Exploratory analysis of Spirulina platensis LB 2340 growth in varied concentrations of anaerobically digested pig effluent (ADPE).

There is a significant interest in novel waste management solutions to treat wastewater from swine operations. Anaerobic digestion is a rising and prominent solution, but this technology still generates highly concentrated effluent that requires further remediation. Therefore, the aim of this study was to explore the feasibility of cultivating the cyanobacterium Spirulina platensis in swine effluent for future applications in biological waste treatment and value-added fermentation. To accomplish this goal, growth of S. platensis was characterized in varying proportions of ideal, synthetic Zarrouk medium and anaerobically digested pig effluent (ADPE) to obtain growth rate models. Results yielded a positive correlation between S. platensis growth rate and Zarrouk medium proportion, with the highest growth rate in 100% Zarrouk media but comparable growth in the 50/50% Zarrouk/ADPE mixture. This study demonstrates the potential for S. platensis to further improve the treatment efficacy of anaerobic digestion systems, and the exploratory analysis also highlights that further testing is required to investigate possible carbon availability, chemical inhibition, and overall nutrient reduction in ADPE. This research contributes important data toward the feasibility of producing value-added cyanobacterial biomass while simultaneously consuming excess nutrients to aid in agricultural wastewater management efforts and generate cost-effective products in a more sustainable manner.

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.

BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency.

PURPOSE: An intact immune system likely contributes to the outcome of treatment and may be important for clearance of drug-resistant tumor cells and for prevention of recurrence. Although pharmacologic inhibition of BRAF(V600E) in melanoma patients, which is linked to immune suppression, results in an initial response rate, these responses are typically of limited duration. Combining immunotherapeutic drugs with kinase-targeted agents is an attractive strategy to increase clinical efficacy. Evidence suggesting that mitogen-activated protein kinase pathway activation in tumor cells contributes to immune suppression suggests that the two approaches may be synergistic, provided that BRAF(V600E) inhibitors are nontoxic to immune cells. METHODS: To assess effects of mutant BRAF inhibition on systemic immunity, we studied 13 patients with tumors carrying a BRAF mutation who underwent treatment with GSK2118436, a V600 mutant BRAF-specific inhibitor. We carried out peripheral blood immunomonitoring before and following one or two 28-day cycles of treatment. RESULTS: GSK2118436 treatment had no detectable impact on most immune parameters tested, including serum cytokine levels, peripheral blood cell counts, leukocyte subset frequencies, and memory CD4(+) and CD8(+) T-cell recall responses. A slight increase in serum TNF-α over the course of treatment was observed. In addition, three of the four human leukocyte antigen-A2-positive patients experienced a modest increase in circulating tumor antigen-specific CD8(+) T cells following BRAF(V600) inhibitor therapy. CONCLUSIONS: GSK2118436 treatment results in no detectable negative impact on existing systemic immunity or the de novo generation of tumor-specific T cells. These findings suggest that future trials combining specific BRAF(V600E) inhibition with immunotherapy should not impair immune response.