Stem cell approaches to treat cardiovascular diseases
Professor Philippe Menasche, Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Paris
Stem cell-based therapy is currently tested in several trials of both acute myocardial infarction and chronic heart failure. While the striking efficacy of early revascularization may question the rationale for an additional cell-based therapy in patients with an acute infarction, the situation is dramatically different for chronic heart failure when patients, the number of whom is escalating, have exhausted conventional treatments and are not candidates for more invasive procedures like cardiac transplantation or implantation of a mechanical assist device. The main question then is to determine how experimental data can be translated into clinical practice. To meet this objective, it is critical to more thoroughly decipher the mechanism of action of the transplanted cells and, more specifically, to validate the currently prevailing hypothesis that these cells fail to rebuild a myocardial tissue by themselves but rather act by harnessing endogenous repair pathways. Namely, the confirmation of this mechanism would have three major clinically relevant consequences: (1) the choice of the optimal cell type, based of head-to-head comparisons of the functional effects of secretomes derived from different cell types, although the already available comparisons clearly favor the use of cardiac-committed cells; (2) the optimization of early cell retention and survival, rather than of sustained cell engraftment, so that the cells reside in the target tissue long enough to deliver the factors underpinning their action, and (3) the reliance on banked, fully qualified allogeneic cells, the expected rejection of which should only have to be delayed since a permanent engraftment would no longer be the objective. One step further, the long term objective of cell therapy could be to use the cells as biofactories exclusively exploited for producing factors and then to only administer them to the patient along with controlled release delivery systems. The whole production process, including manufacturing, quality controls, regulation and costs, would then be closer to that of a biological pharmaceutic, thereby raising the hope of a facilitated and thus expended clinical use.
Fine-tuned T cell receptors for cancer immunotherapy
Dr Bent Jakobsen, Adaptimmune Limited, UK
Human tumours are known to express unique antigens; however tumour immune evasion mechanisms often prevent effective naturally occurring anti-tumour immune responses. Adoptive T cell therapy, in which T Cell Receptors are engineered to identify cancer tumour antigens with increased affinity, is emerging as a promising strategy for the treatment of many forms of cancer, including those with historically bleak outcomes.
Dr Jakobsen and colleagues have developed methods to engineer naturally occurring TCRs and enhance their ability to target and bind to cancer peptides thereby enabling a highly targeted immunotherapy. Unlike current antibody based therapies, affinity enhanced TCRs are able to target a larger pool of intracellular antigens presented on the cell surface as short peptides bound to human leukocyte antigen (HLA). This capability significantly increases the breath of targets, particularly as intracellular targets are known to be more closely associated with cancer.
Target identification and validation, together with a broad and robust preclinical safety testing strategy are critical in the development of affinity-enhanced TCRs. Engineering TCRs requires balancing the need for higher affinity to the target peptide with the risk of cross-reactivity, which increases at higher affinities. Safety considerations include both on-target (antigens expression in normal tissues in addition to tumour) and off-tumour toxicity (recognition of other antigens).
NY-ESO-1 is a cancer antigen which is expressed at high frequency (>30%) in a range of cancers including ovarian, prostate, NSCLC, myeloma, bladder, melanoma, oesophageal and breast. Affinity-enhanced TCRs have been developed to target NY-ESO-1. T cells transduced with affinity enhanced TCRs to NY-ESO are currently in clinical trials for synovial sarcoma, multiple myeloma, melanoma, ovarian and oesophageal cancers. Clinical data, to date, demonstrate encouraging rates of clinical responses and an acceptable tolerability profile.
Use of genetically modified T-cells in treatment of cancer
Professor Carl June, University of Pennsylvania, USA
Cell therapies as medicines
Dr Patrick Vallance FMedSci FRS, Government Chief Scientific Adviser and Head of Government Science and Engineering Profession, UK Government
In oncology and in some genetic diseases it is now clear that genetically manipulated cells have the potential to provide long lasting treatment responses. There is also promise in many other disease areas and a growing confidence that advances in cell/gene therapies will provide an important new treatment option beyond small molecules and biopharmaceutical drugs. Unlike the traditional areas of drug discovery and development, most of the early discovery work, construction of the “medicine”, and the clinical experiments are taking place within academic settings. This is opening up a rapidly expanding range of opportunities, but also raises a challenge: how can these treatments be made available more widely? There are questions about production, quality control, short and long term safety, measurement of effect, patient selection and monitoring, regulatory requirements, and costs to the healthcare systems around the world. In this talk I will outline some of the cell and gene therapies that are being worked on at GSK (in rare diseases and cancer) and across industry and discuss the approaches being taken to turn cell treatments into viable therapeutic options that can be used globally.