Optimized BCMA/CS1 bispecific TRuC-T cells secreting IL-7 and CCL21 robustly control multiple myeloma.

Introduction: Challenges remain in reducing antigen escape and tumor recurrence while CAR-T cell therapy has substantially improved outcomes in the treatment of multiple myeloma. T cell receptor fusion construct (TRuC)-T cells, which utilize intact T cell receptor (TCR)-CD3 complex to eliminate tumor cells in a non-major histocompatibility complex (MHC)-restricted manner, represent a promising strategy. Moreover, interleukin-7 (IL-7) is known to enhance the proliferation and survival of T cells.

NECTIN-4-redirected T cell Antigen Coupler T cells bearing CD28 show superior antitumor responses against solid tumors.

Introduction: T cell Antigen Coupler (TAC) T cells harness all signaling subunits of endogenous T cell receptor (TCR) to trigger T-cell activation and tumor cell lysis, with minimal release of cytokines. Some of the major obstacles to cellular immunotherapy in solid tumors include inefficient cell infiltration into tumors, lack of prolonged cellular persistence, and therapy-associated toxicity.

Methods: To boost the cytotoxic potential of TAC-T cells against solid tumors, we generated a novel NECTIN-4-targeted TAC-T variant, NECTIN-4 TAC28-T, which integrated the co-stimulatory CD28 cytoplasmic region, and compared the anti-tumor activities between NECTIN-4 TAC-T cells and NECTIN-4 TAC28-T cells in vitro and vivo.

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma.

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047).

[Construction of NKG2D CAR-NK92 cells and its killing effect on multiple myeloma cells].

Objective This study aims to construct and identify the chimeric antigen receptor NK92 (CAR-NK92) cells targeting NKG2D ligand (NKG2DL) (secreting IL-15Ra-IL-15) and verify the killing activity of NKG2D CAR-NK92 cells against multiple myeloma cells. Methods The extracellular segment of NKG2D was employed to connect 4-1BB and CD3Z, as well as IL-15Ra-IL-15 sequence to obtain a CAR expression framework. The lentivirus was packaged and transduced into NK92 cells to obtain NKG2D CAR-NK92 cells.

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer.

Objectives: Over the past two decades, great progress has been made in advancing the early detection and multimodal treatment of non-small cell lung cancer (NSCLC). However, overall cure rates and survival rates of NSCLC are still not satisfactory, and research into new therapies is needed. This study attempted to construct human Fibroblast Activation Protein-Chimeric Antigen Receptor Natural killer (NK)-92 cells (hFAP-CAR-NK-92 cells) and explore their potential therapeutic effects in NSCLC.

Biofabricated macrophage and fibroblast membranes synergistically promote skin wound healing.

Effective skin wound healing is a complex process involving anti-inflammation, fibrosis, matrix reconstruction, and angiogenesis. This work aimed to integrate the macrophage-mediated anti-inflammation and fibroblast-assisted matrix reconstruction for enhanced skin wound healing. Herein, we utilized the cytomembranes derived from repolarized M2 macrophages and fibroblasts to prepare the natural biologics.

Combination of 4-1BB and DAP10 promotes proliferation and persistence of NKG2D(bbz) CAR-T cells.

Chimeric antigen receptor (CAR)-T cell therapy has been shown to have considerable therapeutic effects in hematological malignancies, and NKG2D(z) CAR-T cell therapy has been verified to be safe based on clinical trials. However, due to the poor persistence of NKG2D(z) CAR-T cells, their therapeutic effect is not obvious. Here, we constructed NKG2D(bbz) CAR-T cells that can simultaneously activate 4-1BB and DAP10 costimulatory signaling.

A novel multimeric sCD19-streptavidin fusion protein for functional detection and selective expansion of CD19-targeted CAR-T cells.

