Charitable Immunity: The Plague of Modern Tort Concepts

It is the purpose of this paper to analyze the grounds upon which charitable institutions have been granted immunity from tort liability, to consider changing conditions and concepts affecting immunity, and finally, to discuss the extent to which the immunity exception should be abandoned

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Effect of a Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) formulation on cell monolayer viability and mitochondria integrity: Significance of the drug carrier/delivery system

Background: The increasing availability and abuse of recreational and medical cannabis has been associated with patients presenting with cyclical nausea, vomiting, intestinal cramps, and other manifestations, referred to as cannabinoid hyperemesis syndrome. An exact etiologic mechanism, especially on the cellular level, remains unclear. Continual studies are needed to address the effect of cannabinoid activity specifically addressing that which occurs in the gastrointestinal tract.&nbsp;Methods: Cannabinoids in general, are immiscible in water-based cell culture media. Homogenization was performed to bring a THC/CBD formulation into a workable state for in vitro testing. The human colon adenocarcinoma (HT-29) epithelia cell line was used throughout this study. Mitochondrial cytotoxicity testing was performed using a fluorescein conjugated monoclonal antibody to the organelle’s outer membrane protein. Mitochondrial morphology was performed by transmission electron microscopy utilizing a commercially available cannabidiol product. Cell cultures, incubated with 50 to 125 µg/ml of a THC/CBD formulation for 72-h, were viewed daily for the appearance of a monolayer degeneration or a cytopathogenic effect.&nbsp;Results: Cell monolayers treated with non-homogenized THC/CBD in phosphate-buffered saline or utilizing DMSO as analyte diluents, proved unremarkable. However, homogenization of the cannabinoid formulation at &gt; 50 µg/ml affected a loss of monolayer confluency and mitochondrial membrane surface protein. Treatment of monolayers with CBD affected a loss of mitochondrial morphology as observed by an absence of organelle cristae and matrix structure. Mitochondrial loss of surface protein integrity occurred prior to monolayer degeneration.&nbsp;Conclusion: A cytotoxic effect was realized in colon cell cultures following treatment with a cannabinoid liquid tincture formulation at concentrations &gt; 50 µg/ml. The degenerative effect by the cannabinoid formulation was directed initially to a marked loss of mitochondrial morphology and loss of [organelle] surface integrity, followed by a monolayer degeneration. Critically, the immiscible THC/CBD analyte mandated a size distribution of lipid globules to single digit of smaller µM particulates.&nbsp;Globule reduction was achieved by high speed homogenization. Additional studies in the animal model are needed to further address our findings in the search for an etiology to cannabinoid hyperemesis syndrome.&nbsp;</p

Risk Factors for Death of Patients with Cystic Fibrosis Awaiting Lung Transplantation

Rationale: The optimal timing for listing of cystic fibrosis patients for lung transplantation is controversial