Efficient tumor cell lysis by autologous, tumor‐resident T lymphocytes in primary ovarian cancer samples by an EP‐CAM‐/CD3‐bispecific antibody

Wimberger, Pauline; Xiang, Wei; Mayr, Doris; Diebold, Joachim; Dreier, Torsten; Baeuerle, Patrick A.

doi:10.1002/ijc.11056

Cited by 28 publications

(22 citation statements)

References 41 publications

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“…This lysis was highly specific, dependent on the dose of MT110, similar as shown for the anti-Ep-CAM treatment of primary ovarian cells [44]. In addition, specific lysis appeared to be highest in the presence of either a favourable E:T ratio or granzyme B-expressing CD8 ?…”

Section: Discussionsupporting

confidence: 68%

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Witthauer

Schlereth

Brischwein

et al. 2008

Breast Cancer Res Treat

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In the present study, the efficacy of a new drug, i.e. the bispecific single-chain antibody MT110 targeting the epithelial antigen EpCAM and the T-cell antigen CD3 was tested ex vivo in malignant pleural effusions (MPEs). EpCAM ? epithelial cells were found in 78% of the MPEs (n = 18). Ex vivo treatment of seven MPEs resulted in a dose-dependent specific lysis of 37 ± 27% (±SD) EpCAM ? cells with 10 ng/ml (P = 0.03) and 57 ± 29.5% EpCAM ? cells with 1,000 ng/ml MT110 (P = 0.016) after 72 h. As a prerequisite for redirected lysis, stimulation of he autologous CD4 ? and CD8 ? cells in MPE by 1,000 ng/ml MT110 resulted in 21 ± 17% CD4 ? /CD25 ? and 29.4 ± 22% CD8 ? /CD25 ? cells (P = 0.016, respectively) after 72 h. This was confirmed by a 22-fold release of TNF-a and 230-fold release of IFN-c (1,000 ng/ml, 48 h, P = 0.03, respectively). Thus, relapsed breast cancer patients resistant to standard treatment might benefit from targeted therapy using MT110.Keywords Malignant pleural effusion Á Breast cancer Á Bispecific antibody Á EpCAM Á CD3 Á MT110 Á Ex vivo therapy

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Section: Discussionsupporting

confidence: 68%

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Witthauer

Schlereth

Brischwein

et al. 2008

Breast Cancer Res Treat

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“…The particular properties of bscCD19xCD3 and related BiTEs [19][20][21] may also rely on the use of flexibly linked single-chain variable fragments (scFv) that are arranged in tandem. The small antibody fragments joined by a short linker will allow for a much closer approximation of opposing cells than is possible with larger bispecific formats such as quadroma antibodies.…”

Section: Discussionmentioning

confidence: 99%

Serial killing of tumor cells by cytotoxic T cells redirected with a CD19‐/CD3‐bispecific single‐chain antibody construct

Hoffmann

Hofmeister

Brischwein

et al. 2005

Intl Journal of Cancer

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298

231

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Certain bispecific antibodies exhibit an extraordinary potency and efficacy for target cell lysis by eliciting a polyclonal T-cell response. One example is a CD19-/CD3-bispecific single-chain antibody construct (bscCD19xCD3), which at femtomolar concentrations can redirect cytotoxic T cells to eliminate human B lymphocytes, B lymphoma cell lines and patient-derived malignant B cells. Here we have further explored the basis for this high potency. Using video-assisted microscopy, bscCD19xCD3 was found to alter the motility and activity of T cells from a scanning to a killing mode. Individual T cells could eliminate multiple target cells within a 9 hr time period, resulting in nuclear fragmentation and membrane blebbing of target cells. Complete target cell elimination was observed within 24 hr at effector-to-target cell ratios as low as 1:5. Under optimal conditions, cell killing started within minutes after addition of bscCD19xCD3, suggesting that the rate of serial killing was mostly determined by T-cell movement and target cell scanning and lysis. At all times, T cells remained highly motile, and no clusters of T and target cells were induced by the bispecific antibody. Bystanding target-negative cells were not detectably affected. Repeated target cell lysis by bscCD19xCD3-activated T cells increased the proportion of CD19/CD3 double-positive T cells, which was most likely a consequence of transfer of CD19 from B to T cells during cytolytic synapse formation. To our knowledge, this is the first study showing that a bispecific antibody can sustain multiple rounds of target cell lysis by T cells. ' 2005 Wiley-Liss, Inc.

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“…Finally, the EGP-2 is a 40 kDa cell adhesion molecule also known as Ep-CAM or the pancarcinomaassociated antigen 17-1A. 23 Recently, the evidences showed EGP-2 is expressed as a stable transmembrane protein at high levels on the surface of most carcinomas, including the breast, 65,66 ovary, 67 colon, 68 and lung cancers. 69 However, expression of EGP-2 has not yet been reported in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of tumor-specific promoter activities in melanoma

Makhija

Nettelbeck

et al. 2005

Gene Ther

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Gene therapy is a novel therapy for melanoma. To date, however, there is still no powerful tumor specific promoter (TSP) to restrict the transgene expression in melanoma cells. In order to define a useful TSP for targeting in the context of melanoma gene therapy, four promoters, the cyclooxygenase-2 (Cox-2), a-chemokine SDF-1 receptor (CXCR4), epithelial glycoprotein 2 (EGP-2), and survivin, were tested in both established melanoma cell lines and primary melanoma cells. We employed recombinant adenoviral vectors (reAds) each with a candidate TSP (the Cox-2, CXCR4, EGP-2, or survivin), a reporter luciferase gene, and a poly-A signal, all of which were inserted into the E1-deleted region. A reAdGL3Bcytomegalovirus (CMV), containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity. Luciferase activity was measured in multiple tumor cell lines and two primary melanoma cell cultures after infection with reAds. Human epithelial melanocytes, HEM, were used as normal control. In contrast to three other promoters, the survivin promoter exhibited the highest activities within both melanoma cell lines and primary melanoma cells, but not in HEMs. Additionally, the survivin promoter exhibited very low activities in major mouse organs including the liver, in vivo. EGP-2 is not active in melanoma; messenger RNA expressions were correlated to promoter activities both in melanoma cell lines and primary cell cultures. Thus, these data suggest that the survivin promoter achieved a 'tumor-on/ liver-off' profile, and thus represents a potentially useful tumor-specific promoter with applications for transcriptional targeting of Ad vector-based cancer gene therapy or oncolysis to melanoma. Gene Therapy (2005) 12, 330-338.

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Efficient tumor cell lysis by autologous, tumor‐resident T lymphocytes in primary ovarian cancer samples by an EP‐CAM‐/CD3‐bispecific antibody

Cited by 28 publications

References 41 publications

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Serial killing of tumor cells by cytotoxic T cells redirected with a CD19‐/CD3‐bispecific single‐chain antibody construct

Evaluation of tumor-specific promoter activities in melanoma

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