**4. Conclusions**

HSV-1 based OVs have shown promising results in various preclinical studies regarding efficacy based on combined tumor cell killing abilities and immunostimulation in a broad range of cancers. Attempts at clinical translation have often not been successful due to lack of efficacy, although safety has been good even at the maximum achievable doses of these agents. The success of T-Vec in melanoma leading to FDA approval has provided great impetus to the field, proving for the first time that this approach can provide durable clinical benefit. However, melanoma is known to be responsive to immunotherapies, and therefore the challenge now is to come up with approaches that may be broadly applicable in more tumor types, by engineering more potent viruses, with enhanced tumor cell killing and immunogenic responses. As described in this review, treatment with oHSV-1 proved to be safe throughout the various different viruses tested so far. oHSVs have the potential to be an efficient weapon in anti-cancer treatment and qualify as a potent combination partner with chemotherapeutic as well as immunotherapeutic regimens—this possibility has been recognized as several studies on combinatorial treatment are underway. Although effects on the immune system and prolonged survival were observed in some cases, these results have to be critically reviewed since the majority of the studies discussed were phase I clinical trials, designed for evaluation of safety and tolerability. It is therefore of the utmost importance to acquire reliable and detailed clinical data on the influence of oHSVs on the immune response and overall survival in follow-up studies to further characterize efficacy and find

the most suitable combination partners. Better understanding the factors involved in response and resistance will lead to improved application of these agents in future trials.

**Funding:** The authors were supported by NCI P01 CA069246 and P01 CA163205 (E.A.C).

**Conflicts of Interest:** E.A.C. is currently an advisor to Advantagene Inc., Insightec, Inc., Seneca Therapeutics, Immunomic Therapeutics and DNAtrix Inc. and has equity interest in Immunomic Therapeutics, Seneca Therapeutics and DNAtrix; he has also advised Alcyone Biosciences, Voyager Therapeutics, Sangamo Therapeutics, Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, Shanaghai Biotech, Sigilon Therapeutics. He has received research support from NIH, US Department of Defense, American Brain Tumor Association, National Brain Tumor Society, Alliance for Cancer Gene Therapy, Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics and Amgen. He also is a named inventor on patents related to oncolytic HSV1.
