The Early Years

Policy concentration on the early years is of vital importance for the wellbeing of children now and for their future health outcomes and life chances. Evidence-based research points to the need for a focus that is properly holistic and to precipitate intervention to promote a healthy diet, regular patterns of activity and rest and give children the best start in life. In 2005, The United Nations Committee on the Rights of the Child (General Comment No. 7) acknowledged the need for a fresh strategy, pinpointing research findings indicating that a failure to prioritise early years’ welfare exposes children to the ills of ‘malnutrition, disease, poverty, neglect, social exclusion and a range of other adversities.’ Professor Dame Sally Davies, Chief Medical Officer of the United Kingdom, considers that robust early years’ policies make both social and economic sense: ‘Too many children and young people do not have the start in life they need, leading to high costs for society, and too many affected lives’ (Forward to ‘The 1001 Critical Days’, June 16th 2014). This observation is significant because there remains much to do. In 2012, the NSPCC reviewed the United Kingdom policy scenario for babies and very young children and concluded that identifiable advances in maternity and early years’ provision did not detract from the fact that: ‘babies are still particularly vulnerable’ and ‘their rights are not always recognised or realised’. (‘All Babies Count – But what about their rights?’ Sally Knock and Lorriann Robinson, January 2012). Knock and Robinson highlight glaring gaps of support and provision – especially in maternity services whereby the fostering of a strong parent-child bond is invariably sacrificed to a concentration upon purely medical practicalities such as labour, birth and the immunisation programme. The All Party Group on a Fit and Healthy Childhood aims, in this report, to offer the incoming Government recommendations for an early years’ strategy that are credible, feasible and evidence-based and will enable the United Kingdom to set the standard in a crucial policy field both at home and abroad. In defining ‘early childhood’, we follow the example of The United Nations (2005) Convention on the Right of the Child by examining the period of 0-8 including, as it does, the vital transition phase from pre-school to primary school. We consider the antenatal period and maternal physical and mental health, methods of feeding the newborn, parental support services both hospital and home-based and infant nutrition and socioeconomic factors that may impact upon the health and wellbeing of young children. The report examines the optimum balance between sleep, rest and activity, the need for freely-chosen play, safeguarding measures and the importance of respecting cultural diversity in all early years’ settings. Above all, we analyse the relationship between young families and the professionals whose role it is to ensure that babies have the very best start in life, supported by parents who have confidence in the choices that they make and the advice that they are given. Just as new families require mentoring so that they can act in the best interests of their children, so the early years’ workforce needs training and continuous professional development to ensure that the advice given is of the highest possible quality and specifically tailored to the individual family. Early Years’ students from The University of Northampton (interviewed) explain what a positive difference their newly acquired knowledge has made to their performance in the settings and Government recognition of The Early Years as a developmental stage in its own right and the creation of the new posts of Early Years Teacher and Early Years Educator have been positive. Yet as the Ilkeston ‘Mums Group’ (interviewed) makes clear, there is still no guarantee of uniform excellence in the delivery of services nationwide and no assurance of continuity between, for example, advice on feeding from the midwife and the health visitor, or the emphasis put on freely-chosen play in an early years’ setting and a primary school. If young children are to thrive, we believe it is essential that there is a national consensus and political will behind multi-disciplinary working in the early years. We see the early years as a window of opportunity and make no apology for the fact that each section of this report is accompanied by many policy recommendations. It has not been possible to produce a uniform handful of ‘asks’, just as the early years itself is a rich, complex and multifarious developmental phase. However, neither do we consider it to be feasible to achieve everything that we recommend in the lifespan of a single Government. This is a two, even three term journey. However, if the nation’s families and the early years workforce are to embark upon it, the Government must be prepared to provide the resources; the Cabinet Minister for Children and Families, the commitment to multi-disciplinary co-operation to achieve an early years workforce that is truly ‘joined up’ and, above all, the finance to make well–intentioned aspiration a reality. In an age of austerity, by spending early, the later savings to education, health, social or criminal justice services will be immense. Investing in the children of today is not a gambl

Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy

Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics

Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity

The mammalian α/β T cell receptor (TCR) repertoire plays a pivotal role in adaptive immunity by recognizing short, processed, peptide antigens bound in the context of a highly diverse family of cell-surface major histocompatibility complexes (pMHCs). Despite the extensive TCR–MHC interaction surface, peptide-independent cross-reactivity of native TCRs is generally avoided through cell-mediated selection of molecules with low inherent affinity for MHC. Here we show that, contrary to expectations, the germ line-encoded complementarity determining regions (CDRs) of human TCRs, namely the CDR2s, which appear to contact only the MHC surface and not the bound peptide, can be engineered to yield soluble low nanomolar affinity ligands that retain a surprisingly high degree of specificity for the cognate pMHC target. Structural investigation of one such CDR2 mutant implicates shape complementarity of the mutant CDR2 contact interfaces as being a key determinant of the increased affinity. Our results suggest that manipulation of germ line CDR2 loops may provide a useful route to the production of high-affinity TCRs with therapeutic and diagnostic potential

Monoclonal TCR-redirected tumor cell killing

T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy