Radiation combined with oncolytic vaccinia virus provides pronounced antitumor efficacy and induces immune protection in an aggressive glioblastoma model

Storozynsky, Quinn; Agopsowicz, Kate; Noyce, Ryan S.; Han, Xiao; Snyder, Natalie; Umer, Brittany A.; Gamper, Armin M.; Godbout, Roseline; Evans, David H.; Hitt, Mary

doi:10.1016/j.canlet.2023.216169

Cited by 7 publications

(11 citation statements)

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“…Xenografted tumors, for example, are highly susceptible to oncolytic virotherapy, but offer few insights into the challenge of treating tumors in immune-competent hosts. However, we have recently published a study showing that a ΔF4LΔJ2R VACV strain can synergize with IG-IR in an orthotopic and immune-competent murine glioblastoma model, to improve the cure rate 3-to-4-fold relative to either monotherapy [ 22 ]. Chen et al .…”

Section: Discussionmentioning

confidence: 99%

“…This study showed that ΔF4LΔJ2R VACV grows well in irradiated breast cancer cells and that IR can synergize with VACV to kill TUBO and 4T1 cells in vitro ( Fig 1 ). Nevertheless, the results obtained with an orthotopic glioblastoma model [ 22 ] were not replicated in breast cancer models. VACV therapy alone was the least effective TUBO tumor treatment tested, producing a worse outcome than what was seen in the PBS-treated controls ( Fig 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported a striking example of the benefits of combining ΔF4LΔJ2R VACV with IR to treat aggressive orthotopic glioblastoma tumors in immune-competent mice. This study showed that 10 Gy of IR combined with ΔF4LΔJ2R VACV improved the long-term survival from 13% and 21% with virus or radiation alone, respectively, to 67% when radiation was followed by 10 7 PFU of virus [ 22 ]. This showed that an improved therapeutic outcome could be achieved by combining ΔF4LΔJ2R VACV with IR and it raises the question of whether the effect can be obtained in other pre-clinical models of cancer, targeting tumor types that have proven resistant to oncolytic virus treatment.…”

Section: Introductionmentioning

confidence: 99%

“…One factor that complicates the interpretation of some earlier studies, is that the way the radiation was delivered rarely replicated the way tumors are treated in humans. Current methods use image-guided radiation to ensure that most of the dose is distributed in a region defined by the tumor boundaries [ 22 , 23 ]. In our glioblastoma study [ 22 ], and herein, we assessed treatment outcomes when VACV was combined with image-guided ionizing radiation (IG-IR) delivered using a small animal radiation research platform (SARRP).…”

Section: Introductionmentioning

confidence: 99%

“…Current methods use image-guided radiation to ensure that most of the dose is distributed in a region defined by the tumor boundaries [ 22 , 23 ]. In our glioblastoma study [ 22 ], and herein, we assessed treatment outcomes when VACV was combined with image-guided ionizing radiation (IG-IR) delivered using a small animal radiation research platform (SARRP). IG-IR combines tumor mapping with radiation delivery, allowing the operator to deliver a precise dose of radiation to the tumor bed with high spatial accuracy.…”

Section: Introductionmentioning

confidence: 99%

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Oncolytic vaccinia virus immunotherapy antagonizes image-guided radiotherapy in mouse mammary tumor models

Umer,

Noyce,

Kieser

et al. 2024

PLoS ONE

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Ionizing radiation (IR) and oncolytic viruses are both used to treat cancer, and the effectiveness of both agents depends upon stimulating an immune response against the tumor. In this study we tested whether combining image guided ionizing radiation (IG-IR) with an oncolytic vaccinia virus (VACV) could yield a better therapeutic response than either treatment alone. ΔF4LΔJ2R VACV grew well on irradiated human and mouse breast cancer cells, and the virus can be combined with 4 or 8 Gy of IR to kill cells in an additive or weakly synergistic manner. To test efficacy in vivo we used immune competent mice bearing orthotopic TUBO mammary tumors. IG-IR worked well with 10 Gy producing 80% complete responses, but this was halved when the tumors were treated with VACV starting 2 days after IG-IR. VACV monotherapy was ineffective in this model. The antagonism was time dependent as waiting for 21 days after IG-IR eliminated the inhibitory effect but without yielding any further benefits over IR alone. In irradiated tumors, VACV replication was also lower, suggesting that irradiation created an environment that did not support infection as well in vivo as in vitro. A study of how four different treatment regimens affected the immune composition of the tumor microenvironment showed that treating irradiated tumors with VACV altered the immunological profiles in tumors exposed to IR or VACV alone. We detected more PD-1 and PD-L1 expression in tumors exposed to IR+VACV but adding an αPD-1 antibody to the protocol did not change the way VACV interferes with IG-IR therapy. VACV encodes many immunosuppressive gene products that may interfere with the ability of radiotherapy to induce an effective anti-tumor immune response through the release of danger-associated molecular patterns. These data suggest that infecting irradiated tumors with VACV, too soon after exposure, may interfere in the innate and linked adaptive immune responses that are triggered by radiotherapy to achieve a beneficial impact.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%