Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identification and characterization, modulation of tumor immunological responses, combination therapies, and understanding of the rare long-term survivors. Past treatment strategies have failed for various reasons; however, newer strategies in trials today and on the horizon encourage optimism. To help illustrate 'where we have been' with this fatal disease and 'where we are going' with contemporary studies, we include in this review a detailed history of Phase III clinical trials for GBM, with a final emphasis on exciting new treatment strategies that offer hope for future GBM therapy.
Abstract:In the adult population, glioblastoma multiforme is one of the most common primary brain tumors encountered. Unfortunately, this highly malignant tumor represents over 50% of all types of primary central nervous system gliomas. The vast majority of GBMs develops quite rapidly without clinical, radiological, or morphologic evidence of a less malignant precursor lesion (primary or de novo GBMs), as compared to secondary GBMs that develop slowly by progression from diffuse low-grade astrocytomas. These GBM subtypes must be kept in mind because they may constitute distinct disease entities. Even though they look histologically quite similar, they likely involve different genetic alterations and signaling pathways. Decades of surgical therapy, radiotherapy, and chemotherapy have failed to drastically change survival. Clearly, we do not fully understand this tumor; however, the exciting genetic revolution in glioma research over the past decade is providing a promising outlook for exploring this tumor at the genetic level. Science has begun to elucidate the numerous genetic alterations and critical signaling pathways, and it has opened new exciting areas of research such as glioma stem cell biology and neoangiogenesis. This work has already begun to improve our understanding of GBM cell proliferation, migration, and invasion. Indeed, exciting novel targeted therapies are making their way to clinical trials based on this increased knowledge. This review provides the current understanding of GBM oncogenomics, signaling pathways, and glioma stem cell biology and discusses the potential new therapeutic targets on the horizon.
CD19-targeted chimeric antigen receptor-T (CAR-T) cells with CD28 or 4-1BB (28z CAR-T and BBz CAR-T) have shown great promise to treat relapsed or refractory (r/r) B cell non-Hodgkin’s lymphoma (B-NHL). However, comparison of their clinical outcomes has never been reported. This study investigated their efficacy and adverse events in B-NHL therapy. Six patients with r/r B-NHL were initially enrolled and infused with 28z or BBz CAR-T cells at a dose of 0.75–5 × 105/kg. These CAR-T cells showed similar antitumor efficacies, with a complete response (CR) rate of 67% within 3 months. BBz CAR-T was well tolerated. However, severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in the 28z CAR-T cohort, resulting in the termination of further evaluation of 28z CAR-T. Three more patients were enrolled to investigate BBz CAR-T cells in-depth at an escalated dose (1 × 106/kg). All cases achieved CR within 3 months, and only grade 1/2 adverse events occurred. This study suggests that 4-1BB is more beneficial for the clinical performance of CAR-T cells than CD28 in CD19-targeted B-NHL therapy, at least under our manufacturing process.
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