Cutaneous T-cell lymphoma (CTCL) comprises a spectrum of T-cell lymphomas with primary skin involvement. Mycosis fungoides (MF) and Sezary syndrome (SS) are the common subtypes of CTCL in which ...patients present with widely diverse profiles of skin involvement and varying extents of extracutaneous disease. Patients with early-stage disease have an excellent prognosis and are managed primarily with skin-directed therapies; however, those with advanced-stage MF or SS often require multiple lines and recurrent courses of systemic therapies. Many options are available when considering systemic agents, and it is often challenging to know how to prioritize therapies to address a patient's objective disease and quality of life issues. Appreciating the disease heterogeneity and understanding the patient's overall disease profile (eg, skin, lymph nodes, blood, large cell transformation) serve as a useful framework in aligning therapies that can optimally treat active sites of disease. Tissue or blood biomarkers can be integrated into our process of prioritizing therapies and personalizing management in MF or SS. Multidisciplinary management and optimizing supportive care are additional key elements for a favorable outcome. Appropriate patients with high-risk disease should be considered for allogeneic hematopoietic stem cell transplant.
Aims/hypothesis
Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome ...proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes.
Methods
Four groups of male C57BLKS/J
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mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks.
Results
The
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mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1–PGC-1α signalling and of the key downstream effectors, the PPARα–oestrogen-related receptor (ERR)-1α–sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)–Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1–PGC-1α signalling and the downstream effectors, PPARα–ERR-1α–SREBP1.
Conclusions/interpretation
The results suggest that resveratrol prevents diabetic nephropathy in
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mice by the phosphorylation of AMPK and activation of SIRT1–PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.
SummaryBackgroundIPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, ...Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma. MethodsWe did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045. FindingsBetween Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 27% of 44 patients) and fatigue (nine 20%), all of which were grade 1–2. Lymphopenia was the most common grade 3 or worse adverse event (three 7%). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3–20·5). A confirmed global overall response was achieved in 16 (36·4% 95% CI 23·8–51·1) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% 28·0–59·1). InterpretationIPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2. FundingInnate Pharma
Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for ...predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1
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T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.
The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL).
This international, pivotal, single-arm, ...open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells).
Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients.
Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.
Plant homeodomain finger 2 (PHF2) has a role in epigenetic regulation of gene expression by demethylating H3K9-Me2. Several genome-wide studies have demonstrated that the chromosomal region including ...the PHF2 gene is often deleted in some cancers including colorectal cancer, and this finding encouraged us to investigate the tumor suppressive role of PHF2. As p53 is a critical tumor suppressor in colon cancer, we tested the possibility that PHF2 is an epigenetic regulator of p53. PHF2 was associated with p53, and thereby, promoted p53-driven gene expression in cancer cells under genotoxic stress. PHF2 converted the chromatin that is favorable for transcription by demethylating the repressive H3K9-Me2 mark. In an HCT116 xenograft model, PHF2 was found to be required for the anticancer effects of oxaliplatin and doxorubicin. In PHF2-deficient xenografts, p53 expression was profoundly induced by both drugs, but its downstream product p21 was not, suggesting that p53 cannot be activated in the absence of PHF2. To find clinical evidence about the role of PHF2, we analyzed the expressions of PHF2, p53 and p21 in human colon cancer tissues and adjacent normal tissues from patients. PHF2 was downregulated in cancer tissues and PHF2 correlated with p21 in cancers expressing functional p53. Colon and stomach cancer tissue arrays showed a positive correlation between PHF2 and p21 expressions. Informatics analyses using the Oncomine database also supported our notion that PHF2 is downregulated in colon and stomach cancers. On the basis of these findings, we propose that PHF2 acts as a tumor suppressor in association with p53 in cancer development and ensures p53-mediated cell death in response to chemotherapy.
We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC).
The ...PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected toin vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling.
The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations ofFGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib.
FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
Agents targeting the unique biology of mycosis fungoides and Sézary syndrome are quickly being incorporated into clinical management. With these new therapies, we are now capable of inducing more ...durable responses and even complete remissions in advanced disease, outcomes which were exceedingly rare with prior therapies. Yet, even this new generation of therapies typically produce objective responses in only a minority of patients. As our therapeutic options increase, we are now challenged with selecting treatments from a growing list of options. To gain the full benefit of these novel agents, we must develop strategies to match treatments for the patients most likely to benefit from them. Here, we consider both the current approaches to treatment selection based on clinical features and the future of molecular biomarker-guided therapy for patients with this heterogeneous disease.
Mycosis fungoides and Sézary syndrome are heterogeneous diseases for which novel targeted therapies are being incorporated into treatment. In this Perspective, Khodadoust et al describe this new generation of therapies and place them in the context of the need for sequential therapy in most patients. They discuss the current approach to treatment selection as well as speculating on the future of molecularly guided therapy.
Immunotherapies are revolutionizing cancer treatment by boosting the natural ability of the immune system. In addition to antibodies against traditional checkpoint molecules or their ligands (i.e., ...CTLA-4, PD-1, and PD-L1), therapies targeting molecules such as ICOS, IDO-1, LAG-3, OX40, TIM-3, and VISTA are currently in clinical trials. To better inform clinical care and the design of therapeutic combination strategies, the co-expression of immunoregulatory proteins on individual immune cells within the tumor microenvironment must be robustly characterized. Highly multiplexed tissue imaging platforms, such as CO-Detection by indEXing (CODEX), are primed to meet this need by enabling >50 markers to be simultaneously analyzed in single-cells on formalin-fixed paraffin-embedded (FFPE) tissue sections. Assembly and validation of antibody panels is particularly challenging, with respect to the specificity of antigen detection and robustness of signal over background. Herein, we report the design, development, optimization, and application of a 56-marker CODEX antibody panel to eight cutaneous T cell lymphoma (CTCL) patient samples. This panel is comprised of structural, tumor, and immune cell markers, including eight immunoregulatory proteins that are approved or currently undergoing clinical trials as immunotherapy targets. Here we provide a resource to enable extensive high-dimensional, spatially resolved characterization of the tissue microenvironment across tumor types and imaging modalities. This framework provides researchers with a readily applicable blueprint to study tumor immunology, tissue architecture, and enable mechanistic insights into immunotherapeutic targets.
Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody ...directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.
In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.
Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months 95% CI 5·7–10·3 in the mogamulizumab group vs 3·1 months 2·9–4·1 in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.
Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.
Kyowa Kirin.
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