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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.

Virotherapy - 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 are being explored or genetically engineered for selective replication 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 immuno- (viro-) therapy 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 being developed.

The CCU Virotherapy research agenda
We explore new strategies for engineering effective oncolytic viruses and combination therapies, establish processes for manufacturing oncolytic virus formulations, perform early and late phase clinical virotherapy studies and decipher mechanisms of oncolytic immunotherapy in preclinical models and patients (see here for an overview).

Engineering oncolytic agents for maximum anti-tumor efficacy and safety
Our preclinical research program focuses on a measles vaccine virus platform with more recent projects exploring oncolytic adenoviruses and parvoviruses. Using molecular cloning, we engineer oncolytic viruses and explore combination regimens for specific medicinal purposes (see “discovery projects”). For instance, we have designed viruses to

  • direct viral infection to tumors by selective tumor cell entry or post-entry replication control (“targeting”)
  • express therapeutic proteins to implement increased potency (“arming”). Payloads include cytokines, immune checkpoint inhibitors and bispecific antibodies for alerting the patient’s immune system to the tumor (“immuno-virotherapy”)
  • establish effective combination treatments (e.g. “radio-therapy”)
Deciphering mechanisms of immuno-virotherapy
We develop and apply preclinical and patient-derived tumor models and systems immunodiagnostic tools to decipher factors both within tumor cells and the tumor microenvironment that determine oncolytic potency and anti-tumor immune activation. Our research aims at rational strategies for improving oncolytic viruses and identifying potential biomarkers of immuno-virotherapy for clinical translation (see “discovery projects”) and “dissect projects”).

Advancing oncolytic viruses into clinical application
With our research, we constantly aim to identify the most effective immuno-virotherapies for clinical application. Based on our preclinical findings, we are preparing a phase I/II clinical trial with an oncolytic measles virus for immuno-virotherapy of advanced gastrointestinal cancers. To this end, we currently establish GMP-compliant virus manufacturing processes (see “develop projects”). Further completed, ongoing and upcoming trials (phases I - III) explored or explore, e.g. oncolytic parvoviruses, herpes and vaccinia viruses (see “treat projects”). Importantly, the trials we initiate are accompanied by translational research programs to pinpoint mechanisms of action and identify predictive biomarker signatures of successful immuno-virotherapy (see “dissect projects”).


Prof. Dr. Dr. Guy Ungerechts
Virotherapy (D490)
Deutsches Krebsforschungszentrum
und Nationales Centrum für Tumorerkrankungen (NCT)
Im Neuenheimer Feld 460
69120 Heidelberg

Selected Publications

  • Walle T, Bajaj S, Kraske JA, Rösner T, Cussigh CS, Kälber KA, Müller LJ, Boyoung Strobel S, Burghaus J, Kallenberger S, Stein-Thöringer C, Jenzer M, Schubert A, Kahle S, Williams A, Hoyler B, Zielske L, Skatula R, Sawall S, Leber MF, Kunes RZ, Krisam J, Fremd C, Schneeweiss A, Krauss J, Apostolidis L, Berger AK, Haag GM, Zschäbitz S, Halama N, Springfeld C, Kirsten R, Hassel JC, Jäger D, NCT ANTICIPATE Investigators & Ungerechts G. Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy. Nature Cancer, 2022
  • Hajda J, Leuchs B, Angelova AL, Frehtman V, Rommelaere J, Mertens M, Pilz M, Kieser M, Krebs O, Dahm M, Huber B, Engeland CE, Mavratzas A, Hohmann N, Schreiber J, Jäger D, Halama N, Sedlaczek O, Gaida MM, Daniel V, Springfeld C, Ungerechts G. Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma. Clin Cancer Res., 2021
  • 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.
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