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Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations ( PTPN11 , BRAF ) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment. Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.

Adjuvants, materials added to vaccines to enhance the resulting immune response, are important components of vaccination that are many times overlooked. While vaccines always include an antigen to tell the body what to vaccinate to, of equal importance the adjuvant provides the how, a significant factor in producing a complete response. The adjuvant space has been slow to develop with the first use of an adjuvant in a licensed vaccine occurring in the 1930s, and remaining the only adjuvant in licensed vaccines for the next 80 years. However, with vaccination at the forefront of protection against new and complex pathogens, it is important to consider all components when designing an effective vaccine. Here we summarize the adjuvant space in licensed vaccines as well as the novel adjuvant space in clinical trials with a specific focus on the materials utilized and their resulting impact on the immune response. We discuss five major categories of adjuvant materials: aluminum salts, nanoparticles, viral vectors, TLR agonists, and emulsions. For each category, we delve into the current clinical trials space, the impact of these materials on vaccination, as well as some of the ways in which they could be improved. Adjuvants present an exciting opportunity to improve vaccine responses and stability, this review will help inform about the current progress of this space. Translational impact statement In the aftermath of the COVID‐19 pandemic, vaccines for infectious diseases have come into the spotlight. While antigens have always been an important focus of vaccine design, the adjuvant is a significant tool for enhancing the immune response to the vaccine that has been largely underdeveloped. This article provides a broad review of the history of adjuvants and, the current vaccine adjuvant space, and the progress seen in adjuvants in clinical trials. There is specific emphasis on the material landscape for adjuvants and their resulting mechanism of action. Looking ahead, while the novel vaccine adjuvant space features exciting new technologies and materials, there is still a need for more to meet the protective needs of new and complex pathogens.

Proteins are among the most common therapeutics for the treatment of diabetes, autoimmune diseases, cancer, and metabolic diseases, among others. Despite their common use, current protein therapies, most of which are injectables, have several limitations. Large proteins such as monoclonal antibodies (mAbs) suffer from poor absorption after subcutaneous injections, thus forcing their administration by intravenous injections. Even small proteins such as insulin suffer from slow pharmacokinetics which poses limitations in effective management of diabetes. Here, a deep eutectic‐based delivery strategy is used to offer a generalized approach for improving protein absorption after subcutaneous injections. The lead formulation enhances absorption of mAbs after subcutaneous injections by ≈200%. The same composition also improves systemic absorption of subcutaneously injected insulin faster than Humalog, the current gold‐standard of rapid acting insulin. Mechanistic studies reveal that the beneficial effect of deep eutectics on subcutaneous absorption is mediated by their ability to reduce the interactions of proteins with the subcutaneous matrix, especially collagen. Studies also confirm that these deep eutectics are safe for subcutaneous injections. Deep eutectic‐based formulations described here open new possibilities for subcutaneous injections of therapeutic proteins. Here the use of deep eutectic solvents in biologic formulations is reported to improve the pharmacokinetic properties of insulin and monoclonal antibodies. The underlying mechanisms are reported and the safety of deep eutectic biologics formulations in a rodent model is evaluated.

Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-κB activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally to female mice, PVP-057 enhances long-term humoral immunogenicity of varicella-zoster virus glycoprotein E to levels comparable to those induced by the clinical grade standard benchmark adjuvant, AS01B, while concurrently inducing cell-mediated immunity. To demonstrate the large-scale and precise synthesis necessary for the efficient mass production of a small molecule agonist, a green chemistry approach was completed, devising a three-step, 24-hour synthesis scheme for PVP-057, with a reliable purity of ~98%. Featuring highly efficient and scalable synthesis, a distinct TLR3-dependent mechanism of action, and robust adjuvanticity, the PVP-057 pharmacophore has prophylactic and therapeutic potential. Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for antitumor payloads. However, the in vivo persistence of iNSCs limits their therapeutic potential. We hypothesized that by encapsulating iNSCs in the FDA‐approved, hemostatic matrix FLOSEAL®, we could increase their persistence and, as a result, therapeutic durability. Encapsulated iNSCs persisted for 95 days, whereas iNSCs injected into the brain parenchyma persisted only 2 weeks in mice. Two orthotopic GBM tumor models were used to test the efficacy of encapsulated iNSCs. In the GBM8 tumor model, mice that received therapeutic iNSCs encapsulated in FLOSEAL® survived 30 to 60 days longer than mice that received nonencapsulated cells. However, the U87 tumor model showed no significant differences in survival between these two groups, likely due to the more solid and dense nature of the tumor. Interestingly, the interaction of iNSCs with FLOSEAL® appears to downregulate some markers of proliferation, anti‐apoptosis, migration, and therapy which could also play a role in treatment efficacy and durability. Our results demonstrate that while FLOSEAL® significantly improves iNSC persistence, this alone is insufficient to enhance therapeutic durability.

