Chimeric antigen receptor T cell (CAR-T) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin's lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we employed single cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and post-infusion into NHL patients. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a non-proliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate TIGIT blockade alone improves the anti-tumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in NHL patients.

Sequential single cell transcriptional and protein marker profiling reveals TIGIT as a marker of CD19 CAR-T cell dysfunction in patients with non-Hodgkin's lymphoma.

Chimeric antigen receptor (CAR) T cells, which express a synthetic receptor engineered to target specific antigens, have demonstrated remarkable potential to treat haematological malignancies. However, their transition beyond haematological malignancy has so far been unsatisfactory. Here, we discuss recent challenges and improvements for CAR T cell therapy against solid tumors: Antigen heterogeneity which provides an effective escape mechanism against conventional mono-antigen-specific CAR T cells; and the immunosuppressive tumor microenvironment which provides physical and molecular barriers that respectively prevent T cell infiltration and drive T cell dysfunction and hypoproliferation. Further, we discuss the application of CAR T cells in infectious disease and autoimmunity.

CAR T Cell Immunotherapy Beyond Haematological Malignancy

The tumor microenvironment restricts the function and survival of various immune cells by up-regulating inhibitory immune checkpoints, and participates in the immune escape of tumors. The development of immunotherapies targeting immune checkpoints, such as programmed cell death receptor 1 antibody and anti-cytotoxic T lymphocyte-associated antigen 4 antibody, has provided many options for cancer treatment. The efficacy of other immune checkpoint inhibitors is also under development and research. Among them, T cell immunoreceptor with Ig and ITIM domains (TIGIT) has shown excellent clinical application prospects. Correspondingly, poliovirus receptor (PVR, CD155), one of the main ligands of TIGIT, is mainly expressed in various human malignant tumors and myeloid cells. CD155 interacts with TIGIT on natural killer cells and T cells, mediating inhibitory immunomodulatory regulation. This study summarized the mechanism of CD155/TIGIT in regulating immune cells and its role in the occurrence and development of digestive system tumors, aiming to provide a new perspective for immunotherapy of digestive cancers.

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Role of CD155/TIGIT in Digestive Cancers: Promising Cancer Target for Immunotherapy

Introduction The development of therapeutic antibodies targeting immune checkpoint molecules (ICMs) that induce long-term remissions in cancer patients has revolutionized cancer immunotherapy. However, a major drawback is that relapse after an initial response may be attributed to innate and acquired resistance. Additionally, these treatments are not beneficial to all patients. Therefore, the discovery and targeting of novel ICMs and their combination with other immunotherapeutics are urgently needed.Areas covered There has been increasing evidence of the CD96-TIGIT axis as ICMs in cancer immunotherapy in the last five years. This review will highlight and discuss the current knowledge about the role of CD96 and TIGIT in hematological and solid tumor immunotherapy in the context of empirical studies and clinical trials, and provide a comprehensive list of ongoing cancer clinical trials on the blockade of these ICMs, as well as the rationale behind combinational therapies with anti-PD-1/PD-L1 agents, chemotherapy drugs, and radiotherapy. Moreover, we share our perspectives on anti-CD96/TIGIT-related combination therapies.Expert opinion CD96-TIGIT axis regulates anti-tumor immune responses. Thus, the receptors within this axis are the potential candidates for cancer immunotherapy. Combining the inhibition of CD96-TIGIT with anti-PD-1/PD-L1 mAbs and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models. 

Advances in therapeutic targeting of immune checkpoints receptors within the CD96-TIGIT axis: clinical implications and future perspectives

The epidermal growth factor receptor variant III (EGFRvIII) has been investigated as a therapeutic target for chimeric antigen receptor (CAR) T cell therapy in glioblastoma. Earlier research demonstrated that phenotypic and genotypic characteristics in T cells and CAR T product predicted therapeutic success in hematologic malignancies, to date no determinants for clinical response in solid tumors have been identified. We analyzed apheresis and infusion products from the first-in-human trial of EGFRvIII-directed CAR T for recurrent glioblastoma (NCT02209376) by flow cytometry. Clinical response was quantified via engraftment in peripheral circulation and progression-free survival (PFS), as determined by the time from CAR T infusion to first radiographic evidence of progression. The CD4+CAR T cell population in patient infusion products demonstrated PD1 expression which positively correlated with AUC engraftment and PFS. On immune checkpoint inhibitor analysis, CTLA-4, TIM3, and LAG3 did not exhibit significant associations with engraftment or PFS. The frequencies of PD1+GZMB+ and PD1+HLA-DR+ CAR T cells in the CD4+ infusion products were directly proportional to AUC and PFS. No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.

