Simple and effective bacterial-based intratumoral cancer immunotherapy

Background We describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients. Methods Efficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient. Results Significantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided. Conclusion Our data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.g Canberra trial: Canberra Hospital Private Practice Fund, Janice and Ron Parker Fund. Mouse preclinical studies: Lea Chapuis Memorial Fund. Canine preclinical studies: The John and Mary Kibble Trust (grants CT22492, CT21335) and the William Peter Richards Bequest for research into veterinary pathology. CSEC, ERA, and AAA was supported by Australian Government Research Training Program Stipend Scholarships. CSEC and K-MS were supported by Max Lindemann Memorial Foundation, Miam

A phase II randomised controlled trial of intensive insulin therapy in general intensive care patients

To determine the safety and efficacy of an intensive insulin regimen compared with a conventional insulin regimen in general intensive care unit patients.A phase II, randomised controlled trial was conducted in 70 critically ill patients in a closed multidisciplinary ICU of a university-affiliated tertiary hospital. We assessed patient characteristics at baseline. Trial process measures included number of blood glucose measurements per day and number in target range, type and quantity of caloric intake, patient outcome and insulin dosing. The primary outcome was the median blood glucose concentration. Secondary outcome measures were incidence of hypoglycaemia (blood glucose level < 2.2 mmol/L), clinical sequelae of hypoglycaemia and hospital mortality.Thirty-five patients were randomised to each of the two groups. More blood glucose samples were taken per day in the intensive insulin group (16 versus 9), but the number of samples in the normoglycaemic range was 48.5%, compared with 79.8% within the target glucose range in the conventional insulin group. The median (interquartile range) blood glucose concentrations in the intensive and conventional insulin therapy groups were 5.4 (5.1-5.7) mmol/L and 7.9 (7.2-9.0) mmol/L, respectively (difference, 2.5 mmol/L; P < 0.0001). Five patients (14.3%) in the intensive insulin therapy group became hypoglycaemic versus none in the conventional insulin therapy group. There were no detected clinical sequelae of hypoglycaemia.The intensive insulin regimen was effective in achieving the target blood glucose concentration, with clear separation from the conventional insulin regimen. Although the incidence of hypoglycaemia was increased, there was no detectable harm