Monoclonal antibody (mAb) therapy has been successfully used for the treatment of B-cell lymphomas and is currently extended for the treatment of multiple myeloma (MM). New developments in MM therapeutics have achieved significant survival gains in patients but the disease still remains incurable. Elotuzumab (HuLuc63), an anti-CS1 monoclonal IgG1 antibody, is believed to induce anti-tumor activity and MM cytotoxicity through antibody dependent cellular cytotoxicity (ADCC) and inhibition of MM cell adhesion to bone marrow stromal cells (BMSCs). Modulations of the Fc glycan composition at the N297 site by selective mutations or afucosylation have been explored as strategies to develop bio-better therapeutics with enhanced ADCC activity. Afucosylated therapeutic antibodies with enhanced ADCC activity have been reported to possess greater efficacy in tumor growth inhibition at lower doses when compared to fucosylated therapeutic antibodies. The N-linked glycosylation pathway in Pichia pastoris has been engineered to produce human-like N-linked glycosylation with uniform afucosylated complex type glycans. The purpose of this study was to compare afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris with fucosylated anti-CS1 mAb expressed in mammalian HEK293 cells through in vitro ADCC and in vivo tumor inhibition models. Our results indicate that Fc glycosylation is critical for in vivo efficacy and afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris shows a better in vivo efficacy in tumor regression when compared to fucosylated anti-CS1 mAb expressed in HEK293 cells. Glycoengineered Pichia pastoris could provide an alternative platform for generating homogeneous afucosylated recombinant antibodies where Fc mediated immune effector function is important for efficacy.
Copyright © 2015 Elsevier B.V. All rights reserved.

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On March 22, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the presentation of scientific data at the Society of Gynecologic Oncology’s 2016 Annual Meeting on Women’s Cancer being held March 19-22, 2016 in San Diego, CA (Press release, Verastem, MAR 22, 2016, View Source;p=RssLanding&cat=news&id=2150260 [SID:1234509826]).

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"The data presented today at SGO 2016 are important because they provide further scientific evidence that chemotherapy can lead to an increase in ovarian cancer stem cells (CSCs), making the tumor more aggressive and resistant to further treatment," said Dr. Jonathan Pachter, Verastem Head of Research. "At Verastem, we believe that our compounds in development may be especially beneficial as therapeutics when used in combination with other agents, including current and emerging standard of care treatments and immunotherapies, and have the potential to create a more durable clinical response. We look forward to the initiation of a Phase 1/1b clinical trial of the combination of VS-6063 and avelumab, in collaboration with Pfizer and Merck KGaA, for patients with ovarian cancer in the second half of this year."

Verastem, and its collaborators, are presenting these scientific data in support of Verastem’s development programs which utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. The Company’s most advanced clinical product candidates are the Focal Adhesion Kinase inhibitors, VS-6063 and VS-4718, and the dual PI3K/mTOR inhibitor, VS-5584. Research on the FAK and PI3K/mTOR signaling pathways has revealed critical roles for each in cancer stem cell survival and disease progression.

Details for the SGO presentation are as follows:

Oral Presentation

Title: Standard chemotherapy for ovarian cancer increases expression of cancer stem cell biomarkers which is predictive of survival

Session: Scientific Plenary IX: Ovary

Date and time: Tuesday, March 22, 2016 at 8:30 – 10:05 AM

Location: Hall A

Summary: In ovarian cancer, certain molecular mediators are thought to possess CSC characteristics and the presence of these mediators, which is linked to earlier recurrence and shorter survival, is possibly brought about by chemotherapy. The aim of this study was to explore the effect of chemotherapy on ovarian cancer stem-like mediators and to determine if there was a relationship to survival. Researchers obtained matched pre- and post-chemotherapy tumor specimens from stage IIIC/IV ovarian cancer patients (n=22) who all underwent neoadjuvant chemotherapy with interval debulking surgery. Samples were then analyzed for expression of 27 CSC markers. CSC markers were then validated in tumorsphere model and in vivo tumor initiating studies.

