Tumor microenvironment after biodegradable BCNU wafer implantation: special consideration of immune system

Abstract

Biomaterials to treat cancers hold therapeutic potential; however, their translation to bedside treatment requires further study. The carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea; BCNU) wafer, a biodegradable polymer, currently is the only drug that is able to be placed at the surgical site to treat malignant tumors. However, how this wafer affects the surrounding tumor microenvironment is not well understood to date. We retrospectively reviewed all patients with glioblastoma treated with and without BCNU wafers who underwent repeat resection at tumor recurrence. We investigated radiological imaging; the interval between the two surgeries; and immunohistochemistry of CD3, CD4, CD8, CD20, CD68, FOXP3, and PD1. We implanted BCNU wafers in 41 newly diagnosed glioblastoma patients after approval of the wafer in Japan. Of them, 14 underwent surgery at recurrence and tissue was obtained from around the wafers. The interval between the first and second surgeries ranged from 63 to 421 days. The wafer could be observed on magnetic resonance imaging at up to 226 days, whereas intraoperatively the biodegraded material of the wafer could be found at up to 421 days after the initial surgery. Immunohistochemical analysis demonstrated that CD8+ and CD68+ cells were significantly increased, but FOXP3+ cells did not increase, after wafer implantation compared to tissue from cases without wafer implantation. MRI data and immune cells, as well as interval between surgeries and immune cells, demonstrated positive correlation. These results helped us to understand the bioactivity of bioengineered materials and to establish a new approach for immunotherapy.

MACC1 facilitates the escape of nasopharyngeal carcinoma cells from killing by natural killer cells

“…In past studies, a large number of oncogenes have been identified to be closely related to the prognosis, radiotherapy resistance and metastasis of NPC, but the regulation of the immunological characteristics of NPC cells by these oncogenes has rarely been reported [20,21]. Studies show that tumor tissues are infiltrated with a large number of natural and acquired immune cells, such as CD4 þ T cells, CD8 þ T cells, NK cells, macrophages, mast cells, and dendritic cells [22,23]. The distant metastasis of tumor cells requires evasion of tumor cells from surveillance by immune cells, and the roles of oncogenes in this process still need further studies.…”

Symptomatic cerebral vasospasm in the setting of carmustine wafer placement for glioblastoma: A case presentation and review of literature

“…[21,22] High-dose intravenous carmustine (800/m 2 ) has been associated with retinal artery narrowing and obstruction. [31] Carmustine has also been shown to induce vasospasm in rabbit models through inhibition of glutathione reductase activity, indicating presence of local inflammatory reactions secondary to the foreign wafers. [30] In addition, Shibahara et al demonstrated a significant increase in surrounding immune cells with BCNU implantation in GBM patients and augmentation of inflammatory response in nearby tissue.…”

Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer

“…Current trends in drug delivery aim to bypass, breach, and negotiate the BBB. Between them, the use of hyperosmotic solutions [56], FUS [155], biodegradable implants [156], and CED [157] are extensively used and/or investigated in the clinic for their safety and efficacy. On the other hand, to our knowledge, only one model of targeted nanoparticle is under investigation in humans for the treatment of GBM [158].…”