Advanced

Immunological aspects of intratumoral chemotherapy and immunotherapy in malignant brain tumors

Enriquez Perez, Julio LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Advances in surgery, chemo- and radiotherapy have only modestly improved survival rates of malignant brain tumor patients during the last decades. Emerging evidence suggests that an efficient treatment of malignant brain tumors will likely require the management of multiple aspects of tumor pathobiology in order to manipulate features as tumor heterogeneity and tumor immunosuppression. Immunotherapy based on peripheral vaccination of autologous tumor cells target both dividing and non-dividing tumor cells and lead to immunological memory. Moreover, intratumoral administration of chemotherapeutic drugs, also referred to as convection-enhanced delivery (CED), is a technique used to circumvent the blood-brain barrier (BBB) and increase the... (More)
Advances in surgery, chemo- and radiotherapy have only modestly improved survival rates of malignant brain tumor patients during the last decades. Emerging evidence suggests that an efficient treatment of malignant brain tumors will likely require the management of multiple aspects of tumor pathobiology in order to manipulate features as tumor heterogeneity and tumor immunosuppression. Immunotherapy based on peripheral vaccination of autologous tumor cells target both dividing and non-dividing tumor cells and lead to immunological memory. Moreover, intratumoral administration of chemotherapeutic drugs, also referred to as convection-enhanced delivery (CED), is a technique used to circumvent the blood-brain barrier (BBB) and increase the drug distribution within the tumor, while reducing the systemic side effects associated with systemically delivered chemotherapeutic drugs.
In this doctoral thesis, I propose intratumoral delivery of cytostatic drugs and immunotherapy as combined tools to treat malignant brain tumors. Thus, the treatment efficacy and the immune-related mechanisms of CED of clinically relevant cytostatic drugs and immunotherapy were investigated in glioma mouse models. CED of temozolomide (CED-TMZ) cured GL261-bearing mice and acted synergistically with wildtype cell immunizations. In addition, CED- TMZ was more effective and less toxic than single intratumoral injections of TMZ in the GL261 model. CED-TMZ prolonged survival in KR158-bearing mice but cure was only achieved with immunotherapy as a monotherapy and in combination with CED-TMZ. The immune dependence of the therapeutic effect of CED-TMZ was confirmed in immunocompromised mice bearing GL261. Infiltration of CD8+ and CD4+ T cells was increased in both models after CED-TMZ and immunization. CED of cisplatin (CED-CIS) induced cure in the GL261 model. As for CED-TMZ, the effect of CED-CIS was abrogated in immunocompromised mice. However, cell immunizations did not have any additive effect with CED-CIS. CED of mitoxantrone cured both GL261- and SB28-bearing mice. In addition, plasma samples from pediatric brain tumor patients were immune-profiled using cytokine multiplex arrays. We identified two patient groups with distinct preoperative inflammatory cytokine profiles that could be used as peripheral biomarkers to help design, predict or monitor the response of immunotherapy.
Altogether, these results have important implications for the future development and implementation of locally administered cytostatic drugs and immunotherapy against malignant brain tumors. (Less)
Abstract (Swedish)
Hjärntumörer utgör omkring 2 procent av alla cancerdiagnoser och den vanligaste elakartade hjärntumörtypen är glioblastom (GBM). Patienter med GBM behandlas i dag med kirurgi, cellgifter och strålbehandling, men sjukdomen går sällan att bota och det krävs nya och mer effektiva behandlingsstrategier.
I min doktorsavhandling har jag använt tre olika musmodeller, kallade GL261, KR158 och SB28, för att utvärdera en kombinationsbehandling för patienter med GBM.
Behandlingen utgörs dels av cellgifter som ges direkt in i tumören via en läkemedelspump (kallat convection-enhanced delivery, CED, i avhandlingen), dels av ett tumörcellsvaccin vars syfte är att förmå kroppens eget immunförsvar att stöta bort tumören. Jag har undersökt effekten... (More)
Hjärntumörer utgör omkring 2 procent av alla cancerdiagnoser och den vanligaste elakartade hjärntumörtypen är glioblastom (GBM). Patienter med GBM behandlas i dag med kirurgi, cellgifter och strålbehandling, men sjukdomen går sällan att bota och det krävs nya och mer effektiva behandlingsstrategier.
I min doktorsavhandling har jag använt tre olika musmodeller, kallade GL261, KR158 och SB28, för att utvärdera en kombinationsbehandling för patienter med GBM.
Behandlingen utgörs dels av cellgifter som ges direkt in i tumören via en läkemedelspump (kallat convection-enhanced delivery, CED, i avhandlingen), dels av ett tumörcellsvaccin vars syfte är att förmå kroppens eget immunförsvar att stöta bort tumören. Jag har undersökt effekten av tre olika cellgifter, temozolomid, cisplatin och mitoxantron, ensamt eller i kombination med tumörcellsvaccin.