Background: CARs are engineered receptors comprising an immunoglobulin single-chain variable fragment (scFv) that identifies and binds to the target antigen, a transmembrane domain, and an intracellular T-cell signaling domain. CD19 is a B lineage-specific transmembrane glycoprotein and is expressed in more than 95% of B-cell malignancies. Streptavidin (SA) is a homo-tetrameric protein derived from Streptomyces avidinii, which can bind four biotin molecules with an extremely high affinity at a Kd value of 10 M.

TNFα antagonist in combination with PD-1 blocker to prevent or retard malignant transformation of B[a]P-induced chronic lung inflammation.

Benzo[a]pyrene (B[a]P) is a typical complete carcinogen in tobacco, but its mechanism of inducing the development of chronic pneumonia and consequent lung cancer is unclear. Here we elucidated the role of myeloid-derived suppressor cells (MDSCs) in developing B[a]P-induced chronic lung inflammation and efficacy of immunotherapy in preventing subsequent malignant transformation. Our study showed that as B[a]P could induce the accumulation of MDSCs in lung tissues and enhance the immunosuppressive effect regulated by cytokines and metabolites, thereby promoting the formation of immunosuppressive microenvironment, where effector T cells were exhausted, NK cells were dysfunctional, regulatory T (Treg) cells were expanded, polarized alveolar macrophages were transformed from M1 to M2.

The BCMA-Targeted Fourth-Generation CAR-T Cells Secreting IL-7 and CCL19 for Therapy of Refractory/Recurrent Multiple Myeloma.

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.

WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity.

Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional ablation in T cells causes severe autoimmunity associated with increased mammalian target of rapamycin (mTOR) activation and metabolic reprogramming that engender spontaneous activation and accelerated differentiation of peripheral T cells. These mice also manifest diminished antigen-specific T cell responses associated with increased inhibitory receptor expression, dysregulated mitochondrial function, and reduced cell survival upon activation.

Sequential administration of anti-PD-1 and anti-Tim-3 combined with an SA-GM-CSF-anchored vaccine overcomes adaptive immune resistance to reject established bladder cancer.

Program death receptor-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play an important role in tumor immune evasion. PD-1 blockade could produce an effective anti-tumor effect but the response rate was low due to lacking of tumor infiltrating lymphocytes (TILs) and existing of other negative regulatory pathways. Streptavidin(SA)-GM-CSF surface-anchored tumor cells vaccine could induce specific anti-tumor immune response.

Novel method for effectively amplifying human peripheral blood T cells in vitro.

The use of chimeric antigen receptor-modified T cells (CAR T cells) is an effective therapy for advanced cancer, especially hematological malignancies, and this method has attracted widespread attention in the last several years. The type, number and vitality of the effector cells clearly play important roles in this approach. In this study, to expand the possibility of curing cancer through adoptive cell therapy (ACT), we developed a novel method for effectively obtaining abundant T cells in vitro.

[Construction of CAR-T cells targeting CS1 and analysis of their antitumor activity in vitro].

We constructed the CS1-targeted second- and third-generation CAR-T cells with genetic engineered 4-1BB or/and ICOS as a costimulatory signaling molecule by use of lentiviral platform. The CS1-targeted second-generation CAR-T cells with ICOS or 4-1BB had similar anti-neoplastic activity. When effector/target ratio was 1:1, the CAR-T cells with ICOS showed better killing effect on IM9-lucgfp cells than those with 4-1BB.

Inactivation of the A gene affects capsule development and pathogenicity of .

serotype 2 ( 2) is an important swine pathogen and also an emerging zoonotic agent. HtpsA has been reported as an immunogenic cell surface protein on the bacterium. In the present study, we constructed an isogenic mutant strain of A, namely ΔA, to study its role in the development and virulence of 2.

[Construction of a novel lentiviral vector knocking down PD-1 via microRNA and its application in CAR-T cells].

By inserting microRNAs into the intron of EF1α promoter, we constructed a novel lentiviral vector knocking down PD-1 gene via microRNA and applied it to CAR-T cells. Lentiviral transduction efficiency and PD-1-silencing efficiency were detected by flow cytometry. PD-1 expression was detected by Western blotting.

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)].