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PD1 Expression in EGFRvIII-Directed CAR T Cell Infusion Product for Glioblastoma Is Associated with Clinical Response

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells.

A cross-flow air turbine, which is a self-rectifying, air-driven turbine, was designed and proposed for the power take-off (PTO) system of an oscillating water column (OWC) wave energy converter (WEC). To predict the complicated non-linear behavior of the air turbine in the OWC, numerical and experimental investigations were accomplished. The geometries of the nozzle and the rotor of the turbine were optimized under steady-flow conditions, and the performance analysis of the model in bi-directional flows was conducted by commercial computational fluid dynamics (CFD) code ANSYS CFX. Experimentation on the full-scale turbine was then undertaken in a cylindrical-type wave simulator that generated reciprocating air flows, to validate the numerical model. The optimized model had a peak cycle-averaged efficiency of 0.611, which is 1.7% larger than that of the reference model, and a significantly improved band width with an increase in flow coefficients. Under reciprocating-flow conditions, the optimized model had a more improved operating range with high efficiency compared to the performance derived from the steady-flow analysis, but the peak cycle-averaged efficiency was decreased by 4.3%. The numerical model was well matched to the experimental results with an averaged difference of 3.5%. The proposed optimal design having structural simplicity with high performance can be a good option to efficiently generate electricity. 

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Design Optimization of a Cross-Flow Air Turbine for an Oscillating Water Column Wave Energy Converter

Aggregation of intrinsically disordered α-synuclein (αSN) under various conditions is closely related to synucleinopathies. Although various biological membranes have shown to alter the structure and aggregation propensity of αSN, a thorough understanding of the molecular and mechanical mechanism of amyloidogenesis in membranes remains unanswered. Herein, we examined the structural changes, binding properties, and amyloidogenicity of three variations of αSN mutants under two types of liposomes, 1,2-Dioleoyl-sn-glycero-3-Phosphocholine (DOPC) and presynaptic vesicle mimetic (Mimic) membranes. While neutrally charged DOPC membranes elicited marginal changes in the structure and amyloid fibrillation of αSNs, negatively charged Mimic membranes induced dramatic helical folding and biphasic amyloid generation. At low concentration of Mimic membranes, the amyloid fibrillation of αSNs was promoted in a dose-dependent manner. However, further increases in the concentration constrained the fibrillation process. These results suggest the dual effect of Mimic membranes on regulating the amyloidogenesis of αSN, which is rationalized by the amyloidogenic structure of αSN and condensation-dilution of local αSN concentration. Finally, we propose physicochemical properties of αSN and membrane surfaces, and their propensity to drive electrostatic interactions as decisive factors of amyloidogenesis. 

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Dual Effects of Presynaptic Membrane Mimetics on α-Synuclein Amyloid Aggregation

Alpinia officinarum (A. officinarum) is known to exhibit a beneficial effect for anti-inflammatory, anti-oxidant, and anti-hyperlipidemic effects. However, no sufficient research data are available on the cardiovascular effect of A. officinarum. Thus, in this study, we investigate whether A. officinarum extract has direct effects on vascular reactivity.To examine whether A. officinarum extract affects vascular functionality, we measured isometric tension in rat mesenteric resistance arteries using a wire myograph. After arteries were pre-contracted with high-K+ (70 mM), phenylephrine (5 µM), or U46619 (1 µM), A. officinarum extract was treated.A. officinarum extract induced vasodilation in a concentration-dependent manner, and this effect was endothelium independent. To further investigate the mechanism, we incubated arteries in a Ca2+-free and high-K+ solution, followed by the cumulative addition of CaCl2 (0.01-2.5 mM) with or without A. officinarum extract (30 µg/mL). Pre-treatment of A. officinarum extract reduced the contractile responses induced by cumulative administration of Ca2+, which suggests that extracellular Ca2+ influx was inhibited by the treatment of A. officinarum extract. These results were associated with a reduction in phosphorylated MLC20 in VSMCs treated with A. officinarum extract. Furthermore, eucalyptol, an active compound of A. officinarum extract, had a similar effect as A. officinarum extract, which causes vasodilation in mesenteric resistance arteries.A. officinarum extract and its active compound eucalyptol induce concentration-dependent vasodilation in mesenteric resistance arteries. These results suggest that administration of A. officinarum extract could exert beneficial effects to treat high blood pressure. 

https://www.mdpi.com/1420-3049/27/9/2711/pdf?version=1650881322

Zihang Gao

Papers

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells

PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells.

Design Optimization of a Cross-Flow Air Turbine for an Oscillating Water Column Wave Energy Converter

Dual Effects of Presynaptic Membrane Mimetics on α-Synuclein Amyloid Aggregation

Vasodilatory Effect of Alpinia officinarum Extract in Rat Mesenteric Arteries