Validation of a humanized anti-EGFR variant III chimeric antigen receptor for a Phase I trial of CART-EGFRvIII in glioblastoma

Chimeric antigen receptors (CARs) are synthetic molecules designed to re-direct T cells to specific antigens; CAR-modified T cells can mediate long-term durable remissions in B cell malignancies, but expanding this platform to solid tumors requires the discovery of novel surface targets with limited expression in normal tissues. The variant III mutation of the epidermal growth factor receptor (EGFR variant III) results from an in-frame deletion of a portion of the extracellular domain. In glioblastoma, the EGFRvIII mutation is oncogenic, portends a poor prognosis, and is thought to be enriched in glioblastoma stem cells. However, because the neoepitope of EGFR variant III is based on a small peptide sequence, an antibody or single-chain variable fragment (scFv) directed to this epitope must be rigorously tested to confirm lack of cross-reactivity to the ubiquitously expressed wild-type EGFR. We chose a vector backbone encoding a second generation CAR based on efficacy of a murine scFv-based CAR in a xenograft model of glioblastoma. Next, we generated a panel of humanized scFv’s and tested their specificity and function as soluble proteins and in the form of CAR-transduced T cells; a low affinity scFv was chosen based on its specificity for EGFR variant III over wild type EGFR. The lead candidate scFv was tested in vitro for its ability to direct CAR-transduced T cells to specifically lyse, proliferate, and secrete cytokines in response to antigen-bearing targets. We further evaluated the specificity of the lead candidate CAR in vitro against EGFR expressing keratinocytes and in vivo in immunodeficient mice grafted with normal human skin; a cetuximab-based CAR served as a positive control. EGFRvIII-directed CAR-T cells were also able to control tumor growth in xenogeneic subcutaneous and orthotopic models of human EGFR variant III+ glioblastoma. We have designed a phase I clinical study of CAR T cells transduced with humanized scFv directed to EGFR variant III in patients with either residual or recurrent glioblastoma (NCT02209376)

Corporate Governance and Corporate Social Responsibility Disclosures: Evidence from an Emerging Economy

We examine the relationship between corporate governance and the extent of corporate social responsibility (CSR) disclosures in the annual reports of Bangladeshi companies. A legitimacy theory framework is adopted to understand the extent to which corporate governance characteristics, such as managerial ownership, public ownership, foreign ownership, board independence, CEO duality and presence of audit committee influence organisational response to various stakeholder groups. Our results suggest that although CSR disclosures generally have a negative association with managerial ownership, such relationship becomes significant and positive for export-oriented industries. We also find public ownership, foreign ownership, board independence and presence of audit committee to have positive significant impacts on CSR disclosures. However, we fail to find any significant impact of CEO duality. Thus, our results suggest that pressures exerted by external stakeholder groups and corporate governance mechanisms involving independent outsiders may allay some concerns relating to family influence on CSR disclosure practices. Overall, our study implies that corporate governance attributes play a vital role in ensuring organisational legitimacy through CSR disclosures. The findings of our study should be of interest to regulators and policy makers in countries which share similar corporate ownership and regulatory structures.<br /

Coalitions and public action in the reshaping of corporate responsibility: the case of the retail banking industry

This paper addresses the question of whether and how public action via civil society and/or government can meaningfully shape industry-wide corporate responsibility (ICR) behaviour. We explore how, in principle, ICR can come about and what conditions might be effective in promoting more ethical behaviour. We propose a framework to understand attempts to develop more responsible behaviour at an industry level through processes of negotiation and coalition building. We suggest that any attempt to meaningfully influence ICR would require stakeholders to possess both power and legitimacy; moreover, magnitude and urgency of the issue at stake may affect the ability to influence ICR. The framework is applied to the retail banking industry, focusing on post-crisis experiences in two countries—Spain and the UK—where there has been considerable pressure on the retail banking industry by civil society and/or government to change behaviours, especially to abandon unethical practices. We illustrate in this paper how corporate responsibility at the sector level in retail banking is the product of context-specific processes of negotiation between civil society and public authorities, on behalf of customers and other stakeholders, drawing on legal and other institutions to influence industry behaviour