Adoptive immunotherapy based on chimeric antigen receptor-modified T cells (CAR-T) is one of the most promising strategies to treat malignant tumors, but its application in solid tumors is still limited. Glypican-3 (GPC3) is a meaningful diagnostic, therapeutic, and prognostic biomarker for hepatocellular carcinoma (HCC). The second/third generation GPC3-targeted CAR-T cells are generated to treat HCC.

Gain of function mutant p53 protein activates AKT through the Rac1 signaling to promote tumorigenesis.

Tumor suppressor p53 is the most frequently mutated gene in human cancer. Mutant p53 (mutp53) not only loses the tumor suppressive activity of wild type p53, but often gains new oncogenic activities to promote tumorigenesis, defined as mutp53 gain of function (GOF). While the concept of mutp53 GOF is well-established, its underlying mechanism is not well-understood.

Screening and identification of serum biomarkers of osteoarticular tuberculosis based on mass spectrometry.

Background: In view of the current difficulty of clinically diagnosing osteoarticular tuberculosis, our aim was to use mass spectrometry to establish diagnostic models and to screen and identify serum proteins which could serve as potential diagnostic biomarkers for early detection of osteoarticular tuberculosis.

Methods: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to select an osteoarticular tuberculosis-specific serum peptide profile and establish diagnostic models. Further, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify potential serum biomarkers that could be used for auxiliary diagnosis of osteoarticular tuberculosis, and then clinical serum samples were used to verify these biomarkers by enzyme-linked immunosorbent assay (ELISA).

A surface convertible nanoplatform with enhanced mitochondrial targeting for tumor photothermal therapy.

Photothermal therapy emerges as a promising approach in antitumor treatment. A major challenge for conventional photothermal therapy is its unselective hyperthermia distribution within tumor tissues, which leads to detrimental effects on surrounding healthy tissues and compromised therapeutic effectiveness. In this study, a targeted photothermal delivery nanoplatform (P-D-CS-CNTs) was facilely fabricated by decoration of an acidity-labile polyethylene glycol (PEG) derivative onto chitosan nanoparticles encapsulating single-walled carbon nanotubes.

[Eukaryotic expression, protein purification and biological effects research of human CS1-Fc fusion protein].

Signaling lymphocyte activation family 7 (SLAMF7/CS1) is a cell surface glycoprotein that is highly expressed in multiple myeloma cells. CS1 is a sensitive and specific biomarker for multiple myeloma. CAR-T cell immunotherapy is a new method for the treatment of multiple myeloma.

Characterization of the Active Components of the Multimerized sTNFRIIAdiponectin Fusion Protein Showing Both TNFα-Antagonizing and Glucose Uptake-Promoting Activities.

Background: The sTNFRII-adiponectin fusion protein previously showed strong TNFα antagonistic activity. However, the fusion protein exists as mixture of different multimers. The aim of the present study was to characterize its active components.

Increased Tim-3 expression on TILs during treatment with the Anchored GM-CSF vaccine and anti-PD-1 antibodies is inversely correlated with response in prostate cancer.

Programmed death receptor-1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play important roles in tumor immune evasion. PD-1 blockade could produce an effective antitumor effect in many solid tumors except prostate cancer (PCa) because of rare programmed death ligand-1 (PD-L1) expression on PCa cells. Streptavidin (SA)-GM-CSF surface-anchored tumor cell (Anchored GM-CSF) vaccines could increase the number of tumor-infiltrating lymphocytes (TILs) and induce specific antitumor immune responses.

Photo/thermo-responsive and size-switchable nanoparticles for chemo-photothermal therapy against orthotopic breast cancer.

Tumor penetration of nanocarriers is still an unresolved challenge for effective drug delivery. Herein, we described a size-switchable nanoplatform in response to an external near-infrared (NIR) laser for transcellular drug delivery. The nanoplatform was constructed with a poly(-isopropylacrylamide) (PNIPAM)-based nanogel encapsulating chitosan-coated single-walled carbon nanotubes, followed by loading a chemotherapeutic drug, doxorubicin (DOX).