Evaluation of MAGE-A4 expression in breast cancer and its impact on prognosis.

Melanoma-associated antigen (MAGE)-A4, a cancer testis antigen, presents a promising target for chimeric antigen receptor T cell therapy in refractory solid tumors, including breast cancer (BC). However, the lack of highly specific Abs against MAGE-A4 is a major challenge for the development of MAGE-A4-targeted immunotherapies. This study aimed to validate the specificity of a novel MAGE-A4 Ab (E701U) and examine MAGE-A4 expression in clinical BC samples.

MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity.

Background: The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR.

Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4/HLA-A∗02:01 complex.

Despite the revolutionary success of chimeric antigen receptor (CAR)-T therapy for hematological malignancies, successful CAR-T therapies for solid tumors remain limited. One major obstacle is the scarcity of tumor-specific cell-surface molecules. One potential solution to overcome this barrier is to utilize antibodies that recognize peptide/major histocompatibility complex (MHCs) in a T cell receptor (TCR)-like fashion, allowing CAR-T cells to recognize intracellular tumor antigens.

Safety and Efficacy of NY-ESO-1 Antigen-Specific T-Cell Receptor Gene-Transduced T Lymphocytes in Patients with Synovial Sarcoma: A Phase I/II Clinical Trial.

Purpose: To determine, for patients with advanced or recurrent synovial sarcoma (SS) not suitable for surgical resection and resistant to anthracycline, the safety and efficacy of the infusion of autologous T lymphocytes expressing NY-ESO-1 antigen-specific T-cell receptor (TCR) gene and siRNA to inhibit the expression of endogenous TCR (product code: TBI-1301).

Patients And Methods: Eligible Japanese patients (HLA-A*02:01 or *02:06, NY-ESO-1-positive tumor expression) received cyclophosphamide 750 mg/m2 on days -3 and -2 (induction period) followed by a single dose of 5×109 (±30%) TBI-1301 cells as a divided infusion on days 0 and 1 (treatment period). Primary endpoints were safety-related (phase I) and efficacy-related [objective response rate (ORR) by RECIST v1.

Fully closed cell sorter for immune cell therapy manufacturing.

By analyzing patients treated with adoptive immune cell therapies, various immune cell phenotypes have been found in the starting and infused materials as determinants of sustained remission. The isolation of these specific phenotypes for clinical use requires current Good Manufacturing Practice (cGMP)-compliant cell-sorting technologies with multiparameter selection capabilities. Here, we developed a cGMP-requirement-applicable fully closed cell sorter that has a suction mechanism and multiparameter detection using two laser optical settings.

[Exploring for the Development of Personalized Cancer Immunotherapy].

Immune checkpoint inhibitors(ICIs)have become common anti-cancer drugs, and CD19-targeted CAR-T therapies for B-cell malignant hematological diseases are becoming popular in Japan. Accompanied with such innovative progress in immunotherapy, understanding of anti-tumor immune responses have been further accelerated, and clinical trials aiming for the development of cancer immunotherapy targeting solid tumors are becoming increasingly active. Among of them, the development of"personalized cancer immunotherapy"using tumor-reactive T cells/TCRs that specifically recognize mutant antigens, or those mutant antigens has made great progress.

Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.

Introduction: Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A*02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies.

NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome.

Background: Because of the shortage of ideal cell surface antigens, the development of T-cell receptor (TCR)-engineered T cells (TCR-T) that target intracellular antigens such as NY-ESO-1 is a promising approach for treating patients with solid tumors. However, endogenous TCRs in vector-transduced T cells have been suggested to impair cell-surface expression of transduced TCR while generating mispaired TCRs that can become self-reactive.

Methods: We conducted a first-in-human phase I clinical trial with the TCR-transduced T-cell product (TBI-1301) in patients with NY-ESO-1-expressing solid tumors.

IL-17A Is the Critical Cytokine for Liver and Spleen Amyloidosis in Inflammatory Skin Disease.

Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice).

Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients.

The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8 and CD4 T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment.

MAGE-A4, NY-ESO-1 and SAGE mRNA expression rates and co-expression relationships in solid tumours.

Background: Cancer testis (CT) antigens are promising targets for cancer immunotherapies such as cancer vaccines and genetically modified adoptive T cell therapy. In this study, we evaluated the expression of three CT antigens, melanoma-associated antigen A4 (MAGE-A4), New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) and sarcoma antigen gene (SAGE).

