A unique hub-and-spoke model to optimize patient management in lymphoma using novel CAR-T cell therapy in Southeast and South Asia.

Novel therapeutic options for cancer offer hope for patients and their families, particularly when the cancer has not responded to established treatment regimens. The CAR-T cell therapeutic approach has changed the treatment paradigm for relapsed or refractory lymphoma, extending the capacity of the patient's own T cells to detect and eliminate cancer cells through genetic modification of T-cell surface receptors. The process of establishing treatment centers and developing clinical expertize in this novel treatment strategy is complex. Time, resources, and a commitment to focusing health budgets on a new area are required. Currently, Singapore is the only country in southeast and south Asia with market authorization of the CAR-T product, tisagenlecleucel. Availability of CAR-T treatment across international borders provides patients in neighboring countries with choice in therapeutic options. This paper describes the unique hub-and-spoke cross-border collaboration developed between Singapore and its neighbors to provide access to CAR-T cell therapy for patients with relapsed or refractory lymphoma. To date in 2022, four patients have been included in the CAR-T treatment cross-border collaboration. Their stay in Singapore has been at least 2 months' duration, including the pre-treatment evaluation, apheresis, CAR-T cell infusion and post-treatment monitoring. Patient support from referring and treating physicians, critical to the success of the undertaking, is characterized by early communication, patient selection, multi-disciplinary care, post-treatment monitoring, and attention to detail. The patient journey and the development and implementation of this unique collaboration are discussed.

A unique hub-and-spoke model to optimize patient management in lymphoma using novel chimeric antigen receptor-T cell therapy in Southeast and South Asia.

Novel therapeutic options for cancer offer hope for patients and their families, particularly when the cancer has not responded to established treatment regimens. The chimeric antigen receptor (CAR)-T cell therapeutic approach has changed the treatment paradigm for relapsed or refractory lymphoma, extending the capacity of the patient's own T cells to detect and eliminate cancer cells through genetic modification of T-cell surface receptors. The process of establishing treatment centers and developing clinical expertize in this novel treatment strategy is complex. Time, resources, and a commitment to focusing health budgets on a new area are required. Currently, Singapore is the only country in southeast and south Asia with market authorization of the CAR-T product, tisagenlecleucel. Availability of CAR-T treatment across international borders provides patients in neighboring countries with choice in therapeutic options. This paper describes the unique hub-and-spoke cross-border collaboration developed between Singapore and its neighbors to provide access to CAR-T cell therapy for patients with relapsed or refractory lymphoma. To date in 2022, four patients have been included in the CAR-T treatment cross-border collaboration. Their stay in Singapore has been about 2 months' duration, including the pre-treatment evaluation, apheresis, CAR-T cell infusion and post-treatment monitoring. Patient support from referring and treating physicians, critical to the success of the undertaking, is characterized by early communication, patient selection, multi-disciplinary care, post-treatment monitoring, and attention to detail. The patient journey and the development and implementation of this unique collaboration are discussed.

Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition.

Stat3 activation has been implicated as an important driver of brain metastasis in breast cancer, but the critical targets of Stat3 in this process are yet to be fully defined. In this study, we identified the lipid raft organizing protein Caveolin-1 (Cav-1) as a critical genetic target of Stat3 in this process. In human breast cancers, we found that activated Stat3 correlated with attenuation of Cav-1 in brain metastases relative to primary tumors. Cav-1 promoter activity and gene expression were increased by overexpressing an activated form of Stat3 but decreased by attenuation of Stat3 activity or expression. We identified putative Stat3-binding elements in the Cav-1 promoter and showed a direct repression of Cav-1 transcription by Stat3. Reciprocally, we showed that strategies to increase or decrease Cav-1 expression were sufficient to attenuate or promote breast cancer cell invasion. Furthermore, increased expression of Cav-1 phenocopied the effects of Stat3 activation in blocking primary tumor growth and abrogating formation of brain metastases. Collectively, our findings provide clinical and mechanistic evidence that Cav-1 is a critical target for suppression by Stat3 in driving invasion and metastasis of breast cancer cells.

Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the NG2 null mouse.

Tightly regulated crosstalk between endothelial cells and pericytes is required for formation and maintenance of functional blood vessels. When the NG2 proteoglycan is absent from pericyte surfaces, vascularization of syngeneic tumors growing in the C57Bl/6 mouse brain is aberrant in several respects, resulting in retardation of tumor progression. In the NG2 null mouse brain, pericyte investment of the tumor vascular endothelium is reduced, causing deficiencies in both pericyte and endothelial cell maturation, as well as reduced basal lamina assembly. While part of this deficit may be due to the previously-identified role of NG2 in beta1 integrin-dependent periyte/endothelial cell crosstalk, the ablation of NG2 also appears responsible for loss of collagen VI anchorage, in turn leading to reduced collagen IV deposition. Poor functionality of tumor vessels in NG2 null brain is reflected by reduced vessel patency and increased vessel leakiness, resulting in large increases in tumor hypoxia. These findings demonstrate the importance of NG2-dependent pericyte/endothelial cell interaction in the development and maturation of tumor blood vessels, identifying NG2 as a potential target for anti-angiogenic cancer therapy.

Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis.

Our recent study found that activation of signal transducer and activator of transcription 3 (Stat3) is up-regulated in human brain metastatic cells and contributes to brain metastasis of melanoma. However, the molecular mechanisms underlying this increased Stat3 activation and effect on brain metastasis are unknown. In this report, we showed that the expression of Janus-activated kinase 2 (JAK2), a Stat3 activator, was increased, whereas the expression of a negative regulator of Stat3, suppressor of cytokine signaling-1 (SOCS-1), was reduced in the brain metastatic melanoma cell line A375Br, relative to that in the parental A375P cell line. Consistently, SOCS-1 expression was also lower in the human brain metastatic tissues than in the primary melanoma tissues. Mechanistically, increased JAK2 expression in the A375Br cells was due to, at least in part, its decreased degradation, which was directly correlated with low expression of SOCS-1. Moreover, restoration of SOCS-1 expression resulted in the inhibition of Stat3 activation, whereas depletion of SOCS-1 up-regulated Stat3 activation. These clinical, experimental, and mechanistic findings strongly suggest that increased activation of Stat3 in brain metastatic melanoma cells might be due to decreased SOCS-1 expression. Furthermore, restoration of SOCS-1 expression in brain metastatic A375Br cells significantly inhibited brain metastasis in animal models (P<0.001). Additionally, alterations of SOCS-1 expression profoundly affected the expression of matrix metalloproteinase-2 (MMP-2), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) and the melanoma cell invasion and angiogenesis. Collectively, these data suggest that the loss of SOCS-1 expression is a critical event, leading to elevated Stat3 signaling and overexpression of MMP-2, bFGF, and VEGF, as well as enhanced invasion and angiogenesis of melanoma cells, consequently promoting brain metastasis.

A role for the NG2 proteoglycan in glioma progression.

Many human gliomas carry markers characteristic of oligodendrocyte progenitor cells (such as Olig-2, PDGF alpha receptor and NG2 proteoglycan), suggesting these progenitors as the cells of origin for glioma initiation. This review considers the potential roles of the NG2 proteoglycan in glioma progression. NG2 is expressed not only by glioma cells and by oligodendrocyte progenitors, but also by pericytes associated with the tumor microvasculature. The proteoglycan may therefore promote tumor vascularization and recruitment of normal progenitors to the tumor mass, in addition to mediating expansion of the transformed cell population. Along with potentiating growth factor signaling and serving as a cell surface receptor for extracellular matrix components, NG2 also has the ability to mediate activation of beta-1 integrins. These molecular interactions allow the proteoglycan to contribute to critical processes such as cell proliferation, cell motility and cell survival.

FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.

The transcription factor Forkhead box M1 (FoxM1) is overexpressed in malignant glioma. However, the functional importance of this factor in human glioma is not known. In the present study, we found that FoxM1B was the predominant FoxM1 isoform expressed in human glioma but not in normal brain tissue. The level of FoxM1 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of FoxM1 protein expression in human glioblastoma tissues was inversely correlated with patient survival. Enforced FoxM1B expression caused SW1783 and Hs683 glioma cells, which do not form tumor xenografts, to regain tumorigenicity in nude mouse model systems. Moreover, gliomas that arose from FoxM1B-transfected anaplastic astrocytoma SW1783 cells displayed glioblastoma multiforme phenotypes. Inhibition of FoxM1 expression in glioblastoma U-87MG cells suppressed their anchorage-independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that FoxM1 regulates the expression of Skp2 protein, which is known to promote degradation of the cell cycle regulator p27(Kip1). These results showed that FoxM1 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity. Therefore, FoxM1 might be a new potential target of therapy for human malignant gliomas.

Activation of stat3 in human melanoma promotes brain metastasis.

Brain metastasis is a major cause of morbidity and mortality in patients with melanoma. The molecular changes that lead to brain metastasis remain poorly understood. In this study, we developed a model to study human melanoma brain metastasis and found that Stat3 activity was increased in human brain metastatic melanoma cells when compared with that in cutaneous melanoma cells. The expression of activated Stat3 is also increased in human brain metastasis specimens when compared with that in the primary melanoma specimens. Increased Stat3 activation by transfection with a constitutively activated Stat3 enhanced brain metastasis, whereas blockade of Stat3 activation by transfection with a dominant-negative Stat3 suppressed brain metastasis of human melanoma cells in animal models. Furthermore, altered Stat3 activity profoundly affected melanoma angiogenesis in vivo and melanoma cell invasion in vitro and significantly affected the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2) in vivo and in vitro. Finally, Stat3 activity transcriptionally regulated the promoter activity of bFGF in addition to VEGF and MMP-2 in human melanoma cells. These results indicated that Stat3 activation plays an important role in dysregulated expression of bFGF, VEGF, and MMP-2 as well as angiogenesis and invasion of melanoma cells and contributes to brain metastasis of melanoma. Therefore, Stat3 activation might be a new potential target for therapy of human melanoma brain metastases.