Emerging Strategies in TCR-Engineered T Cells

Immunotherapy of cancer has made tremendous progress in recent years, as demonstrated by the remarkable clinical responses obtained from adoptive cell transfer (ACT) of patient-derived tumor infiltrating lymphocytes, chimeric antigen receptor (CAR)-modified T cells (CAR-T) and T cell receptor (TCR)-engineered T cells (TCR-T). TCR-T uses specific TCRS optimized for tumor engagement and can recognize epitopes derived from both cell-surface and intracellular targets, including tumor-associated antigens, cancer germline antigens, viral oncoproteins, and tumor-specific neoantigens (neoAgs) that are largely sequestered in the cytoplasm and nucleus of tumor cells. Moreover, as TCRS are naturally developed for sensitive antigen detection, they are able to recognize epitopes at far lower concentrations than required for CAR-T activation. Therefore, TCR-T holds great promise for the treatment of human cancers. In this focused review, we summarize basic, translational, and clinical insights into the challenges and opportunities of TCR-T. We review emerging strategies used in current ACT, point out limitations, and propose possible solutions. We highlight the importance of targeting tumor-specific neoAgs and outline a strategy of combining neoAg vaccines, checkpoint blockade therapy, and adoptive transfer of neoAg-specific TCR-T to produce a truly tumor-specific therapy, which is able to penetrate into solid tumors and resist the immunosuppressive tumor microenvironment. We believe such a combination approach should lead to a significant improvement in cancer immunotherapies, especially for solid tumors, and may provide a general strategy for the eradication of multiple cancers

Earthquake Forecast via Neutrino Tomography

We discuss the possibility of forecasting earthquakes by means of (anti)neutrino tomography. Antineutrinos emitted from reactors are used as a probe. As the antineutrinos traverse through a region prone to earthquakes, observable variations in the matter effect on the antineutrino oscillation would provide a tomography of the vicinity of the region. In this preliminary work, we adopt a simplified model for the geometrical profile and matter density in a fault zone. We calculate the survival probability of electron antineutrinos for cases without and with an anomalous accumulation of electrons which can be considered as a clear signal of the coming earthquake, at the geological region with a fault zone, and find that the variation may reach as much as 3% for $\bar \nu_e$ emitted from a reactor. The case for a $\nu_e$ beam from a neutrino factory is also investigated, and it is noted that, because of the typically high energy associated with such neutrinos, the oscillation length is too large and the resultant variation is not practically observable. Our conclusion is that with the present reactor facilities and detection techniques, it is still a difficult task to make an earthquake forecast using such a scheme, though it seems to be possible from a theoretical point of view while ignoring some uncertainties. However, with the development of the geology, especially the knowledge about the fault zone, and with the improvement of the detection techniques, etc., there is hope that a medium-term earthquake forecast would be feasible.Comment: 6 pages, 4 figures, 1 tabl

Monoclonal T-Cell Receptors: New Reagents for Cancer Therapy

Adoptive transfer of antigen-specific T lymphocytes is an effective form of immunotherapy for persistent virus infections and cancer. A major limitation of adoptive therapy is the inability to isolate antigen-specific T lymphocytes reproducibly. The demonstration that cloned T-cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. TCR gene-modified lymphocytes display antigen-specific function in vitro, and were shown to protect against virus infection and tumor growth in animal models. A recent trial in humans demonstrated that TCR gene-modified T cells persisted in all and reduced melanoma burden in 2/15 patients. In future trials, it may be possible to use TCR gene transfer to equip helper and cytotoxic T cells with new antigen-specificity, allowing both T-cell subsets to cooperate in achieving improved clinical responses. Sequence modifications of TCR genes are being explored to enhance TCR surface expression, while minimizing the risk of pairing between introduced and endogenous TCR chains. Current T-cell transduction protocols that trigger T-cell differentiation need to be modified to generate “undifferentiated” T cells, which, upon adoptive transfer, display improved in vivo expansion and survival. Both, expression of only the introduced TCR chains and the production of naïve T cells may be possible in the future by TCR gene transfer into stem cells

Metabolomics demonstrates divergent responses of two Eucalyptus species to water stress

Past studies of water stress in Eucalyptus spp. generally highlighted the role of fewer than five “important” metabolites, whereas recent metabolomic studies on other genera have shown tens of compounds are affected. There are currently no metabolite profiling data for responses of stress-tolerant species to water stress. We used GC–MS metabolite profiling to examine the response of leaf metabolites to a long (2 month) and severe (Ψpredawn < −2 MPa) water stress in two species of the perennial tree genus Eucalyptus (the mesic Eucalyptus pauciflora and the semi-arid Eucalyptus dumosa). Polar metabolites in leaves were analysed by GC–MS and inorganic ions by capillary electrophoresis. Pressure–volume curves and metabolite measurements showed that water stress led to more negative osmotic potential and increased total osmotically active solutes in leaves of both species. Water stress affected around 30–40% of measured metabolites in E. dumosa and 10–15% in E. pauciflora. There were many metabolites that were affected in E. dumosa but not E. pauciflora, and some that had opposite responses in the two species. For example, in E. dumosa there were increases in five acyclic sugar alcohols and four low-abundance carbohydrates that were unaffected by water stress in E. pauciflora. Re-watering increased osmotic potential and decreased total osmotically active solutes in E. pauciflora, whereas in E. dumosa re-watering led to further decreases in osmotic potential and increases in total osmotically active solutes. This experiment has added several extra dimensions to previous targeted analyses of water stress responses in Eucalyptus, and highlights that even species that are closely related (e.g. congeners) may respond differently to water stress and re-waterin

Synchrotron Radiation Dominates the Extremely Bright GRB 221009A

The brightest Gamma-ray burst, GRB 221009A, has spurred numerous theoretical investigations, with particular attention paid to the origins of ultra-high energy TeV photons during the prompt phase. However, analyzing the mechanism of radiation of photons in the $\sim$MeV range has been difficult because the high flux causes pile-up and saturation effects in most GRB detectors. In this letter, we present systematic modeling of the time-resolved spectra of the GRB using unsaturated data obtained from Fermi/GBM (precursor) and SATech-01/GECAM-C (main emission and flare). Our approach incorporates the synchrotron radiation model, which assumes an expanding emission region with relativistic speed and a global magnetic field that decays with radius, and successfully fits such a model to the observational data. Our results indicate that the spectra of the burst are fully in accordance with a synchrotron origin from relativistic electrons accelerated at a large emission radius. The lack of thermal emission in the prompt emission spectra supports a Poynting-flux-dominated jet composition.Comment: 12 pages, 6 figures, 2 tables. Accepted for publication in ApJ