Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

Abstract

Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer.

Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose

“…Herpes simplex viruses G207 and NV1020 and poxvirus based therapy have also required doses of 10 7 PFU to cause tumor regression [ 24 , 25 ]. Typically, in vivo cancer models in athymic mice have required a therapeutic dose of 10 6 –10 8 PFU for intravenous delivery [ 22 , 26 , 27 ] and at least 10 7 PFU for intratumoral delivery [ 28 – 30 ]. In our study, in vivo therapeutic efficacy was noted after a single dose of 10 3 PFU and the mice displayed no toxicity.…”

Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy

“…Efficacy was dependent upon the sequence of the virus treatments, and, significantly, upon CD3+ T cells, indicating that the combination of viruses was acting through an immunological prime-boost-like mechanism 41 . The combination of adenovirus and vaccinia virus was also successful in slowing anti-viral, and innate cellular, immune responses leading to better anti-tumor therapy 42 . Similarly, a combination of Semliki Forest Virus and Vaccinia virus was effective at boosting anti-tumor immune responses in a murine ovarian cancer model and generated improved therapy through both oncolysis and enhanced anti-tumor immunity 43 .…”

Immunohistochemical Characterization and Sensitivity to Human Adenovirus Serotypes 3, 5, and 11p of New Cell Lines Derived from Human Diffuse Grade II to IV Gliomas

“…To improve the therapeutic efficacy of HAd5, its tropism has been increased by switching its receptor-binding domain, the so-called fiber knob, to that of other human adenovirus serotypes, such as HAd3 and HAd11p, which utilize more ubiquitous and cancer-overexpressed receptors for infection, desmoglein-2 (DSG-2) and cluster of differentiation 46 (CD46), respectively [10] , [11] , [12] . However, the expression patterns of also these receptors in tumors may be heterogenic, and as we and others have shown, the replication of some oncolytic viruses is also regulated intracellularly, particularly by components of the interferon (IFN)-inducible antiviral defense [13] , [14] , [15] . To complicate matters, most analyses of virus tropism and oncolytic efficacy to date have been made in established cell lines, which are prone to significant transcriptional and phenotypic deviation from the parental tumors they were derived from [16] , [17] , [18] .…”