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Single, self-amplifying RNA molecules condensed by an oppositely charged polyelectrolyte self-assemble into compact globular nanoparticles that can be used as vaccines to generate potent immunological responses at low doses.

Here the authors provide the interim analysis of an ongoing phase 1/2 study of the BNT162b2 vaccine in healthy Japanese adults. They report mainly mild to moderate local reactions and no serious adverse events as well as good antibody induction one month after the second dose.

Samples of serum from individuals immunized with the BNT162b2 vaccine show neutralization activity against engineered SARS-CoV-2s bearing the spike mutations from B.1.617 and other variants.

In the ongoing phase 1/2 BNT211-01 trial, CLDN6-specific chimeric antigen receptor (CAR)-T cells given with or without CARVac, a CAR-T cell-amplifying RNA vaccine, were well-tolerated and exhibited encouraging clinical activity in patients with relapsed or refractory CLDN6-positive solid tumors, with the highest response rate in patients with germ cell tumors.

The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma.

Here the authors show that CD4⁺ effector T cells prevent or reverse CD8⁺ T cell dysfunction by licensing Kupffer cells to trigger IL-27 production, defining a liver-specific immune circuit and a potential target for chronic HBV therapeutics.

De Almeida, Richard and colleagues leverage transfer learning to create ChatNT, a multimodal conversational agent for DNA, RNA and protein sequences that can be instructed in natural language.

In a phase I/II dose-escalation clinical trial, the mRNA COVID-19 vaccine BNT162b1 elicits specific T cell and antibody responses that suggest it has protective potential.

Cystine-knot miniprotein are small, highly stable, disulfide-rich peptides with increasing potential as drugs and tumor imaging agents. Here the authors develop cystine-knot miniproteins targeting the vascular tumor marker EDB, and use them as probes for in vivo tumor vasculature imaging.

In this phase 1 trial, patients with locally advanced or metastatic solid tumors were treated with the individualized mRNA neoantigen-specific immunotherapy (iNeST) autogene cevumeran alone or in combination with the anti-PD-L1 agent atezolizumab, showing long-lasting neoantigen-specific immune responses and preliminary clinical activity, supporting further development of this therapeutic approach.

In a phase 1 trial, patients with pancreatic ductal adenocarcinoma who were treated with surgery and bespoke neoantigen mRNA vaccines combined with anti-PD-L1 and chemotherapy exhibited marked long-lived persistence of neoantigen-specific CD8⁺ T cell clones, which correlated with prolonged recurrence-free survival at a 3.2-year follow-up.

BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge.

In a phase-I/II trial in healthy adults, the BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells against SARS-CoV-2 epitopes that are conserved in a wide range of currently circulating variants.

Results of an exploratory interim analysis from a phase I trial show that an RNA vaccine targeted towards four melanoma-associated antigens produces durable objective responses in patients with melanoma that are accompanied by strong CD4⁺ and CD8⁺ T-cell immunity.

EasyFuse detects gene fusions in cancer transcriptomes for personalized immunotherapy.

RNA vaccines have been associated with high reactogenicity. Mellman and colleagues demonstrate that lipid-formulated RNA vaccines trigger IL-1 production and inflammation in humans but this pathway is dampened in mice.

Phase 1 trial results of the messenger RNA vaccine candidate BNT162b1, which encodes the receptor-binding domain of the SARS-CoV-2 spike protein, show safety and elicitation of antibody and T cell responses in both younger and older Chinese adults.

The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potential efficacy in humans.

The authors show that a large fraction of tumour mutations is immunogenic and predominantly recognized by CD4⁺ T cells; they use these data to design synthetic messenger-RNA-based vaccines specific against tumour mutations, and show that these can reject tumours in mice.

A phase I clinical trial of an adjuvant personalized mRNA neoantigen vaccine, autogene cevumeran, in patients with pancreatic ductal carcinoma demonstrates that the vaccine can induce T cell activity that may correlate with delayed recurrence of disease.

In a dose-escalation study of the COVID-19 RNA vaccine BNT162b1 in 45 healthy adults, RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second vaccine dose.

The therapeutic potential ofin vitro-transcribed mRNA (IVT mRNA) extends from prophylactic and therapeutic vaccines to applications such as protein replacement and genome engineering. In this Review, the authors describe the recent developments in the IVT mRNA field, discuss the class-specific challenges with regards to translating IVT mRNA into a biopharmaceutical, and provide an overview of IVT mRNA drugs in development for different indications.

The re-wiring of the metabolic machinery is a common feature in cancer. Here, the authors show, using paired normal and prostate cancer samples that the cancer samples exhibit a shift to succinate respiration, which is associated with elevated levels of mitochondrial DNA mutations.

Regulatory B cells are important for preventing skin autoimmunity. Here the authors show that NFATc1 suppresses IL-10 transcription in regulatory B cells, and inhibiting NFATc1 decreases immunopathology in a mouse model of imiquimod-induced skin inflammation.

Signaling and transcriptional regulation of MDSC activity remains largely undefined. Here the authors show that monocytic MDSC immunosuppression is triggered by c-FLIP and requires NFκB, implicate this axis in cancer prognosis and response to therapy, and employ ectopic FLIP to treat immunopathology.

Bringing truly personalized cancer vaccination with tumour neoantigens to the clinic will require overcoming the challenges of optimized vaccine design, manufacturing and affordability, and identification of the most suitable clinical setting.

Bispecific antibodies that connect T cells with tumor cells can be delivered in the form of in vitro–transcribed pharmacologically optimized mRNA; when injected into mice, these mRNA-encoded antibodies reject large established tumors as efficiently as the corresponding recombinant antibody protein.

In a phase I trial, highly individualized peptide vaccines against unmutated tumour antigens and neoepitopes elicited sustained responses in CD8⁺ and CD4⁺ T cells, respectively, in patients with newly diagnosed glioblastoma.

The mutant IDH1 protein, which is expressed in a large fraction of human gliomas, is shown to be immunogenic; mutant-specific immune responses can be detected in patients with IDH1 mutated gliomas and generated in mice and are shown to treat established IDH1 mutant tumours in a syngeneic MHC humanized mouse model in a CD4 T-cell-dependent manner.

Mutations in cancer cells can generate tumour-specific neoepitopes, which are attractive targets for anticancer vaccines. This Review discusses the mechanisms of neoantigen T cell recognition and computational approaches to predict which neoantigens might confer proficient antitumour immunity in a given clinical context.