Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study.

BACKGROUND: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. METHODS: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 µg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. FINDINGS: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. INTERPRETATION: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. FUNDING: Trillium Therapeutics.

Personalized diet and exercise recommendations in early rheumatoid arthritis: A feasibility trial.

BACKGROUND: Physical activity and diet have a positive influence on disease activity and cardiovascular risk in patients with rheumatoid arthritis (RA). OBJECTIVE: We tested the feasibility and effect of a brief individualized counselling intervention on physical activity levels and fitness, and dietary intake, compared with standard of care. METHODS: Thirty patients with inflammatory arthritis (<1 year duration) were assigned to standard of care or the intervention, which consisted of individualized visits with a dietetic intern and physiotherapist at two time points, to review age-specific strategies on diet and exercise. Primary outcomes included anthropometric measurements (height, weight, waist and hip circumference), nutritional intake, physical activity (pedometer steps) and physical fitness. Disease activity measures and biochemical testing (blood pressure measurement, inflammatory markers, cholesterol profile and random glucose) were collected. The changes in these outcomes from baseline to 6 months were assessed using paired t-tests between groups. RESULTS: Thirteen patients in the intervention group and 10 in the control group completed the study. There were non-significant trends in improvements in physical activity, low-density lipoprotein cholesterol level and nutritional intake (vitamin C, iron, fibre, vitamin A and folate) in the intervention group. CONCLUSIONS: Poor enrolment and high dropout rates in this short-term study highlighted the difficulty of behavioural change. Those continuing in the study and who received the intervention demonstrated a non-significantly improved activity level and nutritional intake that may benefit long-term outcomes.

Trends of total cadmium, copper, and zinc in the zebra mussel (Dreissena polymorpha) along the upper reach of the St. Lawrence River: 1994-2005.

This study examines spatial and temporal variability of bioaccumulation of cadmium, copper, and zinc in tissues of zebra mussels in the upper reach of the St. Lawrence River which originates at the outflow of Lake Ontario. It was hypothesized that concentrations of these metals in mussel tissues would decline over time and decrease with increasing distance from the outlet of Lake Ontario as a result of on-going efforts to reduce contaminant discharges into the lake. Size of mussels was also evaluated as a factor influencing bioaccumulation. Mussels were collected annually in October from six sites from 1994 to 2005, including one site near a local industry. Individuals were grouped into five or more size classes per site in each year. Soft tissues were analyzed for total cadmium, copper and zinc. Concentrations of cadmium and copper in tissues varied significantly both spatially and temporally. Cadmium concentrations were elevated at most sites; copper concentrations were moderately elevated compared with other studies in the Lake Ontario basin and St. Lawrence River. Zinc showed the most uniformity in mussels possibly due to internal regulation and to low levels of environmental exposure. Animal size correlated with copper concentrations of tissues in approximately 30% of samples but infrequently for cadmium and zinc. Cadmium and copper levels were found to decline downstream over time. Inter-annual variability of metal concentrations in mussel tissues suggests utilization in long-term monitoring programs to discern significant trends.