Intratumoral virotherapy with 4-1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory

Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host ' s inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8(+) T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment. Methods To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of modified vaccinia Ankara (MVA) for intratumoral virotherapy. Results Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8(+) T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA. Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8(+) T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory

Developing a collaborative agenda for humanities and social scientific research on laboratory animal science and welfare.

Improving laboratory animal science and welfare requires both new scientific research and insights from enquiry in the humanities and social sciences. Whilst scientific research provides evidence to replace, reduce and refine procedures involving laboratory animals (the ‘3Rs’), work in the humanities and social sciences can help understand the social, economic and cultural processes that enhance or impede humane ways of knowing and working with laboratory animals. However, communication across these disciplinary perspectives is currently limited, and they frame questions, generate results, engage users, and seek to influence policy in different ways. To facilitate dialogue and future research at this interface, we convened an interdisciplinary group of 45 life scientists, social scientists, humanities scholars, non-governmental organisations and policy-makers to generate a collaborative research agenda. This drew on other agenda-setting exercises in science policy, using a collaborative and deliberative approach for the identification of research priorities. Participants were recruited from across the community, invited to submit research questions and vote on their priorities. They then met at an interactive workshop in the UK, discussed all 136 questions submitted, and collectively defined the 30 most important issues for the group. The output is a collaborative future agenda for research in the humanities and social sciences on laboratory animal science and welfare. The questions indicate a demand for new research in the humanities and social sciences to inform emerging discussions and priorities on the governance and practice of laboratory animal research, including around: international harmonisation, openness and public engagement, ‘cultures of care’, harm-benefit analysis and the future of the 3Rs. The process underlines the value of interdisciplinary exchange for improving mutual understanding of different research cultures and identifies ways of enhancing the effectiveness of future research at the interface between the humanities, social sciences, science and science policy

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

International audienceMedullary thymic epithelial cells (mTECs) serve an essential function in central tolerance through expressing peripheral tissue-antigens. These antigens may be transferred to and presented by dendritic cells. Therefore, it is unclear whether mTECs, besides being an 'antigen-reservoir', also serve a mandatory function as antigen presenting cells. Here, we reduced MHC class II on mTECs through transgenic expression of a C2TA-specific 'designer miRNA'. This resulted in an enlarged polyclonal CD4 single-positive compartment and, among thymocytes specific for model-antigens expressed in mTECs, enhanced selection of regulatory T cells (Treg) at the expense of deletion. Our data document an autonomous contribution of mTECs to dominant and recessive mechanisms of CD4+ T cell tolerance and support an avidity model of Treg development versus deletion

Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from ~20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4–5 years in 70–80% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6% in studies before 2005, has decreased to 0.3% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs

Collins and Sivers asymmetries in muonproduction of pions and kaons off transversely polarised protons

Measurements of the Collins and Sivers asymmetries for charged pions and charged and neutral kaons produced in semi-inclusive deep-inelastic scattering of high energy muons off transversely polarised protons are presented. The results were obtained using all the available COMPASS proton data, which were taken in the years 2007 and 2010. The Collins asymmetries exhibit in the valence region a non-zero signal for pions and there are hints of non-zero signal also for kaons. The Sivers asymmetries are found to be positive for positive pions and kaons and compatible with zero otherwise. © 2015

Intratumoral virotherapy with 4-1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory

Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host ' s inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8(+) T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment. Methods To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of modified vaccinia Ankara (MVA) for intratumoral virotherapy. Results Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8(+) T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA. Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8(+) T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory