Lucas Basler1,2, Aleksandra Kowalczyk3,4, Regina Heidenreich3, Mariola Fotin-Mleczek3, Savas Tsitsekidis5, Daniel Zips5, Franziska Eckert5, Stephan M Huber5. 1. Department of Radiation Oncology, University of Tübingen, Rämistrasse 100, 8091, Tübingen, Germany. Lucas.Basler@usz.ch. 2. Department of Radiation Oncology, University Hospital Zürich, Zurich, Switzerland. Lucas.Basler@usz.ch. 3. CureVac AG, Tübingen, Germany. 4. Boehringer-Ingelheim, Birkendorferstr. 85, 88397, Biberach an der Riss, Germany. 5. Department of Radiation Oncology, University of Tübingen, Rämistrasse 100, 8091, Tübingen, Germany.
Abstract
BACKGROUND: Tumor metastasis and immune evasion present major challenges of cancer treatment. Radiotherapy can overcome immunosuppressive tumor microenvironments. Anecdotal reports suggest abscopal anti-tumor immune responses. This study assesses abscopal effects of radiotherapy in combination with mRNA-based cancer vaccination (RNActive®). METHODS: C57BL/6 mice were injected with ovalbumin-expressing thymoma cells into the right hind leg (primary tumor) and left flank (secondary tumor) with a delay of 4 days. Primary tumors were irradiated with 3 × 2 Gy, while secondary tumors were shielded. RNA and combined treatment groups received mRNA-based RNActive® vaccination. RESULTS: Radiotherapy and combined radioimmunotherapy significantly delayed primary tumor growth with a tumor control in 15 and 53% of mice, respectively. In small secondary tumors, radioimmunotherapy significantly slowed growth rate compared to vaccination (p = 0.002) and control groups (p = 0.01). Cytokine microarray analysis of secondary tumors showed changes in the cytokine microenvironment, even in the non-irradiated contralateral tumors after combination treatment. CONCLUSION: Combined irradiation and immunotherapy is able to induce abscopal responses, even with low, normofractionated radiation doses. Thus, the combination of mRNA-based vaccination with irradiation might be an effective regimen to induce systemic anti-tumor immunity.
BACKGROUND:Tumor metastasis and immune evasion present major challenges of cancer treatment. Radiotherapy can overcome immunosuppressive tumor microenvironments. Anecdotal reports suggest abscopal anti-tumor immune responses. This study assesses abscopal effects of radiotherapy in combination with mRNA-based cancer vaccination (RNActive®). METHODS: C57BL/6 mice were injected with ovalbumin-expressing thymoma cells into the right hind leg (primary tumor) and left flank (secondary tumor) with a delay of 4 days. Primary tumors were irradiated with 3 × 2 Gy, while secondary tumors were shielded. RNA and combined treatment groups received mRNA-based RNActive® vaccination. RESULTS: Radiotherapy and combined radioimmunotherapy significantly delayed primary tumor growth with a tumor control in 15 and 53% of mice, respectively. In small secondary tumors, radioimmunotherapy significantly slowed growth rate compared to vaccination (p = 0.002) and control groups (p = 0.01). Cytokine microarray analysis of secondary tumors showed changes in the cytokine microenvironment, even in the non-irradiated contralateral tumors after combination treatment. CONCLUSION: Combined irradiation and immunotherapy is able to induce abscopal responses, even with low, normofractionated radiation doses. Thus, the combination of mRNA-based vaccination with irradiation might be an effective regimen to induce systemic anti-tumor immunity.
Authors: Alexandros Papachristofilou; Madeleine M Hipp; Ute Klinkhardt; Martin Früh; Martin Sebastian; Christian Weiss; Miklos Pless; Richard Cathomas; Wolfgang Hilbe; Georg Pall; Thomas Wehler; Jürgen Alt; Helge Bischoff; Michael Geißler; Frank Griesinger; Karl-Josef Kallen; Mariola Fotin-Mleczek; Andreas Schröder; Birgit Scheel; Anke Muth; Tobias Seibel; Claudia Stosnach; Fatma Doener; Henoch S Hong; Sven D Koch; Ulrike Gnad-Vogt; Alfred Zippelius Journal: J Immunother Cancer Date: 2019-02-08 Impact factor: 13.751
Authors: Franziska Eckert; Kerstin Zwirner; Simon Boeke; Daniela Thorwarth; Daniel Zips; Stephan M Huber Journal: Front Immunol Date: 2019-03-12 Impact factor: 7.561