Search

BNT162b2, a lipid nanoparticle (LNP) formulated nucleoside-modified messenger RNA (mRNA) that encodes the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) stabilized in the prefusion conformation, has demonstrated 95% efficacy in preventing coronavirus disease-19 (COVID-19)1. Here we extend our previous phase 1/2 trial report2 and present BNT162b2 prime/boost induced immune response data from a second phase 1/2 trial in healthy adults (18-55 years of age). BNT162b2 elicited strong antibody responses, with SARS-CoV-2 serum 50% neutralizing geometric mean titers up to 3.3-fold above those observed in COVID-19 human convalescent samples (HCS) one week post-boost. BNT162b2-elicited sera neutralized 22 pseudoviruses bearing SARS-CoV-2 S variants. Most participants had a strong IFNγ- or IL-2-positive CD8+ and CD4+ T helper type 1 (TH1) T cell response, detectable throughout the full observation period of nine weeks following the boost. pMHC multimer technology identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week post-boost, epitope-specific CD8+ T cells of the early differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ 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 conserved in a broad range of variants at well tolerated doses.

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 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 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 (TH1)-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. 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.

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 tumours1,2. 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. 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.

T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.

Therapeutic vaccination with tumor antigen-encoding RNAs is being investigated in various clinical trials. Typically, the RNA vaccine is administered intradermally, subcutaneously or intranodally with the intention to get expression of the encoded antigens in local antigen-presenting cells (APCs). We have developed a novel class of RNA-lipoplex (RNA(LIP)) immunotherapeutics for intravenous application, which allow systemic targeting of APCs. RNA(LIP) is a novel nanoparticulate formulation of lipid-complexed mRNA which selectively delivers the functional mRNA to APCs in lymphoid compartments body-wide for efficient mRNA uptake and expression of the encoded antigen by APCs. Moreover, this formulation has intrinsically strong adjuvant activity, mimics a systemic viral infection and induces synchronized activation of potent adaptive as well as type-I-IFN-mediated innate immune responses (Kranz et al., Nature 2016). The first-in-human phase I/II dose escalation Lipo-MERIT trial (NCT02410733) conducted in four German study centers assesses the safety, tolerability, and biological efficacy of RNA(LIP) immunotherapy in patients with stage IIIB/C and IV melanoma. This trial is the first to investigate intravenous administration of a RNA-based cancer vaccine. Following antigen expression stratification on routinely collected tumor samples, eligible patients are treated with repeated dosing of the tetravalent Lipo-MERIT vaccine composed of RNA(LIP) products encoding the shared melanoma-associated antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTE. Pharmacodynamic activity and immunogenicity of the vaccine is investigated by concerted immune monitoring and correlative biomarker studies. Clinical activity is assessed following imaging according to irRECIST1.1. As of January 2018, >50 patients have been treated with escalating or constant dosing under the guidance of an independent data safety and monitoring board. The Lipo-MERIT vaccine was generally well-tolerated and no dose-limiting toxicities (DLTs) were observed so far. Further patient enrollment is continuing. Preliminary data on the assessment of vaccine-induced immune responses and clinical responses from the first patients treated will be presented. Citation Format: Robert A. Jabulowsky, Carmen Loquai, Heidrun Mitzel-Rink, Jochen Utikal, Christoffer Gebhardt, Jessica C. Hassel, Roland Kaufmann, Andreas Pinter, Evelyna Derhovanessian, Christine Anft, Sebastian Attig, Alexandra Deubel, Mustafa Diken, Maike Gold, Claudia Guertler, Heinrich Haas, Ludwig Heesen, Alexandra Kemmer-Brück, Lena M. Kranz, Klaus Kuehlcke, Andreas Kuhn, Peter Langguth, Ulrich Luxemburger, Daniel Maurus, Martin Meng, Felicitas Müller, Richard Rae, Fatih Sari, Katharina Schreeb, Doreen Schwarck-Kokarakis, Malte Stein, Dirk Jäger, Stephan Grabbe, Sebastian Kreiter, Christoph Huber, Özlem Türeci, Ugur Sahin. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT156.