Immunological aspects of intratumoral chemotherapy and immunotherapy in malignant brain tumors

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.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.

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