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  • Leach posted an update 10 months, 2 weeks ago

    Pharmacology can be differentiated into two key aspects, pharmacodynamics and pharmacokinetics. Pharmacodynamics describes a drug’s impact on the body while pharmacokinetics describes the body’s impact on a drug. Another way of understanding these terms is that pharmacodynamics is a description of both the positive and negative consequences of drugs attaining certain concentrations in the body while pharmacokinetics is concerned with our ability to reach and then sustain those concentrations. Unlike the drugs for which these concepts were developed, including antibiotics, the bacteriophages (or ‘phages’) that we consider here are not chemotherapeutics but instead are the viruses of bacteria. Here we review the pharmacology of these viruses, particularly as they can be employed to combat bacterial infections (phage therapy). Overall, an improved pharmacological understanding of phage therapy should allow for more informed development of phages as antibacterial ‘drugs’, allow for more rational post hoc debugging of phage therapy experiments, and encourage improved design of phage therapy protocols. Contrasting with antibiotics, however, phages as viruses impact individual bacterial cells as single virions rather than as swarms of molecules, and while they are killing bacteria, bacteriophages also can amplify phage numbers, in situ. Explorations of phage therapy pharmacology consequently can often be informed as well by basic principles of the ecological interactions between phages and bacteria as by study of the pharmacology of drugs. Bacteriophages in phage therapy thus can display somewhat unique as well as more traditional pharmacological aspects.Background Immune checkpoint blockade has emerged as a highly effective treatment for patients with metastatic melanoma and cutaneous squamous cell carcinoma. Nivolumab blocks the interactions between programmed cell death protein 1 and programmed death ligand 1 allowing for activation of a latent immune response against the malignancy. Ipilimumab binds to and blocks cytotoxic T-lymphocyte-associated protein 4, alleviating the negative regulation of T-cell activation that is mediated by that checkpoint. Combination therapy with nivolumab and ipilimumab is associated with longer overall survival at 5 years compared with nivolumab monotherapy. Solid organ transplant recipients have a significantly higher risk of malignancies compared with the general population. There is limited data surrounding the efficacy of combination immunotherapy in solid organ transplant recipients, as these patients were excluded from seminal trials due to risk of organ rejection. Case presentations Here we present four cases of combination immunotherapy in kidney transplant recipients. Three patients had metastatic melanoma, and one patient had metastatic cutaneous squamous cell carcinoma. Two patients had radiographic responses from immunotherapy, one patient had stable disease, and one patient had disease progression. Only one patient had biopsy-proven rejection. At last follow-up, three patients had functioning grafts, though one required hemodialysis after treatment, and one patient succumbed to disease, but graft function remained intact throughout her course. Conclusions These cases describe the use of ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the potential to preserve kidney graft function while effectively treating the disease. Trial registration number NCT03816332.Background Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. Methods Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. Results Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p less then 0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5-∞), with evidence of benefit from postimmunotherapy regimens. Conclusions Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.Background Preliminary evidence indicates that early tumor shrinkage (ETS) following immune checkpoint inhibitor (ICI) initiation may be associated with survival outcomes in patients with advanced melanoma. ETS has not been explored as a biomarker of survival outcomes or patient-reported outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with ICIs. NKCC inhibitor Methods The study pooled data from patients with NSCLC in the randomized trials OAK and POPLAR (atezolizumab vs docetaxel; n=1464), and single-arm atezolizumab trials BIRCH and FIR (n=797). The association between ETS (≥10% decrease in pretreatment sum-of-longest diameters of target-lesions at 6 weeks) and overall survival (OS), progression-free survival (PFS), time to deterioration (TDD) in health-related quality-of-life (HRQoL) and physical function (PF) was assessed using Cox proportional hazard analysis. Results ETS occurred in 20% of atezolizumab-treated patients with NSCLC within OAK and POPLAR and was associated with highly favorable OS (HR 0.

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