Immunological evaluation of peptide vaccination for cancer patients with the HLA-A26 allele

To develop a peptide vaccine for cancer patients with the HLA-A26 allele, which is a minor population worldwide, we investigated the immunological responses of HLA-A26+ ⁄ A26+ cancer patients to four different CTL epitope peptides under personalized peptide vaccine regimens. In personalized peptide vaccine regimens, two to four peptides showing positive peptide-specific IgG responses in pre-vaccination plasma were selected from the four peptide candidates applicable for HLA-A26+ ⁄ A26+ cancer patients and administered s.c. Peptide-specific CTL and IgG responses along with cytokine levels were measured before and after vaccination. Cell surface markers in PBMCs and plasma cytokine levels were also measured. In this study, 21 advanced cancer patients, including seven lung, three breast, two pancreas, and two colon cancer patients, were enrolled. Their HLAA26 genotypes were HLA-A26:01 (n = 24), HLA-A26:03 (n = 10), and HLA-A26:02 (n = 8). One, 14, and 6 patients received two, three, and four peptides, respectively. Grade 1 or 2 skin reactions at the injection sites were observed in the majority of patients, but no severe adverse events related to the vaccination were observed. Peptide-specific CTL responses were augmented in 39% or 22% of patients after one or two cycles of vaccination, respectively. Notably, peptide-specific IgG were augmented in 63% or 100% of patients after one or two cycles of vaccination, respectively. Personalized peptide vaccines with these four CTL epitope peptides could be feasible for HLA-A26+ advanced cancer patients because of their safety and higher rates of immunological responses.This study was supported in part by the Japan Agency for Medical Research and development, AMED, a research program of the Regional Innovation Cluster Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant from the Sendai Kousei Hospital

Digital quantitative analysis of mast cell infiltration in interstitial cystitis

AimsTo evaluate the significance of mast cell infiltration in interstitial cystitis (IC) by comparison with equally inflamed controls using a digital quantification technique. MethodsBladder biopsy specimens from 31 patients with Hunner type IC and 38 patients with non-Hunner type IC were analyzed. Bladder biopsy specimens from 37 patients without IC, including 19 non-specific chronic cystitis (non-IC cystitis) specimens and 18 non-inflamed bladder (normal bladder) specimens, were used as controls. Mast cell tryptase-, CD3-, CD20-, and CD138-immunoreactive cells were quantified using digital image analysis software to evaluate both mast cell and lymphoplasmacytic cell densities. Mast cell and lymphoplasmacytic cell densities were counted independently in the entire lamina propria and detrusor areas and compared among the four groups. ResultsIn the lamina propria, there were no significant differences in mast cell and lymphoplasmacytic cell densities between Hunner type IC and non-IC cystitis or between non-Hunner type IC and normal bladder specimens. In the detrusor, the mast cell densities were not significantly different among the four groups. Mast cell density was correlated with lymphoplasmacytic cell density, but not with clinical parameters. ConclusionsMast cell density is not significantly different between IC specimens and non-IC control specimens with a similar degree of background inflammation. The intensity of mast cell infiltration generally correlated with that of lymphoplasmacytic cells. We conclude that mast cell count is of no value in the differential diagnosis between IC and other etiologies

Clinical Outcomes of Cetuximab and Paclitaxel after Progression on Immune Checkpoint Inhibitors in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Background and Objectives: In recent years, the effectiveness of chemotherapy after immune checkpoint inhibitor administration has attracted attention in various cancers, including head and neck cancers. However, individual assessments of the administered chemotherapy regimens are insufficient. This study aimed to evaluate the efficacy and safety of chemotherapy after immune checkpoint inhibitor administration in recurrent metastatic head and neck cancer by focusing on a single regimen. Materials and Methods: We retrospectively reviewed clinical and radiological data from the medical records of 18 patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who received systemic chemotherapy with weekly cetuximab and paclitaxel (Cmab + PTX) after progression following immune checkpoint inhibitor (ICI) therapy. The objective response rate (ORR) and disease control rate (DCR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: In all patients, the ORR, DCR, median PFS, and median OS were 44.4%, 72.2%, 3.8 months, and 9.6 months, respectively. Regarding AEs, three patients developed grade 3 neutropenia. Grade 3 anemia, paronychia, asthenia, and peripheral neuropathy were observed in one patient each. There were no treatment-related deaths. Conclusions: Cmab + PTX was shown to maintain high efficacy and acceptable safety for R/M HNSCC that progressed after ICI therapy. Further research is needed to establish optimal treatment sequences and drug combinations for recurrent R/M HNSCC

Case-based similar image retrieval for weakly annotated large histopathological images of malignant lymphoma using deep metric learning

In the present study, we propose a novel case-based similar image retrieval (SIR) method for hematoxylin and eosin (H&E)-stained histopathological images of malignant lymphoma. When a whole slide image (WSI) is used as an input query, it is desirable to be able to retrieve similar cases by focusing on image patches in pathologically important regions such as tumor cells. To address this problem, we employ attention-based multiple instance learning, which enables us to focus on tumor-specific regions when the similarity between cases is computed. Moreover, we employ contrastive distance metric learning to incorporate immunohistochemical (IHC) staining patterns as useful supervised information for defining appropriate similarity between heterogeneous malignant lymphoma cases. In the experiment with 249 malignant lymphoma patients, we confirmed that the proposed method exhibited higher evaluation measures than the baseline case-based SIR methods. Furthermore, the subjective evaluation by pathologists revealed that our similarity measure using IHC staining patterns is appropriate for representing the similarity of H&E-stained tissue images for malignant lymphoma

EGFR T790M Mutation as a Possible Target for Immunotherapy; Identification of HLA-A*0201-Restricted T Cell Epitopes Derived from the EGFR T790M Mutation

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, has achieved high clinical response rates in patients with non–small cell lung cancers (NSCLCs). However, over time, most tumors develop acquired resistance to EGFR-TKIs, which is associated with the secondary EGFR T790M resistance mutation in about half the cases. Currently there are no effective treatment options for patients with this resistance mutation. Here we identified two novel HLA-A*0201 (A2)-restricted T cell epitopes containing the mutated methionine residue of the EGFR T790M mutation, T790M-5 (MQLMPFGCLL) and T790M-7 (LIMQLMPFGCL), as potential targets for EGFR-TKI-resistant patients. When peripheral blood cells were repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific IFN-γ secretion, T cell lines responsive to T790M-5 and T790M-7 were established in 5 of 6 (83%) and 3 of 6 (50%) healthy donors, respectively. Additionally, the T790M-5- and T790M-7-specific T cell lines displayed an MHC class I-restricted reactivity against NSCLC cell lines expressing both HLA-A2 and the T790M mutation. Interestingly, the NSCLC patients with antigen-specific T cell responses to these epitopes showed a significantly less frequency of EGFR-T790M mutation than those without them [1 of 7 (14%) vs 9 of 15 (60%); chi-squared test, p = 0.0449], indicating the negative correlation between the immune responses to the EGFR-T790M-derived epitopes and the presence of EGFR-T790M mutation in NSCLC patients. This finding could possibly be explained by the hypothesis that immune responses to the mutated neo-antigens derived from T790M might prevent the emergence of tumor cell variants with the T790M resistance mutation in NSCLC patients during EGFR-TKI treatment. Together, our results suggest that the identified T cell epitopes might provide a novel immunotherapeutic approach for prevention and/or treatment of EGFR-TKI resistance with the secondary EGFR T790M resistance mutation in NSCLC patients

A significant change in selective adsorption behaviour for ethanol by flexibility control through the type of central metals in a metal-organic framework

Closed-open structural transformations in flexible metal-organic frameworks (MOFs) are of interest for potential applications such as separation, because of their complete selectivity for the adsorption of specific guest molecules. Here, we report the control of the adsorption behaviour in a series of flexible MOFs, (H2dab)[M2(ox)3] (H2dab = 1, 4-diammoniumbutane, M = Fe, Co, Ni, Zn, or Mg), having different central metals with analogous crystal structures. We found that a significant change in the selective adsorption behaviour for EtOH over MeCHO and MeCN is caused by the type of central metals, without changes in the crystal structures of all phases (except the Ni compound). A systematic study of adsorption measurements and structural analyses of the analogous MOFs reveals for the first time that the framework flexibility around the central metals of MOFs is truly related to the selective adsorption behaviour

Low temperature ionic conductor: Ionic liquid incorporated within a metal-organic framework

Ionic liquids (ILs) show promise as safe electrolytes for electrochemical devices. However, the conductivity of ILs decreases markedly at low temperatures because of strong interactions arising between the component ions. Metal-organic frameworks (MOFs) are appropriate microporous host materials that can control the dynamics of ILs via the nanosizing of ILs and tunable interactions of MOFs with the guest ILs. Here, for the first time, we report on the ionic conductivity of an IL incorporated within a MOF. The system studied consisted of EMI-TFSA (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide) and ZIF-8 (Zn(MeIM)2, H(MeIM) = 2-methylimidazole) as the IL and the MOF, respectively. While the ionic conductivity of bulk EMI-TFSA showed a sharp decrease arising from freezing, the EMI-TFSA@ZIF-8 showed no marked decrease because there was no phase transition. The ionic conductivity of EMI-TFSA@ZIF-8 was higher than that of bulk EMI-TFSA below 250 K. This result points towards a novel method by which to design electrolytes for electrochemical devices such as batteries that can operate at low temperatures

High seebeck coefficient in middle-temperature thermocell with deep eutectic solvent

Abstract Deep eutectic solvent (DES) was applied to the solvent of thermocell and high Seebeck coefficient (S e) of the thermocell was achieved at high-temperatures operation. The S e of a redox couple of ferricyanide and ferrocyanide ([Fe(CN)6]3−/4−) reaches − 1.67 mV/K in a DES consisting of ethylene glycol and choline chloride. Spectroscopic analysis reveals that this is due to the strong interactions between the redox couple and the DES. Furthermore, the cell can operate over a wide temperature range of 135–165 °C. This result is a desired feature for waste-heat recovery applications

Structure manufacturing of proton-conducting organic–inorganic hybrid silicophosphite membranes by solventless synthesis

We have developed a new class of proton-conducting organic–inorganic hybrid silicophosphite membranes, produced by ethanol condensation of organically modified alkoxysilanes and anhydrous vinylphosphonic acid under solventless, catalyst-free, low-temperature, one-pot conditions. The membranes synthesized in this study are crack-free, large, and flexible, and they exhibit good thermal stability up to intermediate temperatures (~218 °C). Structural analyses using [29]Si and [31]P nuclear magnetic resonance spectroscopy and infrared measurements revealed that ethanol condensation produced an inorganic alternating copolymer structure, Si–O–P, with a phosphole group, and successive polymerization between vinyl and/or methacryl groups enabled these structures to connect with each other. In this way, it is possible to achieve structure manufacturing of inorganic–organic networks. The proton conductivities of the hybrids are as high as 5.2 × 10[−3] S/cm at 85 °C under 80% relative humidity