Stephen Ward

Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.

Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future.

The aim of this study was to determine the prognostic implications of the pretreatment level of Th17 cells compared with regulatory T-cell status in prostate cancer patients receiving active whole cell immunotherapy. Ten-color flow cytometry was used to analyze IL-17-producing CD4(+) T-cells in the peripheral blood of hormone-resistant non-bone metastatic prostate cancer patients prior to immunotherapy with an allogeneic whole-cell vaccine. Surface expression of the chemokine receptors CCR4 and CCR6 was used to further subdivide IL-17-producing cells into subsets with distinct homing properties. The frequency of circulating regulatory T-cells (Tregs), defined as CD3(+)CD4(+)CD127(lo)Foxp3(+)CD25(+) was compared in the same patients. The frequency of CCR4(-)IL-17(+)CD4(+) T-cells prevaccination inversely correlated with time to disease progression (TTP) in 23 prostate cancer patients. Furthermore, responder (R) patients with statistically significant reductions in PSA velocity (PSAV) in response to the immunotherapy (n = 9), showed a Th17 profile similar to healthy male controls and significantly different from non-responder (NR) patients (n = 14) (i.e., those without any significant reduction in PSAV). In contrast, the frequency of Tregs in peripheral blood in PSA-R (n = 11) and -NR (n = 14) patients was similar (but in both cases, significantly higher than in age-matched healthy men). Accordingly, there was no significant correlation between frequency of Tregs and TTP in these late-stage prostate cancer patients undergoing active immunotherapy. These data imply an important role for IL-17-producing helper T-cells in cancer immunology and highlight their potential use as a pretreatment screen to ensure appropriate treatment is offered to hormone-resistant prostate cancer patients.

This re-titled and extensively revised book builds on the success of an established classic text. It also builds on more than thirty five years of successful consulting practice, addressing practical situations that range from major offshore oil development projects to projects limited to replacing a domestic bathroom floor covering. It synthesises this practical experience with a very broad relevant literature.<br/>The target audience includes board level senior managers responsible for project, programme and project portfolio aspects of corporate policy, and their integration with corporate strategy and operations. It includes those charged with implementing projects at all levels, including uncertainty, opportunity and risk management professionals. And it includes aspiring members of these groups.<br/>It shows why current project risk management practice, and related enterprise risk management practice, starts in the wrong place, pursues an inappropriate set of goals, uses the wrong tools, and fails to deliver what is needed.<br/>This book goes beyond current project risk management orthodoxy in a number of ways. One is the use of an ‘uncertainty management’ perspective which transforms the scope of opportunities to enhance corporate performance, a central theme. A second is a ‘whole asset lifecycle’ perspective on all aspects of change management. A third is a holistic integration of quantitative and qualitative uncertainty management processes which clarify opportunity and risk recognising the subjective issues involved. A fourth is showing how uncertainty management and the rest of project management can be integrated, and all aspects of corporate uncertainty, opportunity and risk management can be integrated.<br/>It shows how surprisingly simple approaches can lead to surprisingly powerful insights and results – used in the right place. It also shows why some impressively sophisticated and costly approaches involving common practice tools can create confusion and divert management effort away from what really matters.<br/>Uncertainty management as described in this book is a process driven approach using concepts and tools which replace many common practice risk management ideas. They can be used to make better decisions with less cost, realising more opportunities for less effort, and taking less risk for more reward, to transform corporate performance<br/>