Clinical Cooperation Unit Virotherapy

Prof. Dr. Dr. Guy Ungerechts

Oncolytic viruses are engineered to address therapeutic needs to achieve expression of therapeutic genes („arming“), tumor-specific targeting, protection from premature clearance („stealthing“) and tumor-targeted immunomodulation. The most effective oncolytic agents are brought into clinical trials with accompanying translational research programs.
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Developing a unique type of cancer immunotherapy
Clinical observations of cancer remissions after viral infections laid the foundation for the field of virotherapy. Certain viruses replicate selectively in cancer cells, leading to tumor cell lysis. In recent years, it has become increasingly appreciated that these so-called oncolytic viruses act as a cancer immunotherapy via tumor vaccination effects in particular. In 2015, a first oncolytic virus was approved for the treatment of advanced melanoma in the US and Europe. Several other oncolytic viruses are currently investigated in clinical trials. The CCU virotherapy focuses its preclinical research activities on a measles vaccine virus platform with further projects including oncolytic parvoviruses and adenoviruses. Our clinical research covers Phase I-III clinical trials with diverse oncolytic platforms.

Engineering oncolytic agents for maximum safety and anti-tumor efficacy
Using reverse genetics systems and molecular cloning, oncolytic viruses can be modified for specific medicinal purposes. For instance, the measles vaccine virus offers a versatile platform to meet therapeutic needs. In our preclinical development program, we design viruses to

  • express a therapeutic transgene to implement increased potency (“arming”). Different kinds of payloads are investigated for improved tumor cell killing or enhanced tumor-specific immune responses (“immunovirotherapy”)
  • selectively infect cancer cells via tumor-specific surface molecules (“entry targeting”)
  • block virus replication in healthy cells by exploitation of differential microRNA expression (“post-entry targeting”)
  • avoid antibody neutralization by modification of the virus surface (“stealthing”)
  • establish effective combination treatments (e.g. “radiovirotherapy”)
Deciphering mechanisms of oncolytic immunotherapy
Within the CCU Virotherapy the Research Group „Mechanisms of Oncolytic Immunotherapy“ led by Christine Engeland, MD, PhD investigates determinants of successful cancer immunotherapy using oncolytic viruses. Using preclinical and patient-derived model systems, we decipher factors both within tumor cells and the tumor microenvironment which mediate response or resistance. Our research aims at identifying rational improvement strategies and potential biomarkers for oncolytic immunotherapy for clinical translation.

Bringing oncolytic viruses into clinical application
The aim of our research is to identify the most effective oncolytic immunotherapies for clinical application. Based on our preclinical findings, a Phase I/II clinical trial investigating oncolytic measles virus for immunovirotherapy of advanced gastrointestinal cancers is currently in preparation. Further completed, ongoing and upcoming trials (Phases I - III) explore, e.g. oncolytic parvoviruses, herpes and vaccinia viruses. Importantly, the trials we initiate are accompanied by translational research programs to pinpoint mechanisms of action and identify predictive biomarker signatures of successful oncolytic immunotherapy.

Contact

Prof. Dr. Dr. Guy Ungerechts
Virotherapy (F230)
Deutsches Krebsforschungszentrum
und Nationales Centrum für Tumorerkrankungen (NCT)
Im Neuenheimer Feld 460
69120 Heidelberg

Selected Publications

  • Speck T, Heidbuechel JPW, Veinalde R, Jaeger D, von Kalle C, Ball CR, Ungerechts G, Engeland CE. Targeted BiTE expression by an oncolytic vector augments therapeutic efficacy against solid tumors. Clinical Cancer Research, 2018.
  • Veinalde R, Grossardt C, Hartmann L, Bourgeois-Daigneault MC, Bell JC, Jäger D, von Kalle C, Ungerechts G, Engeland CE. Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation. OncoImmunology, 2017.
  • Hajda J, Lehmann M, Krebs O, Kieser M, Geletneky K, Jäger D, Dahm M, Huber B, Schöning T, Sedlaczek O, Stenzinger A, Halama N, Daniel V, Leuchs B, Angelova A, Rommelaere J, Engeland CE, Springfeld C, Ungerechts G. A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol. BMC Cancer, 2017.
  • Engeland CE, Grossardt C, Veinalde R, Bossow S, Lutz D, Kaufmann JK, Shevchenko I, Umansky V, Nettelbeck DM, Weichert W, Jäger D, von Kalle C, Ungerechts G. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol Ther, 2014.
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