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Abstract Immunotherapy with checkpoint inhibitors (ICIs) has radically changed the landscape of therapeutic opportunities in oncology, but much still needs to be understood from a mechanistic point of view. There is space for further improving tumors’ response to ICIs, as supported by a strong biological rationale. For this achievement a detailed analysis of tumor cell phenotype with functional dissection of the molecular interactions occurring in the TME is required. Galectin-3 is a pleiotropic tumor relevant molecule, which deserves particular attention in immuno-oncology. Due to its ability to finely modulate immune response in vivo, Galectin-3 is a potential target molecule to be considered for overcoming tumor immune escape.

Abstract The lack of a non-invasive test for malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Human galectin-3 (hGal3) has emerged as a promising target for medical TC imaging and diagnosis because of its exclusive overexpression in malignant thyroid tissues. We previously developed a human-chimeric αhGal3 Fab fragment derived from the rat monoclonal antibody (mAb) M3/38 with optimized clearance characteristics using PASylation technology. Here, we describe the elucidation of the hGal3 epitope recognized by mAb M3/38, X-ray crystallographic analysis of its complex with the chimeric Fab and, based on the three-dimensional structure, the rational humanization of the Fab by CDR grafting. Four CDR-grafted versions were designed using structurally most closely related fully human immunoglobulin VH/VL regions of which one—employing the acceptor framework regions of the HIV-1 neutralizing human antibody m66—showed the highest antigen affinity. By introducing two additional back-mutations to the rodent donor sequence, an affinity toward hGal3 indistinguishable from the chimeric Fab was achieved (KD = 0.34 ± 0.02 nM in SPR). The PASylated humanized Fab was site-specifically labelled with the fluorescent dye Cy7 and applied for the immuno-histochemical staining of human tissue sections representative for different TCs. The same protein was conjugated with the metal chelator Dfo, followed by radiolabelling with 89Zr(IV). The resulting protein tracer allowed the highly sensitive and specific PET/CT imaging of orthotopic tumors in mice, which was confirmed by quantitative analysis of radiotracer accumulation. Thus, the PASylated humanized αhGal3 Fab offers clinical potential for the diagnostic imaging of TC.

Background Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice.Methods We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS).Results In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCHmut/HRmut signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCHmut/HRmut genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCHmut/HRmut signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002).Conclusions Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.

Background: Breast implants are biomaterials eliciting a physiological and mandatory foreign body response.Objectives: We designed an animal study to investigate the impact of different implant surfaces on the formation of the perirprosthetic capsule, the inflammatory response and the cellular composition.Methods: We implanted 1 scaled-down version of breast implants by different manufactures on 70 female Sprague Dawley rats. Animals were divided into five groups of 14 animals. Group A received a smooth implant (Ra≈0.5µm) according to the ISO 14607-2018 classification, Group B smooth implant (Ra≈3.2µm), Group C smooth implant (Ra≈5µm), Group D macrotextured implant (Ra≈62µm) and Group E macrotextured implant (Ra≈75µm). At 60 days, all animals received a magnetic resonance imaging (MRI) and 35 animals were sacrificed and their capsules sent for histology (capsule thickness, inflammatory infiltrate) and immunohistochemistry analysis (cellular characterization). The remaining animals repeated the MRI at 120 days and were sacrificed following the same protocol.Results: MRI showed a thinner capsule in the smooth implants (Group A, B, C) at 60 days (p < 0.001) but not at 120 days (p = 0.039), confirmed with histology both at 60 days (p = 0.005) and 120 days (p < 0.001). Smooth implants (Group A, B, C) presented a mild inflammatory response at 60 days that was maintained at 120 days and a high M2-Macrophage concentration (anti-inflammatory).Conclusions: Our study confirms that smooth implants form a thinner capsule, inferior inflammatory infiltrate and a cellular composition that indicates a mild host inflammatory response. A new host inflammatory response classification is elaborated classifying breast implants into mild, moderate, and high. [ABSTRACT FROM AUTHOR]

Background: Breast implants are biomaterials eliciting a physiological and mandatory foreign body response., Objectives: The authors designed an animal study to investigate the impact of different implant surfaces on the formation of the periprosthetic capsule, the inflammatory response, and the cellular composition., Methods: The authors implanted 1 scaled-down version of breast implants by different manufactures on 70 female Sprague Dawley rats. Animals were divided into 5 groups of 14 animals. Group A received a smooth implant (Ra ≈ 0.5 µm) according to the ISO 14607-2018 classification, Group B a smooth implant (Ra ≈ 3.2 µm), Group C a smooth implant (Ra ≈ 5 µm), Group D a macrotextured implant (Ra ≈ 62 µm), and Group E a macrotextured implant (Ra ≈ 75 µm). At 60 days, all animals received a magnetic resonance imaging (MRI), and 35 animals were killed and their capsules sent for histology (capsule thickness, inflammatory infiltrate) and immunohistochemistry analysis (cellular characterization). The remaining animals repeated the MRI at 120 days and were killed following the same protocol., Results: MRI showed a thinner capsule in the smooth implants (Groups A-C) at 60 days (P < .001) but not at 120 days (P = .039), confirmed with histology both at 60 days (P = .005) and 120 days (P < .001). Smooth implants (Groups A-C) presented a mild inflammatory response at 60 days that was maintained at 120 days and a high M2-Macrophage concentration (anti-inflammatory)., Conclusions: Our study confirms that smooth implants form a thinner capsule, inferior inflammatory infiltrate, and a cellular composition that indicates a mild host inflammatory response. A new host inflammatory response classification is elaborated classifying breast implants into mild, moderate, and high., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)