Date of Award

12-2016

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Technology Leadership and Innovation

First Advisor

Kari L. Clase

Committee Chair

Kari L. Clase

Committee Member 1

Stephen R. Byrn

Committee Member 2

Gloria H. Umberger

Abstract

Glioblastoma Multiforme GBM is a very aggressive type of malignant brain tumors that affects peoples’ lives. The diffusive, infiltrative, and metastatic behaviour of GBM is the major reason for the disease recurrence. The morphological and immunohistological characteristics of Central Nervous System (CNS) tumors including GBM are heterogeneous. GBM is either primary (de novo) or secondary to low-grade astrocytomas.

Current treatment options include surgery, radiotherapy, and temozolomide chemotherapy have not achieved any improvement in success rates over the past decades. The survival time reached by GBM patients was approximately 12 months only after being treated with radiotherapy alone without temozolomide. However, the median survival time has been estimated as 14.6 months in patients who received the combined treatment of radiotherapy and chemotherapy with temozolomide. Temozolomide is an alkylating agent that exhibit antitumor activity and prescribed as a single agent for the treatment of recurrent glioma. It diminishes the O6-methylguanine-DNA methyltransferase (MGMT) enzyme, which is responsible for DNA repair. GBM Patientswith activated O6-alkylguanine transferase AGT enzyme were reported to develop resistant to temozolomide.

Targeted therapies are other options for GBM patients. Bevacizumab blocks the effect of Human Vascular Endothelial Growth Factor (VEGF) and inhibits tumor vascular growth. Regulatory concerns about clinical trials conducted with bevacizumab including trial design problems have been raised.

Targeting the immune system will identify successful treatments for GBM with significant clinical benefits. The use of active immunotherapy to increase the native immune response or passive immunotherapy to target the tumor cells in GBM patients are under investigation. Dendritic Cells DCs are the most potent antigen presenting APCs in the immune system. DCs have the ability to stimulate the native T cells and induce primary immune responses and peripheral immunological tolerance through capturing, processing neoantigens, which are formed and released by oncogenesis, and presenting the captured antigens on Histocompatibility Complex I and II (MHCI and MHCII) molecules to T cells. After that T cell responses against the cancer-specific antigens are primed and activated. T cells infiltrate the tumor bed, specifically recognize, bind to, and kill their target cancer cell. The sources of antigen that have been used in DC immunotherapy include exogenous MHC-restricted peptides, acid-eluted tumor peptides, tumor RNA and cDNA, viral vectors, apoptotic tumor cells, tumor cell lysate, and whole glioma cells. Clinical trials showed that treating GBM patients with surgery, TMZ, and Dendritic Cell DC vaccines was safe and achieved meaningful clinical outcomes.

The purpose of this research is to investigate the clinical outcomes of DC vaccines for the treatment of GBM patients through the published data on the rapidly growing field of clinical trials. Furthermore, this research focuses on investigating immune responses that are related to the most beneficial clinical outcomes to identify new prognostic biomarkers and therapeutic targets.

This research’s findings have showed evidence that many different variables were associated with different cancer specific immune responses and clinical outcomes. These variables include loading DC vaccines with tumor material or Tumor Associated Antigens TAAs, and combining DC vaccines with different pre and post vaccination treatment strategies. DC vaccine pulsed with specific synthetic antigens have achieved more beneficial clinical outcome than DC vaccines loaded with tumor material. Pre-vaccination treatment strategy with TMZ has increased the Overall Survival and the Progression Free Survival of GBM patients. Although, pre-vaccination treatment strategy with TMZ+RT has achieved significant improvement of Overall Survival, there was no improvement of the Progression Free Survival associated with the strategy.

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