Phase 1 clinical trial to assess safety and efficacy of NY-ESO-1-specific TCR T cells in HLA-A∗02:01 patients with advanced soft tissue sarcoma.

New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cell receptor (TCR) T cell therapy is effective in tumors with NY-ESO-1 expression, but a safe and effective TCR-T cell therapeutic protocol remains to be improved. Here, we report a phase 1 investigational new drug clinical trial with TCR affinity-enhanced specific T cell therapy (TAEST16001) for targeting NY-ESO-1. Enrolled patients receive TAEST16001 cell infusion after dose-reduced lymphodepletion with cyclophosphamide (15 mg/kg/day × 3 days) combined with fludarabine (20 mg/m2/day × 3 days), and the TCR-T cells are maintained with low doses of interleukin-2 injection post-adoptive transfer. Analysis of 12 patients treated with the regimen demonstrates no treatment-related serious adverse events. The overall response rate is 41.7%. The median progression-free survival is 7.2 months, and the median duration of response is 13.1 months. The protocol of TAEST16001 cells delivers a safe and highly effective treatment for patients with advanced soft tissue sarcoma (ClinicalTrials.gov: NCT04318964).

Combined overexpression of four transcription factors promotes effector T cell dedifferentiation toward early phenotypes.

Effector T cells, which are abundant but are short-lived after reinfusion into the body, are generally used for T-cell therapy, and antitumor immunity is typically not maintained over the long term. Genetic modification by early differentiated T cells and reinfusion has been shown to enhance antitumor immunity in vivo. This study overexpressed the characteristic transcription factors of differentiated early T cells by transfecting effector T cells with transcription factor recombinant lentivirus (S6 group: BCL6, EOMES, FOXP1, LEF1, TCF7, KLF7; S1 group: BCL6, EOMES, FOXP1, KLF7; S3 group: BCL6, EOMES, FOXP1, LEF1) to induce a sufficient number of effector T cells to dedifferentiate and optimize the transcription factor system. The results revealed that overexpression of early characteristic transcription factors in effector T cells upregulated the expression of early T cell differentiation markers (CCR7 and CD62L), with the S1 group having the highest expression level, while the rising trend of late differentiation marker (CD45RO) expression was suppressed. Moreover, the expression of early differentiation-related genes (ACTN1, CERS6, BCL2) was significantly increased, while the expression of late differentiation-related genes (KLRG-1) and effector function-related genes (GNLY, GZMB, PRF1) was significantly decreased; this difference in expression was more significant in the S1 group than in the other two experimental groups. The antiapoptotic ability of each experimental group was significantly enhanced, while the secretion ability of TNF-α and IFN-γ was weakened, with the effector cytokine secretion ability of the S1 group being the weakest. Transcriptomic analysis showed that the gene expression profile of each experimental group was significantly different from that of the control group, with differences in the gene expression pattern and number of differentially expressed genes in the S1 group compared with the other two experimental groups. The differentially expressed gene enrichment pathways were basically related to the cell cycle, cell division, and immune function. In conclusion, overexpression of early characteristic transcription factors in effector T cells induces their dedifferentiation, and induction of dedifferentiation by the S1 group may be more effective.

Development of a system for low-temperature ultrafast optical study of three-dimensional magnon and spin orbital torque dynamics.

An ultrafast vector magneto-optical Kerr effect (MOKE) microscope with integrated time-synchronized electrical pulses, two-dimensional magnetic fields, and low-temperature capabilities is reported. The broad range of capabilities of this instrument allows the comprehensive study of spin-orbital interaction-driven magnetization dynamics in a variety of novel magnetic materials or heterostructures: (1) electrical-pump and optical-probe spectroscopy allows the study of current-driven magnetization dynamics in the time domain, (2) two-dimensional magnetic fields along with the vector MOKE microscope allow the thorough study of the spin-orbital-interaction induced magnetization re-orientation in arbitrary directions, and (3) the low-temperature capability allows us to explore novel materials/devices where emergent phenomena appear at low temperature. We discuss the details and challenges of this instrument development and integration and present two datasets that demonstrate and benchmark the capabilities of this instrument: (a) a room-temperature time-domain study of current-induced magnetization dynamics in a ferromagnet/heavy metal bilayer and (b) a low-temperature quasi-static polar MOKE study of the magnetization of a novel compensated ferrimagnet.

