A double-blind, placebo-controlled, randomized, phase 2 study to evaluate the efficacy and safety of switch maintenance therapy with the anti-TA-MUC1 antibody PankoMab-GEX after chemotherapy in patients with recurrent epithelial ovarian carcinoma

Ledermann, JA; Sehouli, Jalid; Żurawski, Bogdan; Raspagliesi, Francesco; Giorgi, Ugo De; Banerjee, Susana; Arija, J.A. Arranz; Marín, Mar; Lisyanskaya, Alla Sergeevna; Póka, Ròbert; Mihutiu, Simona; Markowska, Janina; Cebotaru, C.; Herráez, A. Casado; Colombo, Nicoletta; Коваленко, Н. В.; Kutarska, E.; Hall, Marcia; Belli, Riccardo; Zurlo, Alfredo

doi:10.1093/annonc/mdx440.035

Cited by 12 publications

(14 citation statements)

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“…A tendency of reduced survival was also shown for patients with membranous expression of TA-MUC1 [14]. Staining of TA-MUC1 was successfully performed with Gatipotuzumab, a therapeutic antibody which showed safety and tolerability but no clinical benefit in clinical trials so far [26,27]. 134 cases (85.9%) showed a positive TA-MUC1 expression with median IRS = 8 (total range 0-12) (Supplementary file Figure S6).…”

Section: High Mdr1+ Immune Cell Infiltration Is Associated With Worsementioning

confidence: 99%

M2 Macrophages Infiltrating Epithelial Ovarian Cancer Express MDR1: A Feature That May Account for the Poor Prognosis

Badmann

Heublein

Mayr

et al. 2020

Cells

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Multi drug resistance protein 1 (MDR1) expression on tumor cells has been widely investigated in context of drug resistance. However, the role of MDR1 on the immune cell infiltrate of solid tumors remains unknown. The aim of this study was to analyze the prognostic significance of a MDR1+ immune cell infiltrate in epithelial ovarian cancer (EOC) and to identify the MDR1+ leucocyte subpopulation. MDR1 expression was analyzed by immunohistochemistry in 156 EOC samples. In addition to MDR1+ cancer cells, we detected a MDR1+ leucocyte infiltrate (high infiltrate >4 leucocytes per field of view). Correlations and survival analyses were calculated. To identify immune cell subpopulations immunofluorescence double staining was performed. The MDR1+ leucocyte infiltrate was associated with human epidermal growth factor receptor 2 (HER2) (cc = 0.258, p = 0.005) and tumor-associated mucin 1 (TA-MUC1) (cc = 0.202, p = 0.022) expression on cancer cells. A high MDR1+ leucocyte infiltrate was associated with impaired survival, especially in patients whose carcinoma showed either serous histology (median OS 28.80 vs. 50.64 months, p = 0.027, n = 91) or TA-MUC1 expression (median OS 30.60 vs. 63.36 months, p = 0.015, n = 110). Similar findings for PFS suggest an influence of MDR1+ immune cells on the development of chemoresistance. A Cox regression analysis confirmed the independency of a high MDR1+ leucocyte infiltrate as prognostic factor. M2 macrophages were identified as main part of the MDR1+ leucocyte infiltrate expressing MDR1 as well as the M2 marker CD163 and the pan-macrophage marker CD68. Infiltration of MDR1+ leucocytes, mostly M2 macrophages, is associated with poor prognosis of EOC patients. Further understanding of the interaction of M2 macrophages, MDR1 and TA-MUC1 appears to be a key aspect to overcome chemoresistance in ovarian cancer.

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Section: High Mdr1+ Immune Cell Infiltration Is Associated With Worsementioning

confidence: 99%

M2 Macrophages Infiltrating Epithelial Ovarian Cancer Express MDR1: A Feature That May Account for the Poor Prognosis

Badmann

Heublein

Mayr

et al. 2020

Cells

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“…Tumor control activity of the antibody seemed to be particularly high in a patient with highly pretreated OC [8]. A second study evaluated Gatipotuzumab as a maintenance therapy in OC [9]. This randomized, placebo controlled phase 2 study—though not fully published yet—reported that Gatipotuzumab did not alter outcome of patients when applied as a maintenance therapy for relapsed OC [9].…”

