Human primary brain cancer is one of the most lethal and clinically challenging malignancies.The failure of conventional therapies to alleviate its poor outcome has prompted efforts to find innovative treatments.Recen...Human primary brain cancer is one of the most lethal and clinically challenging malignancies.The failure of conventional therapies to alleviate its poor outcome has prompted efforts to find innovative treatments.Recent breakthroughs in immunotherapy across a variety of solid tumors have set immune-based therapeutics as a pillar for brain cancer treatment.However,the unique features of brain malignancies including intratumoral heterogeneity,immunosuppressive microenvironment,and impervious blood-brain barrier,thwart the success of immunotherapeutic approaches.Yet,seminal findings regarding tumor-driven enrichment of specific immune cells granted the field novel insights to harness the immune cells to fight cancer.This review discusses the anatomical,microenvironmental,and immunobiological features of the human brain and presents an overview of immunotherapies tested for primary brain cancer patients with a special emphasis on registered phase 2,3,and combinatorial clinical trials.Immune checkpoint inhibitors,immune cell-based therapies,cancer vaccines,oncolytic viral therapy,and combination therapies are investigated in clinical settings for the treatment of human brain tumors.Despite their occasional adverse effects,immune-targeted therapies provide a promising opportunity for primary brain cancer patients to enhance survival and improve prognosis.展开更多
Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMA...Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1.ATRT has no standard treatment,and a major limiting factor in therapeutic development is the lack of reliable ATRT models.We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells(Epi-iPSCs),followed by brief neural induction,to generate an ATRT-like model.The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers.High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines.Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids.Nucleophosmin,Osteopontin,and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids.In summary,the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels.Ribociclib,PTC-209,and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells.This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.展开更多
基金in part supported by Florida Department of Health(FDOH)Live Like Bella award(9LA01)funded in part by the Florida State University+1 种基金funded by an Endowed Chair Professorship in Cancer Research from anonymous donorsa Lebanese grant
文摘Human primary brain cancer is one of the most lethal and clinically challenging malignancies.The failure of conventional therapies to alleviate its poor outcome has prompted efforts to find innovative treatments.Recent breakthroughs in immunotherapy across a variety of solid tumors have set immune-based therapeutics as a pillar for brain cancer treatment.However,the unique features of brain malignancies including intratumoral heterogeneity,immunosuppressive microenvironment,and impervious blood-brain barrier,thwart the success of immunotherapeutic approaches.Yet,seminal findings regarding tumor-driven enrichment of specific immune cells granted the field novel insights to harness the immune cells to fight cancer.This review discusses the anatomical,microenvironmental,and immunobiological features of the human brain and presents an overview of immunotherapies tested for primary brain cancer patients with a special emphasis on registered phase 2,3,and combinatorial clinical trials.Immune checkpoint inhibitors,immune cell-based therapies,cancer vaccines,oncolytic viral therapy,and combination therapies are investigated in clinical settings for the treatment of human brain tumors.Despite their occasional adverse effects,immune-targeted therapies provide a promising opportunity for primary brain cancer patients to enhance survival and improve prognosis.
文摘Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1.ATRT has no standard treatment,and a major limiting factor in therapeutic development is the lack of reliable ATRT models.We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells(Epi-iPSCs),followed by brief neural induction,to generate an ATRT-like model.The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers.High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines.Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids.Nucleophosmin,Osteopontin,and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids.In summary,the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels.Ribociclib,PTC-209,and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells.This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.