All 27 CSC markers demonstrated a mean increase in gene expression after exposure to chemotherapy. A 3-fold or greater increase in gene expression after exposure to chemotherapy was seen in 8 of 27 (30%) markers: ABCG2, ALDH1A1, CTGF, DPP4, MYC, CD133, SOX2, and POSTN. Three markers demonstrated a significant fold increase that correlated with platinum resistance: POSTN (4.1-fold), ALDH1A1 (5-fold), and SOX2 (14.5-fold). When implanted into immunocompromised mice, SOX2(hi) cells exhibited significantly higher levels of tumorsphere forming potential than SOX2(lo) cells and were more tumorigenic. High gene expression in these 3 markers demonstrated shorter progression free survival, compared to low expression. These results support the further investigation of directed agents to inhibit these CSC markers to potentially extend survival for patients with ovarian cancer.

A copy of the oral presentation will be available at http://bit.ly/R3M6wc

High hydrostatic pressure (HHP) has been shown to induce immunogenic cell death of cancer cells, facilitating their uptake by dendritic cells (DC) and subsequent presentation of tumor antigens. In the present study, we demonstrated immunogenicity of the HHP-treated tumor cells in mice. HHP was able to induce immunogenic cell death of both TC-1 and TRAMP-C2 tumor cells, representing murine models for human papilloma virus-associated tumors and prostate cancer, respectively. HHP-treated cells induced stronger immune responses in mice immunized with these tumor cells, documented by higher spleen cell cytotoxicity and increased IFNγ production as compared to irradiated tumor cells, accompanied by suppression of tumor growth in vivo in the case of TC-1 tumors, but not TRAMP-C2 tumors. Furthermore, HHP-treated cells were used for DC-based vaccine antigen pulsing. DC co-cultured with HHP-treated tumor cells and matured by a TLR 9 agonist exhibited higher cell surface expression of maturation markers and production of IL-12 and other cytokines, as compared to the DC pulsed with irradiated tumor cells. Immunization with DC cell-based vaccines pulsed with HHP-treated tumor cells induced high immune responses, detected by increased spleen cell cytotoxicity and elevated IFNγ production. The DC-based vaccine pulsed with HHP-treated tumor cells combined with docetaxel chemotherapy significantly inhibited growth of both TC-1 and TRAMP-C2 tumors. Our results indicate that DC-based vaccines pulsed with HHP-inactivated tumor cells can be a suitable tool for chemoimmunotherapy, particularly with regard to the findings that poorly immunogenic TRAMP-C2 tumors were susceptible to this treatment modality.

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We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases.
The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays. We compared survival of mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer (NSCLC) brain metastases that were treated with vehicle, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy.
Cancer cells and tumor-associated endothelial cells expressed activated forms of AKT and MAPK in vehicle- and paclitaxel-treated groups in both metastasis models, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins Bcl2L1, Gsta5, and Twist1 that localized to cancer cells and tumor-associated endothelial cells in vehicle- and paclitaxel-treated tumors were suppressed by macitentan. Macitentan or paclitaxel alone had no effect on survival. However, when macitentan was combined with paclitaxel, we noted a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells. Moreover, macitentan plus paclitaxel therapy significantly increased overall survival by producing complete responses in 35 of 35 mice harboring brain metastases.
Dual antagonism of ETAR and ETBR signaling sensitizes experimental brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.
© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

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Monoclonal antibodies (mAbs) have revolutionized the diagnosis and treatment of many human diseases and the application of combinations of mAbs has demonstrated improved therapeutic activity in both preclinical and clinical testing. Combinations of antibodies have several advantages such as the capacities to target multiple and mutating antigens in complex pathogens and to engage varied epitopes on multiple disease-related antigens (e.g. receptors) to overcome heterogeneity and plasticity. Oligoclonal antibodies are an emerging therapeutic format in which a novel antibody combination is developed as a single drug product. Here, we will provide historical context on the use of oligoclonal antibodies in oncology and infectious diseases and will highlight practical considerations related to their preclinical and clinical development programs.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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