Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
1.
Nature ; 618(7963): 144-150, 2023 Jun.
Article in English | MEDLINE | ID: covidwho-2318679

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.


Subject(s)
Antigens, Neoplasm , Cancer Vaccines , Carcinoma, Pancreatic Ductal , Lymphocyte Activation , Pancreatic Neoplasms , T-Lymphocytes , Humans , Adjuvants, Immunologic/therapeutic use , Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/therapy , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunotherapy , Lymphocyte Activation/immunology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/therapy , T-Lymphocytes/cytology , T-Lymphocytes/immunology
2.
MAbs ; 13(1): 1978130, 2021.
Article in English | MEDLINE | ID: covidwho-1442969

ABSTRACT

Recent years have seen unparalleled development of microfluidic applications for antibody discovery in both academic and pharmaceutical research. Microfluidics can support native chain-paired library generation as well as direct screening of antibody secreting cells obtained by rodent immunization or from the human peripheral blood. While broad diversities of neutralizing antibodies against infectious diseases such as HIV, Ebola, or COVID-19 have been identified from convalescent individuals, microfluidics can expedite therapeutic antibody discovery for cancer or immunological disease indications. In this study, a commercially available microfluidic device, Cyto-Mine, was used for the rapid identification of natively paired antibodies from rodents or human donors screened for specific binding to recombinant antigens, for direct screening with cells expressing the target of interest, and, to our knowledge for the first time, for direct broad functional IgG antibody screening in droplets. The process time from cell preparation to confirmed recombinant antibodies was four weeks. Application of this or similar microfluidic devices and methodologies can accelerate and enhance pharmaceutical antibody hit discovery.


Subject(s)
Antibodies, Neutralizing/isolation & purification , Immunoglobulin G/isolation & purification , Microfluidics/methods , Animals , Antibodies, Bacterial/immunology , Antibodies, Bacterial/isolation & purification , Antibodies, Monoclonal/isolation & purification , Antibodies, Viral/isolation & purification , Antibody Specificity , Antigens/immunology , Antigens, Neoplasm/immunology , Blood Preservation , COVID-19/immunology , Fluorescence Resonance Energy Transfer , Humans , Hybridomas/immunology , Immunomagnetic Separation , Lab-On-A-Chip Devices , Mice , Microfluidics/instrumentation , Muromonab-CD3/immunology , Plasma Cells , Recombinant Proteins/immunology , SARS-CoV-2/immunology , Tetanus Toxoid/immunology , Vaccination
3.
J Immunol ; 206(12): 2819-2827, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1261380

ABSTRACT

The etiology and pathology of Kawasaki disease (KD) remain elusive. Cub domain-containing protein 1 (CDCP1), a cell-surface protein that confers poor prognosis of patients with certain solid tumors, was recently identified as one of the most significantly upregulated genes in SARS-CoV-2-infected children who developed systemic vasculitis, a hallmark of KD. However, a potential role of CDCP1 in KD has not previously been explored. In this study, we found that CDCP1 knockout (KO) mice exhibited attenuated coronary and aortic vasculitis and decreased serum Candida albicans water-soluble fraction (CAWS)-specific IgM/IgG2a and IL-6 concentrations compared with wild-type mice in an established model of KD induced by CAWS administration. CDCP1 expression was not detectable in cardiomyocytes, cardio fibroblasts, or coronary endothelium, but constitutive expression of CDCP1 was observed on dendritic cells (DCs) and was upregulated by CAWS stimulation. CAWS-induced IL-6 production was significantly reduced in CDCP1 KO DCs, in association with impaired Syk-MAPK signaling pathway activation. These novel findings suggest that CDCP1 might regulate KD development by modulating IL-6 production from DCs via the Syk-MAPK signaling pathway.


Subject(s)
Antigens, Neoplasm/immunology , Cell Adhesion Molecules/immunology , Dendritic Cells/immunology , Disease Models, Animal , Mucocutaneous Lymph Node Syndrome/immunology , Animals , Cell Adhesion Molecules/deficiency , Cells, Cultured , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
4.
Mol Cancer ; 20(1): 52, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1136226

ABSTRACT

In vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.


Subject(s)
Cancer Vaccines/genetics , Cancer Vaccines/immunology , Neoplasms/etiology , Neoplasms/therapy , RNA, Messenger/genetics , RNA, Messenger/immunology , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cancer Vaccines/administration & dosage , Drug Delivery Systems , Gene Expression Regulation, Neoplastic , Gene Transfer Techniques , Humans , Immunity , Immunotherapy , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Neoplasms/pathology , RNA Stability , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
SELECTION OF CITATIONS
SEARCH DETAIL