**10. Translational Considerations, Perspectives, and Conclusions**

As a consequence of the observed dose–response relationships, highest feasible doses are administered in current trials. However, large-scale manufacturing of the required hightiter, highly purified good manufacturing practice (GMP)-grade recombinant MeV remains challenging [149], despite development of processes including production in serum-free cell culture, tangential flow filtration, and diafiltration [150–152]. Nevertheless, these efforts seem worthwhile, given the versatility of MeV as an oncolytic vector platform [47], the excellent safety record of MeV vaccines [10], as well as the biosafety profile [153] and genetic stability [154] of recombinant MeV.

As outlined above, several rational combination approaches to cancer immunovirotherapy employing MeV and different immunomodulators will be under clinical investigation in the future. Other OVs have already been combined successfully with immune checkpoint inhibitors [155] in clinical trials. Moreover, clinical translation of second-generation MeV engineered to encode relevant immunomodulators as illustrated above will most likely further improve clinical outcomes.

Moving forward in this direction, it will be decisive to validate predictive markers of response and resistance in a clinical setting. These markers should not only incorporate tumor cell characteristics, but also signatures of antitumor immune activation. By defining criteria of successful immunovirotherapy, these results will also assist in prioritizing the most effective therapeutic payloads and combination therapies. Towards this end, even early stage clinical trials must encompass comprehensive correlative research programs to accelerate the advancement of effective immunovirotherapies.

**Author Contributions:** Conceptualization, C.E.E. and G.U.; writing—original draft preparation, C.E.E.; writing—review and editing, G.U. and C.E.E.; visualization, C.E.E. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** We acknowledge Gemma Pidelaserra Martí and Johannes Heidbuechel for comments on the draft manuscript. We thank Alessia Floerchinger for providing micrographs for Figure 1c. Graphical abstract, Figures 1a, 2–4 were created with Biorender.com.

**Conflicts of Interest:** C.E.E. and G.U. are listed as inventors on patent applications related to the use of measles viruses for cancer immunotherapy. G.U. acts as CMO, CSO, and COO of CanVirex.