Exchange-Driven Spin Relaxation in Ferromagnet-Oxide-Semiconductor Heterostructures.

We demonstrate that electron spin relaxation in GaAs in the proximity of a Fe/MgO layer is dominated by interaction with an exchange-driven hyperfine field at temperatures below 60 K. Temperature-dependent spin-resolved optical pump-probe spectroscopy reveals a strong correlation of the electron spin relaxation with carrier freeze-out, in quantitative agreement with a theoretical interpretation that at low temperatures the free-carrier spin lifetime is dominated by inhomogeneity in the local hyperfine field due to carrier localization. As the regime of large nuclear inhomogeneity is accessible in these heterostructures for magnetic fields <3 kG, inferences from this result resolve a long-standing and contentious dispute concerning the origin of spin relaxation in GaAs at low temperature when a magnetic field is present. Further, this improved fundamental understanding clarifies the importance of future experiments probing the time-dependent exchange interaction at a ferromagnet-semiconductor interface and its consequences for spin dissipation and transport during spin pumping.

Identification of peptide-specific TCR genes by in vitro peptide stimulation and CDR3 length polymorphism analysis.

Identification of TCR genes specific for tumor-associated antigens (TAAs) is necessary for TCR gene modification of T cells, which is applied in anti-tumor adoptive T cell therapy (ACT). The usual identification methods are based on isolating single peptide-responding T cells and cloning the TCR gene by in vitro expansion or by single-cell RT-PCR. However, the long and exacting in vitro culture period and demanding operational requirements restrict the application of these methods. Immunoscope is an effective tool that profiles a repertoire of TCRs and identifies significantly expanded clones through CDR3 length analysis. In this study, a survivin-derived mutant peptide optimized for HLA-A2 binding was selected to load DCs and activate T cells. The monoclonal expansion of TCRA and TCRB genes was separately identified by Immunoscope analysis and following sequence identification, the properly paired TCR genes were transferred into T cells. Peptide recognition and cytotoxicity assays indicated that TCR-modified PBMCs could respond to both the mutant and wild type peptides and lyse target cells. These results show that combining Immunoscope with in vitro peptide stimulation provides an alternative and superior method for identifying specific TCR genes, which represents a significant advance for the application of TCR gene-modified T cells.

Differences in TCR-Vß repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age.

Tumor infiltrating lymphocytes (TIL) reflect the host's anti-tumor immune response, and can be a valuable predictor of prognosis. However, many properties of TIL are not fully understood. In the present study, TCR-Vß repertoires of cancer patients were primarily analyzed by flow cytometry. Abnormally expressed TCR-Vß subfamilies were generally found in both TIL and peripheral blood lymphocytes (PBL) of each patient. Of note, increased patient age was associated with increasingly biased TCR-Vß repertoire in TIL but not in PBL, and the dispersion degree of the differences of TCR-Vß subfamilies between TIL and PBL correlated positively with age (P = 0.007). Utilizing immunoscope analysis, we identified the age-related reduction in TCR-Vß diversity, but polyclonal pattern was predominant in significantly expanded TCR-Vß subfamilies. In addition, we found that older patients possessed a decreased ratio of CD8+CD62L+ non-effector cells in TIL compared to PBL, implying age-related increase of CD8+CD62L- effector cells in TIL. The colocalization analysis of CD8 and CD3, however, suggested the suppressed activity of these effector cells in tumor microenvironment. These findings further elucidate the properties of TIL, showing an increasing difference between TIL and PBL with age, which may provide insight for the development of effective immunotherapies for cancer patients of different ages.