Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004

Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were <10 years old, compared with those who did not require replacement. Twenty-three patients received replacement for hypofibrinogenemia (<1.5 g/L); 9 of them developed marked hypofibrinogenemia (<1 g/L). Very low fibrinogen levels (<1 g/L) were documented in patients before maximal CRS (n = 1), during maximal CRS (n = 7), and at CRS improvement (n = 1). Although hypofibrinogenemia was the most clinically significant coagulopathy, some patients also developed prolonged prothrombin time and activated partial thromboplastin time and increased international normalized ratio, further increasing the risk of bleeding. Hypofibrinogenemia was effectively managed using fibrinogen concentrate or cryoprecipitate replacement; severe (grade 4) bleeding events were rare (n = 2). CRS-associated coagulopathy with hypofibrinogenemia is manageable according to empiric guidelines of fibrinogen replacement for CAR-T trials. Fibrinogen concentrate should be used when cryoprecipitate is not reliably available. Monitoring fibrinogen levels in patients with moderate or severe CRS is essential for avoiding potentially fatal bleeding events

Unanswered Questions Following Reports of Secondary Malignancies After Car-T Cell Therapy

Reports of T cell malignancies after CAR-T cell therapy should be investigated, but existing data from follow-up studies suggest a low risk compared with other cancer treatments

Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)–an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved

Euclid: Early Release Observations -- Overview of the Perseus cluster and analysis of its luminosity and stellar mass functions

The Euclid ERO programme targeted the Perseus cluster of galaxies, gathering deep data in the central region of the cluster over 0.7 square degree, corresponding to approximately 0.25 r_200. The data set reaches a point-source depth of IE=28.0 (YE, JE, HE = 25.3) AB magnitudes at 5 sigma with a 0.16" and 0.48" FWHM, and a surface brightness limit of 30.1 (29.2) mag per square arcsec. The exceptional depth and spatial resolution of this wide-field multi-band data enable the simultaneous detection and characterisation of both bright and low surface brightness galaxies, along with their globular cluster systems, from the optical to the NIR. This study advances beyond previous analyses of the cluster and enables a range of scientific investigations summarised here. We derive the luminosity and stellar mass functions (LF and SMF) of the Perseus cluster in the Euclid IE band, thanks to supplementary u,g,r,i,z and Halpha data from the CFHT. We adopt a catalogue of 1100 dwarf galaxies, detailed in the corresponding ERO paper. We identify all other sources in the Euclid images and obtain accurate photometric measurements using AutoProf or AstroPhot for 138 bright cluster galaxies, and SourceExtractor for half a million compact sources. Cluster membership for the bright sample is determined by calculating photometric redshifts with Phosphoros. Our LF and SMF are the deepest recorded for the Perseus cluster, highlighting the groundbreaking capabilities of the Euclid telescope. Both the LF and SMF fit a Schechter plus Gaussian model. The LF features a dip at M(IE)=-19 and a faint-end slope of alpha_S = -1.2 to -1.3. The SMF displays a low-mass-end slope of alpha_S = -1.2 to -1.35. These observed slopes are flatter than those predicted for dark matter halos in cosmological simulations, offering significant insights for models of galaxy formation and evolution.Comment: Submitted to A&A, 44 pages, 35 figures, Part of the A&A special issue `Euclid on Sky', which contains Euclid key reference papers and first results from the Euclid Early Release Observation