Medicine and Health Sciences Commons^™

Vaccines: A Promising Therapy For Myelodysplastic Syndrome, Kriti Gera, Anjali Chauhan, Paul Castillo, Maryam Rahman, Akash Mathavan, Akshay Mathavan, Elizabeth Oganda-Rivas, Leighton Elliott, John R Wingard, Elias J Sayour

Journal Articles

Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole …

Challenges And Opportunities For Immunotherapeutic Intervention Against Myeloid Immunosuppression In Glioblastoma, Mark A Exley, Samantha Garcia, Amelia Zellander, Jenny Zilberberg, David W. Andrews

Department of Neurosurgery Faculty Papers

Glioblastoma multiforme (GBM), the most common and deadly brain cancer, exemplifies the paradigm that cancers grow with help from an immunosuppressive tumor microenvironment (TME). In general, TME includes a large contribution from various myeloid lineage-derived cell types, including (in the brain) altered pathogenic microglia as well as monocyte-macrophages (Macs), myeloid-derived suppressor cells (MDSC) and dendritic cell (DC) populations. Each can have protective roles, but has, by definition, been coopted by the tumor in patients with progressive disease. However, evidence demonstrates that myeloid immunosuppressive activities can be reversed in different ways, leading to enthusiasm for this therapeutic approach, both alone and …

Glioma Stem Cells As Immunotherapeutic Targets: Advancements And Challenges, Keenan Piper, Lisa Depledge, Michael Karsy, Charles Cobbs

Department of Neurosurgery Faculty Papers

Glioblastoma is the most common and lethal primary brain malignancy. Despite major investments in research into glioblastoma biology and drug development, treatment remains limited and survival has not substantially improved beyond 1–2 years. Cancer stem cells (CSC) or glioma stem cells (GSC) refer to a population of tumor originating cells capable of self-renewal and differentiation. While controversial and challenging to study, evidence suggests that GCSs may result in glioblastoma tumor recurrence and resistance to treatment. Multiple treatment strategies have been suggested at targeting GCSs, including immunotherapy, posttranscriptional regulation, modulation of the tumor microenvironment, and epigenetic modulation. In this review, we …

A Narrative Review Of Targeted Therapy In Meningioma, Pituitary Adenoma, And Craniopharyngioma Of The Skull Base., Nina L. Martinez, Omaditya Khanna, Christopher J. Farrell

Department of Neurosurgery Faculty Papers

Management of solid tumors involving the skull base are primarily managed with surgery and radiation, though proximity to important vascular and neuroanatomic structures often limit the extent of resection and permissible radiation dose. Meningiomas are the most common primary brain tumor in adults, and although the majority of skull base meningiomas are low-grade, their location in proximity to critical anatomical structures precludes aggressive surgical resection, and larger tumors are often resistant to radiation treatment. In patients with clinically aggressive, unresectable meningiomas, several molecular biomarkers of angiogenesis, as well as genetic mutations (SMO, AKT1, PIK3CA, KLF4, POLR2, SMARCE1, and TRAF7), have …

Multiple Sclerosis Outcomes After Cancer Immunotherapy, Catherine R. Garcia, Rani Jayswal, Val R. Adams, Lowell B. Anthony, John L. Villano

Markey Cancer Center Faculty Publications

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.

METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.

RESULTS: We identified 14 cases of MS …

Distinct Role Of Il-27 In Immature And Lps-Induced Mature Dendritic Cell-Mediated Development Of Cd4, Fang Zhou, Guang-Xian Zhang, A. M. Rostami

Department of Neurology Faculty Papers

Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4⁺ T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4⁺ CD127⁺3G11⁺ regulatory T cell subset …

Neurological Complications Of Immune Checkpoint Inhibitors: What Happens When You 'Take The Brakes Off' The Immune System., Marinos Dalakas

Department of Neurology Faculty Papers

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events …

Amyloid-Beta Solubility In The Treatment Of Alzheimer's Disease, Michael Paul Murphy

Molecular and Cellular Biochemistry Faculty Publications

No abstract provided.

Emerging Immunopharmacological Targets In Multiple Sclerosis., Mojtaba Farjam, Guang-Xian Zhang, Bogoljub Ciric, Abdolmohamad Rostami

Department of Neurology Faculty Papers

Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS), a chronic debilitating disease that affects more than 2.5 million individuals worldwide. It has been widely accepted, although not proven, that the major pathogenic mechanism of MS involves myelin-reactive T cell activation in the periphery and migration into the CNS, which subsequently triggers an inflammatory cascade that leads to demyelination and axonal damage. Virtually all MS medications now in use target the immune system and prevent tissue damage by modulating neuroinflammatory processes. Although current therapies such as commonly prescribed disease-modifying medications decrease the relapse rate …

Targeting And Killing Of Glioblastoma With Activated T Cells Armed With Bispecific Antibodies, Ian M. Zitron, Archana Thakur, Oxana Norkina, Geoffrey R. Barger, Lawrence G. Lum, Sandeep Mittal

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2.

Methods

ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and ⁵¹Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines.

Results

EGFRBi-armed ATC killed up to 85% of U87, …