טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShraibman Bracha
SubjectToward Development of Personalized Immunotherapy and
Early Detection for Glioblastoma
DepartmentDepartment of Biology
Supervisor Professor Arie Admon
Full Thesis textFull thesis text - English Version


Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median survival of less than 15 months. The current therapy for this deadly disease includes maximal surgical resection followed by radiation and Temozolomide chemotherapy. Nevertheless, in order to prolong patients’ lives, additional and more targeted treatments are needed, as well as improvement in prognostic biomarkers that will help to facilitate disease diagnosis. The recent success of immunotherapy in the treatment of other cancers has aroused interest in vaccine therapy for the treatment of Glioblastoma. Successful immunotherapy is dependent on the identification of tumor-specific antigens, against which an immune reaction can be mounted. Cancer/testis antigens (CTA) are desirable targets for cancer immunotherapy since they are expressed in cancerous cells but not in the non-immune-privileged healthy tissues of the body. The degradation products of such tumor antigens can be presented as HLA peptides at the surface of tumors cells (mHLA), as well as in the plasma of patients (sHLA), and be exploited as anti-cancer immunotherapeutics and as biomarkers for early detection of the disease.

This study includes three main subprojects, all aiming to develop better immunotherapy for GBM:

1. Large-scale analyses of the membranal HLA peptidomes of GBM tumors and of soluble HLA peptidomes derived from GBM patients’ plasma. These analyses resulted in identification of about thirty thousand HLA peptides presented on the tumor tissues and especially in the plasma samples. Many of these identified HLA peptides were derived from the tumor antigens, and therefore can serve as GBM personalized immunotherapeutics, as well as for early disease diagnosis and relapse follow-up.

2. Chemotherapy drug effects on the HLA peptidomes of cultured human GBM cells. Treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (Decitabine), a commonly used chemotherapeutic, led to the presentation of CTA-derived HLA peptides in three different GBM cultured cell lines, which can be exploited in the future for enhanced killing of tumor cells by CTA and drug induced-specific T cells.

3. The effects of Decitabine and immune checkpoint inhibitor (PD-1 inhibitor) on the tumors’ MHC peptidome of a pre-clinical GBM mouse model. The presentation of CTA-derived MHC peptides was observed, therefore, up-regulation of such antigens and enhanced killing of tumor cells by CTA specific T cells suggest that immunotherapy targeting CTAs in combination with drug treatment is potentially useful for improved cancer outcome.

To conclude, this research aims to advance the survival rate of GBM patients by developing targeted therapeutic strategies, as well as by finding biomarkers for an early detection of the disease.