Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL.

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.

Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.

BACKGROUND: Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. METHODS: This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988. FINDINGS: Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine [20%] of 44 patients), neutropenia (three [7%]), and hyperglycaemia (three [7%]). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose. INTERPRETATION: The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing. FUNDING: Curis, Inc, and the Leukemia and Lymphoma Society.

Spectrophotometric titration of bimetallic metal cation binding in polyamido(amine) dendrimer templates.

Spectrophotometric titration and a binding isotherm were used to accurately assess the loading capacity of generation four polyamido(amine) (PAMAM) dendrimer templates with terminal alcohol groups (G4-OH). Preparation of bimetallic G4-OH dendrimer-encapsulated metal nanoclusters (DENs) necessitates knowledge of the precise metal-ion binding capacity. The binding of metal ions such as Pt(2+) and Pd(2+) has proven difficult to assess via UV-vis spectroscopy because the absorbance shifts associated with metal-ion binding within the dendrimer template are masked by the absorbance of the PAMAM dendrimer itself. In contrast, the binding of Cu(2+) to G4-OH PAMAM dendrimer results in a strong, distinct absorption band at 300 nm, making UV-vis spectrophotometric titration with copper straightforward. Here we use copper binding as a means to assess the number of binding sites remaining within the PAMAM G4-OH dendrimer after the complexation of a specified molar excess of Pd(2+) or Pt(2+). In addition, we use a binding isotherm to mathematically estimate the loading capacity of the dendrimer in each case. The loading capacities for M(2+) in the G4-OH dendrimer were found to be ∼16 for copper alone, ∼21 for copper combined with palladium, and ∼25 for copper combined with platinum.

KT&G: From Korean monopoly to 'a global name in the tobacco industry'.

Until the late 1980s, the former South Korean tobacco monopoly KT&G was focused on the protected domestic market. The opening of the market to foreign competition, under pressure from the U.S. Trade Representative, led to a steady erosion of market share over the next 10 years. Drawing on company documents and industry sources, this paper examines the adaptation of KT&G to the globalization of the South Korean tobacco industry since the 1990s. It is argued that KT&G has shifted from a domestic monopoly to an outward-looking, globally oriented business in response to the influx of transnational tobacco companies. Like other high-income countries, South Korea has also seen a decline in smoking prevalence as stronger tobacco control measures have been adopted. Faced with a shrinking domestic market, KT&G initially focused on exporting Korean-manufactured cigarettes. Since the mid-2000s, a broader global business strategy has been adopted including the building of overseas manufacturing facilities, establishing strategic partnerships and acquiring foreign companies. Trends in KT&G sales suggest an aspiring transnational tobacco company poised to become a major player in the global tobacco market. This article is part of the special issue 'The emergence of Asian tobacco companies: Implications for global health governance'.

USC-HN2, a new model cell line for recurrent oral cavity squamous cell carcinoma with immunosuppressive characteristics.

Head and neck squamous cell carcinomas (HNSCC) are common and aggressive tumors that have not seen an improvement in survival rates in decades. These tumors are believed to evade the immune system through a variety of mechanisms and are therefore highly immune modulatory. In order to elucidate their interaction with the immune system and develop new therapies targeting immune escape, new pre-clinical models are needed. A novel human cell line, USC-HN2, was established from a patient biopsy specimen of invasive, recurrent buccal HNSCC and characterized by morphology, heterotransplantation, cytogenetics, phenotype, gene expression, and immune modulation studies and compared to a similar HNSCC cell line; SCCL-MT1. Characterization studies confirmed the HNSCC origin of USC-HN2 and demonstrated a phenotype similar to the original tumor and typical of aggressive oral cavity HNSCC (EGFR(+)CD44v6(+)FABP5(+)Keratin(+) and HPV(-)). Gene and protein expression studies revealed USC-HN2 to have highly immune-modulatory cytokine production (IL-1ß, IL-6, IL-8, GM-CSF, and VEGF) and strong regulatory T and myeloid derived suppressor cell (MDSC) induction capacity in vitro. Of note, both USC-HN2 and SCCL-MT1 were found to have a more robust cytokine profile and MDSC induction capacity when compared to seven previously established HNSCC cell lines. Additionally, microarray gene expression profiling of both cell lines demonstrate up-regulation of antigen presenting genes. Because USC-HN2 is therefore highly immunogenic, it also induces strong immune suppression to evade immunologic destruction. Based upon these results, both cell lines provide an excellent model for the development of new suppressor cell-targeted immunotherapies.

A binding domain on mesothelin for CA125/MUC16.

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296-359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

Association between parental history of type 2 diabetes and glycemic control in urban African Americans.

OBJECTIVE: The purpose of this study was to examine the association between parental history of type 2 diabetes and glycemic control among diabetic urban African Americans. RESEARCH DESIGN AND METHODS: Study participants included 359 African Americans with type 2 diabetes from Baltimore, Maryland, enrolled in Project Sugar 2. Participants underwent an interview-administrated questionnaire that asked about family history, sociodemographics, clinical characteristics, and knowledge and perception of adequate glycemic control. Regression analysis was used to determine the association between parental history of diabetes and glycemic control, as measured by A1C. RESULTS: In the comparisons between participants with and without a parental history of diabetes, those with a positive parental history tended to be younger, have higher glucose levels, and have higher blood glucose levels before calling a doctor (all P < 0.05). After adjustments for age, sex, and BMI, there was a significant association (P = 0.02) between A1C and parental history with the mean A1C difference between those with a positive and a negative parental history being 0.58%. However, after adjustment for duration of diabetes, the association was no longer significant (P = 0.11). However, there was a tendency for individuals with two diabetic parents to have higher A1C (P = 0.011). CONCLUSIONS: From these results, we conclude that among the urban African American participants who were aware of their parental history of diabetes, a positive parental history was associated with worse glycemic control, partly due to longer duration of diabetes. Parental history did not appear to be associated with better knowledge or perception of adequate glycemic control.