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From flicker to FLASH: Exploring FLASH and conventional radiotherapy in experimental glioblastoma

Liljedahl, Emma LU (2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Glioblastoma is our most common and most fatal primary brain tumor. Although continuous progress in the cancer research-field the prognosis for glioblastoma remains detrimental. Radiotherapy is a corner stone in the treatment arsenal and can induce an immune response, needed to achieve better tumor control. A limitation that remains is the side-effects on healthy tissue. The new implementation of FLASH- RT in the field has in previous studies proven to reduce the unwanted side-effects. It has yet to be extensively explored in fully immunocompetent animals. Also, it is important to establish that it is equal in anti-tumor efficacy compared to conventional radiotherapy (CONV-RT).
Combining radiotherapy and immunotherapy is another... (More)
Glioblastoma is our most common and most fatal primary brain tumor. Although continuous progress in the cancer research-field the prognosis for glioblastoma remains detrimental. Radiotherapy is a corner stone in the treatment arsenal and can induce an immune response, needed to achieve better tumor control. A limitation that remains is the side-effects on healthy tissue. The new implementation of FLASH- RT in the field has in previous studies proven to reduce the unwanted side-effects. It has yet to be extensively explored in fully immunocompetent animals. Also, it is important to establish that it is equal in anti-tumor efficacy compared to conventional radiotherapy (CONV-RT).
Combining radiotherapy and immunotherapy is another treatment option to try and overcome the challenges presented by glioblastoma. Yet, no such treatment is used in the clinical practice. In the present work, we have explored the effects of stimulation of the complement system. The complement system is part of the innate immune system and is swiftly activated. Through its activation it can function as a bridge between innate and adaptive immune responses. We have previously demonstrated that glioblastoma cells inhibit important pathways in the complement cascade to escape immune detection and eradication.
Utilizing a fully immunocompetent Fischer 344 rat model inoculated with glioblastoma cell line in both the intracranial and subcutaneous setting, we set out to explore both FLASH-efficacy and safety and the implementation of radiotherapy with complement activation by using anti-C1-INH antibodies.
We could see that the dose response was similar for CONV-RT and FLASH-RT in our present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose. In the intracranial setting survival was prolonged in animals treated with FLASH or CONV-RT, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.
Anti-C1-INH treatment could improve the efficacy of irradiation delivered at sub-therapeutic doses and delay tumor growth in the subcutaneous tumor microenvironment. In the intracranial setting, the doses of anti-C1-INH were not enough to achieve any survival effect in the present setting.
Taken together, we have demonstrated that FLASH is equally effective compared to CONV-RT in fully immunocompetent animals with glioblastoma, both in terms of short-term and long-term tumor control. (Less)
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author
supervisor
opponent
  • Professor Schültke, Elisabeth, University of Rostock, Department of Radiooncology
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Glioblastoma (GBM), C1-inhibitor, Complement System, Experimental glioma models, CONV-RT, Radiotherapy, FLASH-RT, FLASH
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2024:146
pages
96 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/67407026798
defense date
2024-12-06 13:00:00
ISSN
1652-8220
ISBN
978-91-8021-643-2
language
English
LU publication?
yes
id
29fa859d-41a5-437e-98a8-3a64578f08b5
date added to LUP
2024-11-17 20:55:32
date last changed
2024-11-21 06:06:25
@phdthesis{29fa859d-41a5-437e-98a8-3a64578f08b5,
  abstract     = {{Glioblastoma is our most common and most fatal primary brain tumor. Although continuous progress in the cancer research-field the prognosis for glioblastoma remains detrimental. Radiotherapy is a corner stone in the treatment arsenal and can induce an immune response, needed to achieve better tumor control. A limitation that remains is the side-effects on healthy tissue. The new implementation of FLASH- RT in the field has in previous studies proven to reduce the unwanted side-effects. It has yet to be extensively explored in fully immunocompetent animals. Also, it is important to establish that it is equal in anti-tumor efficacy compared to conventional radiotherapy (CONV-RT).<br/>Combining radiotherapy and immunotherapy is another treatment option to try and overcome the challenges presented by glioblastoma. Yet, no such treatment is used in the clinical practice. In the present work, we have explored the effects of stimulation of the complement system. The complement system is part of the innate immune system and is swiftly activated. Through its activation it can function as a bridge between innate and adaptive immune responses. We have previously demonstrated that glioblastoma cells inhibit important pathways in the complement cascade to escape immune detection and eradication.<br/>Utilizing a fully immunocompetent Fischer 344 rat model inoculated with glioblastoma cell line in both the intracranial and subcutaneous setting, we set out to explore both FLASH-efficacy and safety and the implementation of radiotherapy with complement activation by using anti-C1-INH antibodies.<br/>We could see that the dose response was similar for CONV-RT and FLASH-RT in our present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose. In the intracranial setting survival was prolonged in animals treated with FLASH or CONV-RT, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.<br/>Anti-C1-INH treatment could improve the efficacy of irradiation delivered at sub-therapeutic doses and delay tumor growth in the subcutaneous tumor microenvironment. In the intracranial setting, the doses of anti-C1-INH were not enough to achieve any survival effect in the present setting.<br/>Taken together, we have demonstrated that FLASH is equally effective compared to CONV-RT in fully immunocompetent animals with glioblastoma, both in terms of short-term and long-term tumor control.}},
  author       = {{Liljedahl, Emma}},
  isbn         = {{978-91-8021-643-2}},
  issn         = {{1652-8220}},
  keywords     = {{Glioblastoma (GBM); C1-inhibitor; Complement System; Experimental glioma models; CONV-RT; Radiotherapy; FLASH-RT; FLASH}},
  language     = {{eng}},
  number       = {{2024:146}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{From flicker to FLASH: Exploring FLASH and conventional radiotherapy in experimental glioblastoma}},
  url          = {{https://lup.lub.lu.se/search/files/200015156/Avhandling_Emma_Liljedahl_LUCRIS.pdf}},
  year         = {{2024}},
}