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.
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.
Background: IL-10 is anti-inflammatory and stimulates the cytotoxicity and proliferation of CD8þ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated and exhausted CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1 antibody. 4 of 16 heavily pre-treated pts with poor-or intermediaterisk mRCC, achieved a PR with AM0010 alone. Methods: 38 pts with metastatic RCC were enrolled from 2/20/2015 to 11/18/16 on AM0010 (10 or 20 ug/kg daily SC) and nivolumab (n ¼ 29; 3mg/kg, q2wk IV) or pembrolizumab (n ¼ 9; 2mg/kg, q3wk IV). Three had favorable and 30 had intermediate or poor-risk by IMDC (5 data not available). Pts had a median of 1 prior therapy (range: 1-3), and at least one VEGFR-TKI. One patient with prior AM0010 was included the safety population only. Tumor responses were assessed by irRC. Serum cytokines, blood derived T cells, clonal identity of peripheral T cells, and tumor DNA sequence and mRNA profiling were assayed. Results: AMO010 plus nivolumab (nivo) or pembrolizumab (pembro) was well tolerated. TrAEs were reversible and transient. G3/4 TrAE in patients on AM0010 and nivo or pembro included anemia (10), thrombocytopenia (7), and hypertriglyceridemia (6). Two pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis (HLH) most likely precipitated by T-cell activation, as both pts had a PRs. Patients treated with 10ug/kg AM0010 and nivo or pembro did not have G3/4 anemia or thrombocytopenia. As of August 11 2017, PRs were observed in 14 of 34 evaluable pts (41%). An additional 13 pts had stable disease (38%), 8 of those had a tumor reduction of more than 30% following irRC (in progress). Median PFS and median OS have not been reached, at median FU of 13.5 months (range: 0.5-29.83) for the nivolumab arm. mRNA analysis was used to distinguish patients with CR/PR/SD from progressive disease. Responding patients had a higher degree of CD8þ T cell invigoration. Conclusions: The combination of AM0010 with nivo or pembro is well-tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The observed efficacy is very promising and further studies of AM0010 and nivo or pembro in mRCC are in preparation. Clinical trial identification: NCT02009449Legal entity responsible for the study: ARMO BioSciences Funding: ARMO BioSciences Disclosure: A. Hung, P. Van Vlasselaer: Employee of ARMO BioSciences. M. Oft: Founder and employee of ARMO BioSciences. All other authors have declared no conflicts of interest.
Dieser Aufsatz zieht eine Zwischenbilanz des Rückzugs des Staates aus unternehmerischen Tätigkeiten in der OECD Welt seit 1980. Wir präsentieren einen kritischen Überblick über empirische Studien zu den Bestimmungsfaktoren der nationalen Unterschiede in den Bereichen Privatisierung, Subventionszahlungen und Regulierung. Wir zeigen, dass erhebliche Forschungslücken bestehen und skizzieren abschließend Wege für die künftige Forschung, um zu einem umfassenderen Bild der Entwicklung des unternehmerisch tätigen Staates zu gelangen.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.