However, both subsets have the potential to regulate helper activity as well as cytotoxic functions.…”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated that IFN-γ-producing tumour-infiltrating lymphocytes (TIL) infiltrate the tumour area in immunocompetent animals given four repeated injections of Fab-SEA (Dohlsten et al, 1995a). In order to determine which T-cell subset was required to obtain maximal infiltration of TIL, CD4 KO and CD8 KO mice were treated with Fab-SEA, and the cell infiltration as well as the IFN-γ production was monitored.…”

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confidence: 99%

The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens

et al. 1999

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Summary To target T-cells to the tumour area we created a recombinant protein of the bacterial superantigen (SAg) Staphylococcal enterotoxin A (SEA) and the Fab-fragment of a tumour-reactive antibody. This antibody-targeted SAg immunotherapy therapy has been shown to be highly efficient, eliminating > 95% of the pulmonary metastasis in mice carrying established melanoma micrometastases. Earlier studies demonstrated that elimination of the C215-expressing B16-melanoma lung metastasis was dependent on interferon (IFN)-γ release and expression of perforin. In the present study, therapeutic effector functions were analysed both locally at the tumour site and systemically in the spleen. In order to elucidate the role of each T-cell subset during Fab-SEA therapy, CD4 knock-out (KO) and CD8 KO mice were used. Tumour size reduction was statistically significant in Fab-SEA-based tumour therapy in both types of T-cell-deficient mice compared to wildtype mice. CD4 KO mice displayed a drastic reduction in the number of tumour-infiltrating macrophages and CD8 + T-cells. Therapy-induced accumulation of perforin-containing cells at the tumour site was significantly impaired in CD8 KO mice, and marginally in CD4 KO mice. Moreover, CD4 KO mice failed to produce substantial amounts of the tumour suppressive cytokine IFN-γ. This is in sharp contrast to normal mice where a massive local release was recorded. CD8 KO mice displayed a spontaneous production of interleukin (IL)-4 and IL-10 locally in the tumour. Neither normal nor CD4 KO mice produced detectable levels of these Th-2-associated cytokines. The high level of IL-10 was demonstrated to inhibit Fab-SEA tumour therapy, since the therapeutic efficacy was significantly higher in IL-10 KO mice. These results illustrate the importance of a finely tuned cellular collaboration to regulate the various phases of an efficient anti-tumour immune response.

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Immune response during tumor therapy with antibody-superantigen fusion proteins

Rosendahl¹,

Hansson²,

Sundstedt³

et al. 1996

Int. J. Cancer

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To engineer superantigens (SAg) to express tumor reactivity, we genetically fused the Fab-part of the tumor-reactive MAb C215 and the bacterial SAg staphylococcal enterotoxin A (SEA). Treatment of mice carrying established lung micrometastases of the C215-transfected syngeneic B16 melanoma with 3-4 daily injections of C215Fab-SEA resulted in strong antitumor effects, while only moderate effects were seen when treatment was given every 4th day (intermittent treatment). High serum levels of IL-2, TNF-alpha, IFN-gamma and strong induction of CTLs (cytotoxic T lymphocytes) were noted after priming with the fusion protein. T cells responded well to 3 daily injections of C215Fab-SEA and then gradually entered a hyporesponsive state, characterized by a reduced ability to produce IL-2, TNF-alpha and IFN-gamma and failure to mediate cytotoxicity in vitro. Intermittent treatment was characterized by increased levels of IL-10, concomitant with accentuated loss of IL-2, TNF-alpha and IFN-gamma production. A 10-fold increase in SEA-reactive TCR V(beta)3+ CD4+ cells was observed in the spleen, while a loss of TCR V(beta)3+ CD8+ and V(beta)11+ CD8+ cells was noted. This is in striking contrast to injections of native SEA which induced a marked deletion of TCR V(beta)3+ CD4+ T cells, but not of CD8+ cells. Recovery of the TH1 cytokine profile occurred within 1-2 weeks, while restoration of cytotoxicity required several months and correlated with recovery of TCR V(beta)3+ CD8+ and TCR V(beta)11+ CD8+ T cells. These results show that the temporal relationship of SAg stimulations dictates the cytokine profile. Moreover, different mechanisms appear to regulate hyporesponsiveness in CD4+ and CD8+ T cells.

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Antibody-targeted superantigens are potent inducers of tumor-infiltrating T lymphocytes in vivo.

Cited by 59 publications

References 16 publications

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens

Immune response during tumor therapy with antibody-superantigen fusion proteins

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