The present contribution focuses on the nature of the β → α transformation in Ti-5333 alloy at intermediate temperatures. It is indeed still unclear whether this transformation is only controlled by bulk diffusion or whether interfacial kinetics may play a role. To address this issue, we have combined SEM and STEM-EDX to measure the concentrations of Al, Cr, Mo, V and Fe in α intragranular precipitates as well as in the abutting β matrix, paying a particular attention to the concentrations at flat interfaces corresponding to the precipitates habit planes. The comparison with Calphad calculations suggests that interfaces are not at equilibrium during the thickening of the plates.

In the version of this article originally published, the graph in Extended Data Fig. 2c was a duplication of Extended Data Fig. 2b. The correct version of Extended Data Fig. 2c is now available online.

Vaccination is a strategy that has been utilized for centuries for the prevention of infectious diseases globally. Adjuvants can be utilized in vaccines to enhance the resulting immune response as well as specify it to the needs of the pathogen for complete protection. Despite the potential of adjuvants to improve vaccination, there has been slow development in the field, resulting in a small material landscape. There is a need for more adjuvants, specifically those that can result in strong humoral and cellular immune responses. Ionic liquids have many enticing material properties for use as adjuvants including their manufacturability and tunability. In this thesis, I develop multiple ionic liquid candidates by varying the anion hydrophobicity and screen them for vaccine adjuvancy. By screening the ionic liquid candidates through in vitro immune cell activation, antigen stability, and in vivo immune responses, an ionic liquid comprised of choline and sorbic acid, ChoSorb, was found that produced a balanced antigen-specific immune responses. ChoSorb was then explored mechanistically, firstly revealing its low dose potency and autonomous efficacy when delivered separately from the antigen. The innate immune response to ChoSorb was evaluated as well as the cell death pathways initiated in the injection site for heightened understanding of ChoSorb's initial impact on the body upon vaccination. Finally, the clinical vaccine, FluBlok, was adjuvanted with ChoSorb and delivered through two routes of administration to assess the breadth of the adjuvant: displaying enhanced and balanced immune responses upon adjuvantation. Altogether, this work introduces ionic liquids as robust adjuvants for use in infectious disease vaccines and reveals the potential mechanism and range of the first balanced ionic liquid adjuvant, ChoSorb.

In the absence of pyuria, positive urine cultures are unlikely to represent infection. Conditional urine reflex culture policies have the potential to limit unnecessary urine culturing. We evaluated the impact of this diagnostic stewardship intervention. We conducted a retrospective, quasi-experimental (nonrandomized) study, with interrupted time series, from August 2013 to January 2018 to examine rates of urine cultures before versus after the policy intervention. We compared 3 intervention sites to 3 control sites in an aggregated series using segmented negative binomial regression. The study included 6 acute-care hospitals within the Veterans' Health Administration across the United States. Adult patients with at least 1 urinalysis ordered during acute-care admission, excluding pregnant patients or those undergoing urological procedures, were included. At the intervention sites, urine cultures were performed if a preceding urinalysis met prespecified criteria. No such restrictions occurred at the control sites. The primary outcome was the rate of urine cultures performed per 1,000 patient days. The safety outcome was the rate of gram-negative bloodstream infection per 1,000 patient days. The study included 224,573 urine cultures from 50,901 admissions in 24,759 unique patients. Among the intervention sites, the overall average number of urine cultures performed did not significantly decrease relative to the preintervention period (5.9% decrease; P = 0.8) but did decrease by 21% relative to control sites (P < .01). We detected no significant difference in the rates of gram-negative bloodstream infection among intervention or control sites (P = .49). Conditional urine reflex culture policies were associated with a decrease in urine culturing without a change in the incidence of gram-negative bloodstream infection.

It has been acknowledged for many years that radiation exposure induces delayed, non-targeted effects in the progeny of the irradiated cell. Evidence is beginning to demonstrate that among these delayed effects of radiation are epigenetic aberrations, including altered DNA methylation. To test the hypothesis that differences in radiation quality affect radiation-induced DNA methylation profiles, normal AG01522 and RKO colon carcinoma cells were exposed to low-LET X rays and protons or high-LET iron ions. DNA methylation was then evaluated at delayed times using assays for p16 and MGMT promoter, LINE-1 and alu repeat element, and global methylation. The results of these experiments demonstrated radiation-induced changes in repeat element and global DNA methylation patterns at ∼20 population doublings postirradiation. Further, radiation-induced changes in repeat element and global DNA methylation were more similar between proton- and iron-ion-irradiated cells than X-irradiated cells, suggesting that radiation quality rather than LET alone affects the radiation-induced epigenetic profile. Since alterations in DNA methylation have also emerged as one of the most consistent molecular alterations in cancer, these data also suggest the possibility that radiation-induced carcinogenic risk might be affected by radiation quality.