The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme

Abstract

A high percentage of malignant gliomas are infected by human cytomegalovirus (HCMV), and the endogenous expression of HCMV genes and their products are found in these tumors. HCMV antigen expression and its implications in gliomagenesis have emerged as a promising target for adoptive cellular immunotherapy (ACT) strategies in glioblastoma multiforme (GB) patients. Since antigen-specific T cells in the tumor microenvironments lack efficient anti-tumor immune response due to the immunosuppressive nature of glioblastoma, CMV-specific ACT relies on in vitro expansion of CMV-specific CD8+ T cells employing immunodominant HCMV antigens. Given the fact that several hurdles remain to be conquered, recent clinical trials have outlined the feasibility of CMV-specific ACT prior to tumor recurrence with minimal adverse effects and a substantial improvement in median overall survival and progression-free survival. This review discusses the role of HCMV in gliomagenesis, disease prognosis, and recent breakthroughs in harnessing HCMV-induced immunogenicity in the GB tumor microenvironment to develop effective CMV-specific ACT.

Cancer combination therapies by silencing of CTLA‐4, PD‐L1, and TIM3 in osteosarcoma

“…In line with these findings, a randomized phase II clinical trial found that dual treatment with nivolumab and ipilimumab is efficacious and promising for patients with metastatic sarcoma 16 . Conversely, immunopathological assays demonstrated that immunocoexpression of PD‐L1 and TIM3 is most frequent in TILs from solid tumors and that these subsets characterize the most dysfunctional or exhausted fraction of TILs 37,38 . Accordingly, we hypothesized that the TIM3 blockade will act cooperatively with CTLA‐4 and PD‐L1 blockade to elicit anti‐tumor effects.…”

“…16 Conversely, immunopathological assays demonstrated that immunocoexpression of PD-L1 and TIM3 is most frequent in TILs from solid tumors and that these subsets characterize the most dysfunctional or exhausted fraction of TILs. 37,38 Accordingly, we hypothesized that the TIM3 blockade will act cooperatively with CTLA-4 and PD-L1 blockade to elicit anti-tumor effects.…”

Recent findings on chimeric antigen receptor (CAR)-engineered immune cell therapy in solid tumors and hematological malignancies

“…The utilization of CAR T-cells in glioblastoma (GB) has been limited, owing to the lack of well-described tumor-specific antigens that are expressed homogenously and frequently [ 177 ]. Cell surface antigens confined to tumor cells are ideal candidates, as they avoid the toxic effects caused by CAR T-cells recognizing normal organ tissue [ 178 ].…”

“…HER2 is being studied as a potential target in a number of clinical trials (NCT03389230, NCT03423992). Moreover, to target GB-related surface proteins, some therapeutic trials have used genetically modified cytomegalovirus (CMV)-specific T-cells that express CARs [ 177 ]. In this context, Ahmed et al showed that the administration of autologous HER2-CAR-modified virus-specific T-cells (VSTs) could be correlated with clinical benefit in patients with advanced GB [ 186 ].…”

Cytomegalovirus infection of brain tumors and CMV immunotherapy

“…Існує велика кількість імунотерапевтичних способів лікування, які розділяють на специфічні та неспецифічні, активні та пасивні, клітинні та антигенні, інфекційні та молекулярно-генетичні тощо. Велику увагу приділяють вивченню можливості створення високоактивних імунотерапевтичних препаратів, які б мали високу антигенність за рахунок ад'ювантів та вірусів і здатність спричинити специфічну протипухлинну відповідь в організмі [1,2]. Варті уваги дослідження з вивчення та с творення імунотерапевтичних препаратів із інфікованих вірусами пухлин, які мають як високу антигеність, так і сильну здатність стимулювати цитотоксичну активність імунних клітин в умовах пухлинної імуносупресії [1,2].…”