Novel methods of malignant brain tumor treatment utilizing the tumor microenvironment
Kopecky, Jan LU
(2022)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Malignant brain tumors constitute a disaster in the lives of patients, either in the form of extremely low survival in glioblastoma, or the serious long-term adverse effects of therapy in medulloblastoma. These two tumor types represent the most common malignant brain entities in adults and children, respectively. Ever since the early 2000’s, no major improvement of patient outcomes occurred. Immunotherapy, which recorded revolutionary successes in several tumor types, has so far failed in brain tumors. This disappointing phenomenon is the result of intrinsic characteristics of glioblastoma and medulloblastoma and their microenvironment. Therefore, other treatment modalities that exploit the distinct attributes of malignant brain tumors... (More)
- Malignant brain tumors constitute a disaster in the lives of patients, either in the form of extremely low survival in glioblastoma, or the serious long-term adverse effects of therapy in medulloblastoma. These two tumor types represent the most common malignant brain entities in adults and children, respectively. Ever since the early 2000’s, no major improvement of patient outcomes occurred. Immunotherapy, which recorded revolutionary successes in several tumor types, has so far failed in brain tumors. This disappointing phenomenon is the result of intrinsic characteristics of glioblastoma and medulloblastoma and their microenvironment. Therefore, other treatment modalities that exploit the distinct attributes of malignant brain tumors are urgently needed.
In this thesis, I describe the features of both tumor types and the development of their therapy until today. Moreover, general features of tumor microenvironment are contrasted to the unique aspects of the brain tumor counterpart. Next, I outline the underlying mechanisms of conventional immunotherapy and recount the natural features of both tumors that prevent its effective deployment. Finally, I suggest alternative approaches that circumvent the challenges encountered so far, such as avoiding the blood brain barrier via local treatment administration or focusing on macrophages as the principal agent of immunotherapy instead of T cells. Antisecretory factor (AF), a new agent in cancer treatment, as well as modulation of CD24/Siglec10 “don’t eat me” signaling are examples of the latter.
Following is a summary of the four projects. In publication I, the concept of intratumoral temozolomide treatment is investigated from the perspective of tumor immune microenvironment. Publication II describes the effects of AF16 on macrophages and glioblastoma cells. Publication III is a pilot clinical trial of an AF preparation in patients with newly diagnosed glioblastoma. Manuscript IV examines the modulation of CD24 and Siglec10 to reduce antiphagocytic signaling in glioblastoma and medulloblastoma.
The impact of this research is represented by the first published immunological effects of local delivery of temozolomide through convection-enhanced delivery in murine glioblastoma; first investigation of AF16, macrophages and tumor cells; first Salovum human cancer trial; laying the groundwork for CD24-Siglec10 signaling modulation in human glioblastoma and medulloblastoma. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4f770e22-2c67-45a3-9c97-dd5d6192ecfa
- author
- Kopecky, Jan
LU
- supervisor
-
- Anna Darabi LU
- Peter Siesjö LU
- Mattias Belting LU
- opponent
-
- associated professor Vik-Mo, Einar Osland, Surgical Neuro-Oncology Section, Oslo University Hospital, Oslo, Norway
- organization
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- Brain tumors, Glioblastoma, Medulloblastoma, Convection-enhanced delivery, Antisecretory factor, AF16, Salovum, Macrophages, Immunology, Cancer, CD24, Siglec10, Antiphagocytic signaling
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2022:90
- pages
- 101 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Föreläsningssalen, EA-blocket plan 4, Klinikgatan 17 A, Skånes universitetssjukhus i Lund. Join by Zoom: https://lu-se.zoom.us/j/66726673557
- defense date
- 2022-06-15 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-251-9
- language
- English
- LU publication?
- yes
- id
- 4f770e22-2c67-45a3-9c97-dd5d6192ecfa
- date added to LUP
- 2022-05-25 23:13:52
- date last changed
- 2022-06-29 14:38:33
@phdthesis{4f770e22-2c67-45a3-9c97-dd5d6192ecfa,
abstract = {{Malignant brain tumors constitute a disaster in the lives of patients, either in the form of extremely low survival in glioblastoma, or the serious long-term adverse effects of therapy in medulloblastoma. These two tumor types represent the most common malignant brain entities in adults and children, respectively. Ever since the early 2000’s, no major improvement of patient outcomes occurred. Immunotherapy, which recorded revolutionary successes in several tumor types, has so far failed in brain tumors. This disappointing phenomenon is the result of intrinsic characteristics of glioblastoma and medulloblastoma and their microenvironment. Therefore, other treatment modalities that exploit the distinct attributes of malignant brain tumors are urgently needed.<br/>In this thesis, I describe the features of both tumor types and the development of their therapy until today. Moreover, general features of tumor microenvironment are contrasted to the unique aspects of the brain tumor counterpart. Next, I outline the underlying mechanisms of conventional immunotherapy and recount the natural features of both tumors that prevent its effective deployment. Finally, I suggest alternative approaches that circumvent the challenges encountered so far, such as avoiding the blood brain barrier via local treatment administration or focusing on macrophages as the principal agent of immunotherapy instead of T cells. Antisecretory factor (AF), a new agent in cancer treatment, as well as modulation of CD24/Siglec10 “don’t eat me” signaling are examples of the latter.<br/>Following is a summary of the four projects. In publication I, the concept of intratumoral temozolomide treatment is investigated from the perspective of tumor immune microenvironment. Publication II describes the effects of AF16 on macrophages and glioblastoma cells. Publication III is a pilot clinical trial of an AF preparation in patients with newly diagnosed glioblastoma. Manuscript IV examines the modulation of CD24 and Siglec10 to reduce antiphagocytic signaling in glioblastoma and medulloblastoma. <br/>The impact of this research is represented by the first published immunological effects of local delivery of temozolomide through convection-enhanced delivery in murine glioblastoma; first investigation of AF16, macrophages and tumor cells; first Salovum human cancer trial; laying the groundwork for CD24-Siglec10 signaling modulation in human glioblastoma and medulloblastoma.}},
author = {{Kopecky, Jan}},
isbn = {{978-91-8021-251-9}},
issn = {{1652-8220}},
keywords = {{Brain tumors; Glioblastoma; Medulloblastoma; Convection-enhanced delivery; Antisecretory factor; AF16; Salovum; Macrophages; Immunology; Cancer; CD24; Siglec10; Antiphagocytic signaling}},
language = {{eng}},
number = {{2022:90}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Novel methods of malignant brain tumor treatment utilizing the tumor microenvironment}},
url = {{https://lup.lub.lu.se/search/files/119045692/e_spik_ex_Jan.pdf}},
year = {{2022}},
}