Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell–mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific ...for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients’ blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.
The formation of transient hybrid nanoscale metal species from homogeneous molecular precatalysts has been demonstrated by in situ NMR studies of catalytic reactions involving transition metals with ...N‐heterocyclic carbene ligands (M/NHC). These hybrid structures provide benefits of both molecular complexes and nanoparticles, enhancing the activity, selectivity, flexibility, and regulation of active species. However, they are challenging to identify experimentally due to the unsuitability of standard methods used for homogeneous or heterogeneous catalysis. Utilizing a sophisticated solid‐state NMR technique, we provide evidence for the formation of NHC‐ligated catalytically active Pd nanoparticles (PdNPs) from Pd/NHC complexes during catalysis. The coordination of NHCs via C(NHC)−Pd bonding to the metal surface was first confirmed by observing the Knight shift in the 13C NMR spectrum of the frozen reaction mixture. Computational modeling revealed that as little as few NHC ligands are sufficient for complete ligation of the surface of the formed PdNPs. Catalytic experiments combined with in situ NMR studies confirmed the significant effect of surface covalently bound NHC ligands on the catalytic properties of the PdNPs formed by decomposition of the Pd/NHC complexes. This observation shows the crucial influence of NHC ligands on the activity and stability of nanoparticulate catalytic systems.
This research explores the formation of hybrid nanoscale metal species from molecular precatalysts, which exhibit the unique attributes of molecular complexes and nanoparticles. This study addresses their detection difficulties and introduces solid‐state NMR to demonstrate the generation of catalytically active Pd nanoparticles from Pd/NHC complexes. The findings underscore the critical role of NHC ligands in catalytic nanoparticle system stability and activity.
Tolerance to self-antigens prevents the elimination of cancer by the immune system
. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor ...rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27
CD45RO
CD8
T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27
PD-1
CD8
CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.
Student-oriented Learning and “Living Values” of the University: Strategic Interaction Kulikovskaya, Galina A.; Kulikovskaya, Nina A.
Vestnik Rossijskogo universiteta družby narodov. Seriâ Gosudarstvennoe i municipalʹnoe upravlenie/Vestnik Rossijskogo universiteta družby narodov. Seriâ: Gosudarstvennoe i municipalʹnoe upravlenie,
12/2020, Letnik:
7, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The purpose of the article is to consider possible ways to improve the effectiveness of student-oriented education in Russian universities through strategic interaction with the basic principles of ...their life. It is well known that the involvement of students in the management of higher education institutions (HEIs), their active participation in determining the individual trajectories of their professional training increases the motivation of students, and therefore the quality of education. To do this, it is necessary not only to fix the principles of student self-government in the local regulations of the University, but also to build mechanisms for implementing these principles. In particular, this can be expressed in the structure and content of educational programs developed in accordance with educational standards, consisting of a mandatory part and a part formed by participants in educational relations. Project-based learning will help bridge the gap between theory and practice in teaching students. Inclusive education should be provided not only with infrastructure, but also with special training of teachers and the inclusion of specialized adaptation modules in educational programs. To ensure quality control of students ' knowledge, the professional level of teachers and the organization of the educational process, intra-University quality management systems for training specialists are being created.an important element of this system should also be the structure of student self-government. It is also necessary to understand that student-oriented learning is not limited to the educational process, but covers the organization of campus life, the possibility of self-realization of students in various public organizations, in creative teams, i.e. it is inextricably linked to the entire system of principles, goals, priorities - the Living Values of the University. In the context of improving the competitiveness of education in Russian universities, the article identifies and justifies ways to improve the effectiveness of student-oriented learning. In particular, there was a high demand for the possibility of students influence on their individual learning paths, self-realization through participation in projects, both in the educational process and in public life. The research uses the results of sociological research based on surveys of students and teachers, including online surveys, as well as the practice of organizing the educational process and extracurricular activities in Russian universities. The results obtained can be used to further improve the development strategies of higher education institutions, including to increase their attractiveness for foreign students.
The doctrinal provisions of the institution of international human and civil rights and freedoms in the second half of the twentieth century became critical among other institutions of international ...and national legislation. This institution has become an indispensable attribute of the legal state representing a significant result of the legal development of society. The problems of legal regulation and the need to protect human rights in modern society have not been sufficiently developed, and require a holistic, comprehensive approach to the study of the institution of human rights and freedoms and citizens. Currently, the recognition of human and civil rights and freedoms reveals the level of development of the country, shows the readiness of the state for international legal integration and further interaction with other states at a higher level.
Investigation of catalytic reactions using nuclear magnetic resonance (NMR) is a crucial task, which is often challenging to perform due to rather complex transformations at the metal center. In this ...work, it was shown that electrophoretic NMR can be a suitable method for studying catalytic reactions and for observing the changes in the catalyst nature. As an important example involving palladium catalysts with N‐heterocyclic carbine ligands (NHCs), the breakage of the Pd‐NHC bond can occur during the catalytic process. Electrophoretic NMR allows the distinction of compounds in the spectra depending on the charge, thus bringing new opportunities to mechanistic studies. Here, we present independent evidence of R‐NHC product formation in the Pd‐catalyzed Mizoroki–Heck reaction—the key process for catalyst change from the molecular to nano‐scale type.
Electrophoretic NMR distinguishes compounds in the spectra depending on their charge. Application of electrophoretic NMR to study the transformations of organometallic compounds in chemical reactions opens up new possibilities for mechanistic studies.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a ...CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility ...of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (
) and TCRβ (
), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1;
), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.
The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers
. However, little is known about the long-term potential and ...clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia
who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4
population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4
CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8
CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.
Thermodynamic instability of the trivalent phosphorus embedded in a carbon plane was estimated experimentally and theoretically. The change in the electronic state of phosphorus upon exposure of the ...sample to air was demonstrated using XPS and solid state NMR methods.
PDF
