Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with ...treatment-refractory tumours
. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4
and CD8
T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data ...from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) ofthe SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 pg ofBNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-pg dose) to 3.5-fold (50-pg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. interferon-у was produced by a large fraction ofRBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.
BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in ...preventing COVID-19.sup.1. Here we extend a previous phase-I/II trial report.sup.2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNgamma.sup.+ or IL-2.sup.+ CD8.sup.+ and CD4.sup.+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8.sup.+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8.sup.+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.
Synthetic biology advances the rational engineering of mammalian cells to achieve cell-based therapy goals. Synthetic gene networks have nearly reached the complexity of digital electronic circuits ...and enable single cells to perform programmable arithmetic calculations or to provide dynamic remote control of transgenes through electromagnetic waves. We designed a synthetic multilayered gaseous-fragrance-programmable analog-to-digital converter (ADC) allowing for remote control of digital gene expression with 2-bit AND-, OR- and NOR-gate logic in synchronized cell consortia. The ADC consists of multiple sampling-and-quantization modules sensing analog gaseous fragrance inputs; a gas-to-liquid transducer converting fragrance intensity into diffusible cell-to-cell signaling compounds; a digitization unit with a genetic amplifier circuit to improve the signal-to-noise ratio; and recombinase-based digital expression switches enabling 2-bit processing of logic gates. Synthetic ADCs that can remotely control cellular activities with digital precision may enable the development of novel biosensors and may provide bioelectronic interfaces synchronizing analog metabolic pathways with digital electronics.
Abstract only
3136
Background: Cancer vaccines are considered unsuitable for patients with advanced tumours and have not been clinically successful. Methods: Lipo-MERIT is an ongoing phase 1/2 trial ...(NCT02410733) with melanoma FixVac, a liposomal RNA vaccine targeting four non-mutant shared tumour-associated antigens (TAAs) (MAGE-A3, NY-ESO-1, tyrosinase, TPTE). Patients with stage IIIB-C and IV melanoma are eligible. The trial comprises 7 dose escalation and 3 dose expansion cohorts, the latter with FixVac alone or combined with anti-PD1. Eight doses of FixVac are administered i.v. weekly/bi-weekly followed by optional continued monthly treatment. This abstract summarizes the findings of an exploratory interim analysis (cut-off JUL2019) of 89 patients. Results: 42 of 89 patients had measurable disease at baseline and were eligible for assessment of best objective overall response. All but one patient were stage IV and had undergone previous lines of treatment, 41 patients were checkpoint-inhibitor (CPI)-experienced, and 35 had been exposed to both anti-CTLA4 and anti-PD1 therapy. In the vaccine monotherapy group (n = 25) three patients experienced a partial response (PR) and 7 patients had stable disease (SD). An additional patient showed a complete metabolic remission of metastatic lesions based on
18
F-FDG PET/CT imaging. In the group of patients treated with melanoma FixVac and PD1 blockade, 6 of 17 patients developed a PR. Patients with PR showed induction of poly-epitopic and strong CD4
+
and CD8
+
T cell immunity against the vaccine antigens. The number of antigen-specific cytotoxic T cells in some responders reached up to low 2-digit percentages of circulating CD8
+
T cells and was maintained at high levels by continued vaccination. Overall, 75% of the 50 patients tested by ex vivo IFNg ELISpot analysis and all 20 patients tested by IFNg ELISpot after in vitro stimulation showed vaccine-induced immune responses against at least one vaccine antigen. Typically, antigen-specific T cells ramped up within the first 4-8 weeks to single-digit and low double-digit percent fractions of circulating CD8
+
T cells. Immune responses were of effector memory phenotype and their strength and frequency did not depend on disease status at baseline (measurable versus non-measurable disease), on vaccine dose or on treatment (FixVac alone versus in combination with anti-PD1). Conclusions: FixVac alone and in combination with anti-PD1 mediates durable objective responses in pre-treated, CPI experienced patients with advanced progressing melanoma. Clinical trial information: NCT02410733 .
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data ...from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein
. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 μg of BNT162b1 elicited robust CD4
and CD8
T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-μg dose) to 3.5-fold (50-μg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (T
1)-skewed T cell immune responses with RBD-specific CD8
and CD4
T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8
and CD4
T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.
Microbes hold the key to life. They hold the secrets to our past (as the descendants of the earliest forms of life) and the prospects for our future (as we mine their genes for solutions to some of ...the planet's most pressing problems, from global warming to antibiotic resistance). However, the piecemeal approach that has defined efforts to study microbial genetic diversity for over 20 years and in over 30,000 genome projects risks squandering that promise. These efforts have covered less than 20% of the diversity of the cultured archaeal and bacterial species, which represent just 15% of the overall known prokaryotic diversity. Here we call for the funding of a systematic effort to produce a comprehensive genomic catalog of all cultured Bacteria and Archaea by sequencing, where available, the type strain of each species with a validly published name (currently∼11,000). This effort will provide an unprecedented level of coverage of our planet's genetic diversity, allow for the large-scale discovery of novel genes and functions, and lead to an improved understanding of microbial evolution and function in the environment.
In recent years, innovations in molecular techniques and sequencing technologies have resulted in a rapid expansion in the number of known viral sequences, in particular those with circular ...replication-associated protein (Rep)-encoding single-stranded (CRESS) DNA genomes. CRESS DNA viruses are present in the virome of many ecosystems and are known to infect a wide range of organisms. A large number of the recently identified CRESS DNA viruses cannot be classified into any known viral families, indicating that the current view of CRESS DNA viral sequence space is greatly underestimated. Animal faecal matter has proven to be a particularly useful source for sampling CRESS DNA viruses in an ecosystem, as it is cost-effective and non-invasive. In this study a viral metagenomic approach was used to explore the diversity of CRESS DNA viruses present in the faeces of domesticated and wild animals in New Zealand. Thirty-eight complete CRESS DNA viral genomes and two circular molecules (that may be defective molecules or single components of multicomponent genomes) were identified from forty-nine individual animal faecal samples. Based on shared genome organisations and sequence similarities, eighteen of the isolates were classified as gemycircularviruses and twelve isolates were classified as smacoviruses. The remaining eight isolates lack significant sequence similarity with any members of known CRESS DNA virus groups. This research adds significantly to our knowledge of CRESS DNA viral diversity in New Zealand, emphasising the prevalence of CRESS DNA viruses in nature, and reinforcing the suggestion that a large proportion of CRESS DNA viruses are yet to be identified.
•Discovery of 38 single-stranded DNA viruses in New Zealand animal faecal samples•Identification of 18 gemycirculaviruses representing nine new species•Identification of 12 smacoviruses representing ten new species•Identification of eight novel CRESS DNA viruses and two circular molecules•Novel DNA-RNA hybrid virus identified in Chamois (Rupicapra rupicapra) faeces
PDF