Section: Introductionmentioning

confidence: 99%

Potential Interplay of the Gatipotuzumab Epitope TA-MUC1 and Estrogen Receptors in Ovarian Cancer

Heublein

Page

Mayr

et al. 2019

IJMS

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Anti-tumor efficacy of Gatipotuzumab, a therapeutic antibody targeting Tumor-Associated Mucin-1 (TA-MUC1), in relapsed ovarian cancer (OC) appeared to be rather heterogeneous. Whether adding a second anti-neoplastic drug may augment response towards Gatipotuzumab, has not been elucidated so far. Since it is known that anti-MUC1 antibodies may alter estrogen receptor activity in breast cancer, this potential interplay was investigated in OC. The correlation between TA-MUC1, estrogen receptors (ERs) and another 12 protein markers as well as their correlation with clinico-pathological parameters in 138 ovarian cancer cases was studied. Finally, Gatipotuzumab and 4-Hydroxy-TTamoxifen (4-OHT) as well as the combination of both was tested for its impact on cell viability in COV318, OV-90, OVCAR-3, and SKOV-3 cells. A strong positive correlation between TA-MUC1 and ERs was detected in OC tissue. Those cases missing ERs but staining positive for TA-MUC1 had significantly reduced overall survival. The combination of 4-OHT and Gatipotuzumab significantly reduced cell viability and was more effective than treatment with Gatipotuzumab alone. Co-stimulation with Gatipotuzumab enhanced the efficacy of 4-OHT in OVCAR-3 and SKOV-3. The data suggest an interplay of TA-MUC1 and ERs in OC. Whether the combination of Gatipotuzumab and TTamoxifen may enhance efficacy of either of the two drugs in vivo, or may even translate into a clinically relevant benefit over the respective monotherapies, remains to be investigated.

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“…73 74 Yet, the subsequent phase II trial did not to show any outcome advantage. 75 Another high-affinity mAb named 5E5 targets the aberrant Tn glycoform of mucin MUC1 and has been shown to lyse breast cancer cells via both ADCC and CDC. 76 Glycosylation is also under investigation to be used as tool for the enhancement of ADCC and CDC immune response mechanisms.…”

Section: Modalities To Target Tumor-associated Glycans Adcc and Cdcmentioning

confidence: 99%

Section: Modalities To Target Tumor-associated Glycansmentioning

confidence: 99%

Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

Mantuano

Natoli

Zippelius

et al. 2020

J Immunother Cancer

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During oncogenesis, tumor cells present specific carbohydrate chains that are new targets for cancer immunotherapy. Whereas these tumor-associated carbohydrates (TACA) can be targeted with antibodies and vaccination approaches, TACA including sialic acid-containing glycans are able to inhibit anticancer immune responses by engagement of immune receptors on leukocytes. A family of immune-modulating receptors are sialic acid-binding Siglec receptors that have been recently described to inhibit antitumor activity mediated by myeloid cells, natural killer cells and T cells. Other TACA-binding receptors including selectins have been linked to cancer progression. Recent studies have shown that glycan-lectin interactions can be targeted to improve cancer immunotherapy. For example, interactions between the immune checkpoint T cell immunoglobulin and mucin-domain containing-3 and the lectin galectin-9 are targeted in clinical trials. In addition, an antibody against the lectin Siglec-15 is being tested in an early clinical trial. In this review, we summarize the previous and current efforts to target TACA and to inhibit inhibitory immune receptors binding to TACA including the Siglec-sialoglycan axis.

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A double-blind, placebo-controlled, randomized, phase 2 study to evaluate the efficacy and safety of switch maintenance therapy with the anti-TA-MUC1 antibody PankoMab-GEX after chemotherapy in patients with recurrent epithelial ovarian carcinoma

Cited by 12 publications

References 0 publications

M2 Macrophages Infiltrating Epithelial Ovarian Cancer Express MDR1: A Feature That May Account for the Poor Prognosis

M2 Macrophages Infiltrating Epithelial Ovarian Cancer Express MDR1: A Feature That May Account for the Poor Prognosis

Potential Interplay of the Gatipotuzumab Epitope TA-MUC1 and Estrogen Receptors in Ovarian Cancer

Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy

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