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Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model

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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.

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Abbreviations

BED:

Biologically effective dose

DAMP:

Danger-associated molecular pattern

DC:

Dendritic cell

PGE2:

Prostaglandin E2

s.c.:

Subcutaneously

RT:

Radiotherapy

TAM:

Tumor-associated macrophage

Treg :

Regulatory T

VEGF:

Vascular endothelial growth factor

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Funding

Lucas Basler was funded by a grant of the IZKF Promotionskolleg (Interdisziplinäres Zentrum für Klinische Forschung, Interdisciplinary Centre for Clinical Research, University of Tübingen). Franziska Eckert was partly funded by the Else-Kroener-Fresenius research grant “Therapy resistance of solid tumors” (2015_Kolleg.14).

Author information

Author notes

  1. Lucas Basler

    Present address: Department of Radiation Oncology, University Hospital Zürich, Zurich, Switzerland

  2. Aleksandra Kowalczyk

    Present address: Boehringer-Ingelheim, Birkendorferstr. 85, 88397, Biberach an der Riss, Germany

Authors and Affiliations

  1. Department of Radiation Oncology, University of Tübingen, Rämistrasse 100, 8091, Tübingen, Germany

    Lucas Basler, Savas Tsitsekidis, Daniel Zips, Franziska Eckert & Stephan M. Huber

  2. CureVac AG, Tübingen, Germany

    Aleksandra Kowalczyk, Regina Heidenreich & Mariola Fotin-Mleczek

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  1. Lucas Basler
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Contributions

LB conducted the experiments and wrote the manuscript. AK helped with the experiments. RH revised the manuscript. MFM helped with the experiments. ST performed the dosimetry experiments. DZ revised the manuscript. FE wrote the manuscript. SMH designed the experiments and revised the manuscript.

Corresponding author

Correspondence to Lucas Basler.

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Conflict of interest

Aleksandra Kowalczyk, Regina Heidenreich, and Mariola Fotin-Mleczek were employees of CureVac AG at the time of the experiments’ performance or preparation of the manuscript. The others authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the animal protection laws and regulations, and were approved by the local authorities.

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Basler, L., Kowalczyk, A., Heidenreich, R. et al. Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model. Cancer Immunol Immunother 67, 653–662 (2018). https://doi.org/10.1007/s00262-018-2117-0

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