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

Witthauer, Juliane; Schlereth, Bernd; Brischwein, Klaus; Winter, Hauke; Funke, I.; Jauch, Karl‐Walter; Baeuerle, Patrick A.; Mayer, Barbara

doi:10.1007/s10549-008-0185-0

Cited by 18 publications

(19 citation statements)

References 48 publications

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“…The influence of 4-1BB blockade on direct and Rituximabinduced lysis of CLL cells by autologous NK cells was determined by FACS as previously described [43]. In brief, PBMCs of CLL patients were incubated with or without Rituximab in the presence or absence of blocking 4-1BB antibodies or isotype control.…”

Section: Facs-based Analysis Of Cll Cell Lysismentioning

confidence: 99%

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

et al. 2011

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NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.

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Section: Facs-based Analysis Of Cll Cell Lysismentioning

confidence: 99%

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

et al. 2011

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“…Clinical studies are ongoing in adult and pediatric patients with relapsed/refractory B-precursor ALL, adults with persistent minimal residual disease B-precursor ALL, and adults with relapsed diffuse large B cell lymphoma (DLBCL), (ClinicalTrials.gov identifiers NCT01471782, NCT01207388, NCT01466179, and NCT01741792). Solitomab targets EpCAM on both epithelial carcinomas as well as tumor-initiating cells, [50][51][52] and has entered a Phase I trial in patients with solid tumors that express EpCAM (ClinicalTrials.gov identifier NCT00635596). AMG 212 is being tested in a Phase I trial in patients with castration-resistant prostate adenocarcinoma (ClinicalTrials.gov identifier NCT01723475).…”

Section: Introductionmentioning

confidence: 99%

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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A Hammond (2014) CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas, mAbs, 6:6, 1571-1584, DOI: 10.4161/19420862.2014 To link to this article: https://doi.org/10. 4161/19420862.2014 Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE Ò antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

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“…Mouse models have shown high levels of activity of BiTE antibodies targeted against EphA2 and CD19 (Dreier et al, 2003;Schlereth et al, 2006;Brischwein et al, 2006;Offner et al, 2006;Hammond et al, 2007). Witthauer et al (2008) reported that a BiTE targeting EpCAM could lead to T-cell-mediated killing of breast cancer cells in pleural effusions. Recently, Bargou et al (2008) reported clinical activity and a safety profile suitable for continued development of the BiTE antibody blinatumomab (also called MT103/MEDI-538) with dual specificity for CD19 and CD3 in a study of non-Hodgkin's B-cell lymphoma patients who had experienced relapse after standard therapies.…”

mentioning

confidence: 99%

Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody

Osada

Hsu

Hammond³

et al. 2009

Br J Cancer

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BACKGROUND: Novel technologies to redirect T-cell killing against cancer cells are emerging. We hypothesised that metastatic human colorectal cancer (CRC) previously treated with conventional chemotherapy would be sensitive to T-cell killing mediated by carcinoembryonic antigen (CEA)/CD3-bispecific T-cell-engaging BiTE antibody (MEDI-565). METHODS: We analysed proliferation and lysis of CEA-positive (CEA þ ) CRC specimens that had survived previous systemic chemotherapy and biologic therapy to determine whether they could be killed by patient T cells engaged by MEDI-565 in vitro. RESULTS: At low concentrations (0.1 -1 ng ml À1 ), MEDI-565 þ T cells caused reduced proliferation and enhanced apoptosis of CEA þ human CRC specimens. High levels of soluble CEA did not impair killing by redirected T cells and there was no increase in resistance to T-cell killing despite multiple rounds of exposure. CONCLUSIONS: This study shows for the first time that metastatic CRC specimens derived from patients previously treated with conventional chemotherapy can be lysed by patient T cells. Clinical testing of cancer immunotherapies, such as MEDI-565 that result in exposure of tumours to large numbers of T cells, is warranted.

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

Cited by 18 publications

References 48 publications

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody

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