Effective anti-tumor immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, which are T cell epitopes with tumor-specific expression arising from non-silent somatic mutations. They are highly immunogenic because they are not expressed in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumor immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively-parallel sequencing for detection of all coding mutations within tumors, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous HLA molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T cell populations and induce a broader repertoire of new T cell specificities in cancer patients, tipping the intra-tumoral balance in favor of enhanced tumor control. Here we demonstrate the feasibility, safety and immunogenicity of a vaccine that targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%), respectively, of the 97 unique neoantigens used across patients. These T cells discriminated mutated from wildtype antigens, and in some cases, directly recognized autologous tumor. Of 6 vaccinated patients, 4 had no recurrence at 25 months post-vaccination, while 2 with progressive disease were subsequently treated with anti-PD-1 therapy and experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint therapies.
A new energy paradigm, consisting of greater reliance on renewable energy sources and increased concern for energy efficiency in the total energy lifecycle, has accelerated research into energy-related technologies. Due to their ubiquity, magnetic materials play an important role in improving the efficiency and performance of devices in electric power generation, conditioning, conversion, transportation, and other energy-use sectors of the economy. This review focuses on the state-of-the-art hard and soft magnets and magnetocaloric materials, with an emphasis on their optimization for energy applications. Specifically, the impact of hard magnets on electric motor and transportation technologies, of soft magnetic materials on electricity generation and conversion technologies, and of magnetocaloric materials for refrigeration technologies, are discussed. The synthesis, characterization, and property evaluation of the materials, with an emphasis on structure-property relationships, are discussed in the context of their respective markets, as well as their potential impact on energy efficiency. Finally, considering future bottlenecks in raw materials, options for the recycling of rare-earth intermetallics for hard magnets will be discussed.
BACKGROUND Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. METHODS In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point. RESULTS After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively. CONCLUSIONS In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)
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