Methods: MAGE-A4, NY-ESO-1 and/or SAGE antigen expression in tumour samples was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR).

Relationship between T cell receptor clonotype and PD-1 expression of tumor-infiltrating lymphocytes in colorectal cancer.

Adoptive T cell therapy using tumor-specific T cells or TCR-modified T cells is a promising next-generation immunotherapy. The major source of tumor-reactive T cells is PD-1 tumor-infiltrating lymphocytes (TILs). In contrast, PD-1 TILs have received little attention.

First-in-human phase I clinical trial of the NY-ESO-1 protein cancer vaccine with NOD2 and TLR9 stimulants in patients with NY-ESO-1-expressing refractory solid tumors.

Cholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines.

Development of INSOL-tag for proteome-wide protein handling and its application in protein array analysis.

Proteomic analysis requires protein tags that enable high-throughput handling; however, versatile tags that can be used in in vitro expression systems are currently lacking. In this study, we developed an insoluble protein tag, INSOL-tag, derived from human transcription factor MafG. The INSOL-tagged target protein is expressed in a eukaryotic in vitro expression system and recovered as a pellet following centrifugation at 19,000 × g for 20 min.

First Case of Cytokine Release Syndrome after Nivolumab for Gastric Cancer.

Introduction: Cytokine release syndrome (CRS) is a potentially life-threatening systemic disease that has been observed after treatment with antibodies and adoptive T cell therapies. In this case, we observed nivolumab-induced CRS in a patient with gastric cancer.

Case Presentation: A 43-year-old male with advanced gastric cancer was treated with nivolumab as a third-line chemotherapy.

Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance.

Immune checkpoint inhibitors and adoptive transfer of gene-engineered T cells have emerged as novel therapeutic modalities for hard-to-treat solid tumors; however, many patients are refractory to these immunotherapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. By comparing the tumor microenvironment of checkpoint inhibition-sensitive and -resistant murine solid tumors, we observed that the resistant tumors had low immunogenicity. We identified antigen presentation by CD11b+F4/80+ tumor-associated macrophages (TAMs) as a key factor correlated with immune resistance.

NY-ESO-1 antigen expression and immune response are associated with poor prognosis in MAGE-A4-vaccinated patients with esophageal or head/neck squamous cell carcinoma.

MAGE-A4 antigen is a cancer-testis antigen that is frequently expressed in tumor tissues. Cholesteryl pullulan (CHP) is a novel antigen delivery system for cancer vaccines. This study evaluated the safety, immune responses and clinical outcomes of patients who received a CHP-MAGE-A4 vaccine.

Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination.

The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target.

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers.

The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy.

Clinical Implications of CD4CD25Foxp3Regulatory T Cell Frequencies After CHP-MAGE-A4 Cancer Vaccination.

Background/aim: The aim of this study was to explore whether the treatment effect or immune response to a cancer vaccine can be predicted by the percentage of CD4CD25Foxp3 regulatory T cells (Tregs) in peripheral blood mononuclear cells (PBMCs) after vaccination.

Patients And Methods: Sixteen patients (9 men, 7 women; median age 61.5 years) enrolled in the CHP-MAGE-A4 cancer vaccine clinical trial who had a fixed dose (300 μg of CHP-MAGE-A4 cancer vaccine and 0.

Serum immunoglobulin E response as a marker for unfavorable prognosis following cholesteryl pullulan-MAGE A4 vaccination.

Since 2009, a cancer vaccine clinical trial was conducted with melanoma antigen gene-A4 as an immunogenic agent. The levels of IgG1, IgG2 and IgG3, which are known to be Type 1 T helper cell-associated antibodies, and the levels of IgG4 and IgE, which are known to be Type 2 T helper cell-associated antibodies, were measured and used as biomarkers for predicting therapeutic effect. The results of the present study indicated a strong positive correlation between IgG2 and IgG4, with a correlation coefficient of R=0.

Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS.

Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells.

Identification of an immunogenic neo-epitope encoded by mouse sarcoma using CXCR3 ligand mRNAs as sensors.

The CXCR3 ligands CXCL9, 10, and 11 play critical roles in the amplification of immune responses by recruiting CXCR3 immune effector cells to the tumor site. Taking advantage of this property of CXCR3 ligands, we aimed to establish a novel approach to identify immunogenic mutated-antigens. We examined the feasibility of using CXCR3 ligand mRNAs as sensors for detection of specific immune responses in human and murine systems.