CED av temozolomid, eller tumörcellsvaccin, botade en viss andel av möss med hjärntumören GL261, och vid kombinationsbehandling sågs en större effekt än den sammanlagda effekten av behandlingarna var för sig. Möss med den mer aggressiva hjärntumören KR158 botades inte av enbart temozolomid, men en viss andel kunde botas med tumörcellsvaccin. Vidare visade jag att CED av temozolomid var ett mer effektivt och mindre giftigt alternativ jämfört med att ge en injektion av samma mängd läkemedel vid ett enskilt tillfälle.
Även CED av cisplatin och mitoxantron botade en viss andel av möss med hjärntumören GL261, men till skillnad från temozolomid sågs med cisplatin ingen ytterligare effekt när behandlingen kombinerades med tumörcellsvaccin. Dock verkar både effekten av temozolomid och effekten av cisplatin vara kopplad till immunförsvaret, eftersom ingen behandlingseffekt sågs hos möss med ett dysfunktionellt immunförsvar. CED av mitoxantron hade även effekt hos möss med hjärntumören SB28, men inte KR158.
I avhandlingens sista del undersökte jag blodprover från patienter med olika typer av hjärntumörer, och kunde se att det finns viktiga skillnader i faktorer som är kopplade till immunförsvaret. Dessa faktorer skulle kunna användas som markörer för att visa hur samspelet mellan tumör och immunförsvar ser ut under en pågående behandling.
Sammanfattningsvis visar denna avhandling att CED av cellgifter, med eller utan tumörcellsvaccin, är en lovande behandlingsstrategi för patienter med GBM. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Langmoen, Iver, Oslo University Hospital, Oslo, Norway
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Glioblastoma (GBM), Immunotherapy, Mouse glioma, Convection-enhanced delivery, Intratumoral chemotherapy, Glioblastom, Immuneterapi
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:20
pages
108 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2020-02-28 13:00:00
ISSN
1652-8220
ISBN
978-91-7619-880-3
language
English
LU publication?
yes
id
6f107ade-24c0-4ad0-8075-477884ac1f84
date added to LUP
2020-01-30 11:31:26
date last changed
2020-03-20 12:32:39
@phdthesis{6f107ade-24c0-4ad0-8075-477884ac1f84,
  abstract     = {Advances in surgery, chemo- and radiotherapy have only modestly improved survival rates of malignant brain tumor patients during the last decades. Emerging evidence suggests that an efficient treatment of malignant brain tumors will likely require the management of multiple aspects of tumor pathobiology in order to manipulate features as tumor heterogeneity and tumor immunosuppression. Immunotherapy based on peripheral vaccination of autologous tumor cells target both dividing and non-dividing tumor cells and lead to immunological memory. Moreover, intratumoral administration of chemotherapeutic drugs, also referred to as convection-enhanced delivery (CED), is a technique used to circumvent the blood-brain barrier (BBB) and increase the drug distribution within the tumor, while reducing the systemic side effects associated with systemically delivered chemotherapeutic drugs.<br/>In this doctoral thesis, I propose intratumoral delivery of cytostatic drugs and immunotherapy as combined tools to treat malignant brain tumors. Thus, the treatment efficacy and the immune-related mechanisms of CED of clinically relevant cytostatic drugs and immunotherapy were investigated in glioma mouse models. CED of temozolomide (CED-TMZ) cured GL261-bearing mice and acted synergistically with wildtype cell immunizations. In addition, CED- TMZ was more effective and less toxic than single intratumoral injections of TMZ in the GL261 model. CED-TMZ prolonged survival in KR158-bearing mice but cure was only achieved with immunotherapy as a monotherapy and in combination with CED-TMZ. The immune dependence of the therapeutic effect of CED-TMZ was confirmed in immunocompromised mice bearing GL261. Infiltration of CD8+ and CD4+ T cells was increased in both models after CED-TMZ and immunization. CED of cisplatin (CED-CIS) induced cure in the GL261 model. As for CED-TMZ, the effect of CED-CIS was abrogated in immunocompromised mice. However, cell immunizations did not have any additive effect with CED-CIS. CED of mitoxantrone cured both GL261- and SB28-bearing mice. In addition, plasma samples from pediatric brain tumor patients were immune-profiled using cytokine multiplex arrays. We identified two patient groups with distinct preoperative inflammatory cytokine profiles that could be used as peripheral biomarkers to help design, predict or monitor the response of immunotherapy.<br/>Altogether, these results have important implications for the future development and implementation of locally administered cytostatic drugs and immunotherapy against malignant brain tumors.},
  author       = {Enriquez Perez, Julio},
  isbn         = {978-91-7619-880-3},
  issn         = {1652-8220},
  language     = {eng},
  number       = {2020:20},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Immunological aspects of intratumoral chemotherapy and immunotherapy in malignant brain tumors},
  url          = {https://lup.lub.lu.se/search/ws/files/77393474/Julio_Enriquez_Avhandling.pdf},
  year         = {2020},
}