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DEFINING THE ROLE OF IMMUNE THERAPY IN PEDIATRIC CNS MALIGNANCY

Dorand, Rodney Dixon, Jr.

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Pathology.
Understanding the mechanisms tumors employ to escape detection by both the innate and adaptive immune systems is imperative for developing new immune based therapeutics. Available evidence now favors the view that physiological immune surveillance by members of the innate and adaptive immune systems play an essential role in suppressing tumor development in vivo, and the failure of immune surveillance mechanisms favors tumor development and metastasis formation (1, 2). Whether it is altering cell surface markers, secreting cytokines, or even altering its genome, tumors can evolve much faster than the immune system. New and innovative approaches to cancer therapy are necessary to combat all cancer types, but especially solid tumors as current immunotherapies are more effective at targeting non-solid tumors. Even further complicating physiologic immune surveillance, tumors that develop within the central nervous system (CNS) do so behind the blood brain barrier (BBB) that can serve as an impediment to both the small molecules employed in immunotherapeutics, as well as, the infiltrating lymphocytes necessary for tumor elimination. Medulloblastoma (MB) is the most common malignant CNS neoplasm in the pediatric setting, accounting for 20% of pediatric CNS malignancies overall. It is a WHO-Grade IV primitive neuroectodermal tumor (PNET) that develops in the cerebellum and often invades into surrounding structures including the fourth ventricle and brain stem (3). While treatment modalities and, more importantly, post treatment cognitive instruction has improved outcomes, surviving patients still suffer cognitive sequelae (4). Unique to CNS neoplasms are microglia, an additional immune cell type that plays a pivotal role in normal immune surveillance of the CNS, phagocytosis, and neuroinflammation (5). Microglia reside in the brain parenchyma and help maintain the homeostatic immunosuppressive environment partially due to their expression of CX3CR1. Fractalkine (FKN) is constitutively expressed by neurons and astrocytes leading to tonic inhibition of microglial activation (6). In the presence of malignancy, FKN signaling is disrupted and we found MB can even express FKN itself. Understanding the intricacies of the FKN signaling axis may provide the key signals leading to immune suppression in the CNS in the context of malignant tumors. Furthermore, strategies that augment physiologic immune surveillance, such as the development of tumor vaccines and the addition of small molecule inhibitors, have the potential to benefit therapeutic approaches for CNS malignancies. Whether using a conventional ex vivo vaccine approach (7), or new in situ approaches centered around plant viral nanoparticles (8), vaccination strategies hold great possibilities for enhancing CNS tumor surveillance by vigorously activating the adaptive immune system. To ensure continued activation of the immune response, other therapeutic approaches focus on targeting known immune checkpoint molecules such as CTLA-4, PD-1, or PD-L1, which are expressed on the surface of either immune cells or tumors and inhibit the immune response (9, 10). Additionally, novel approaches can be employed to disrupt the very signaling mechanisms that lead to the surface expression of these immune checkpoint molecules (11). Understanding both the basics of CNS immune cell physiology and how combining targeted immunotherapy with supplemental treatment can counteract suppressive mechanisms is imperative to prevent tumor immune evasion. Enhanced immunotherapeutic approaches to malignant diseases in the CNS have the potential to produce significant increases in overall survival and better prognosis for brain tumor patients.
Alex Huang, MD, PhD (Advisor)
George Dubyak, PhD (Committee Chair)
Clive Hamlin, PhD (Committee Member)
Man-Sun Sy, PhD (Committee Member)
Gary Landreth, PhD (Committee Member)
Agne Petrosiute, MD (Committee Member)
190 p.

Recommended Citations

Citations

  • Dorand, Jr., R. D. (2016). DEFINING THE ROLE OF IMMUNE THERAPY IN PEDIATRIC CNS MALIGNANCY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1465566883

    APA Style (7th edition)

  • Dorand, Jr., Rodney. DEFINING THE ROLE OF IMMUNE THERAPY IN PEDIATRIC CNS MALIGNANCY. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1465566883.

    MLA Style (8th edition)

  • Dorand, Jr., Rodney. "DEFINING THE ROLE OF IMMUNE THERAPY IN PEDIATRIC CNS MALIGNANCY." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1465566883

    Chicago Manual of Style (17th edition)