Immune modulation following α and β radionuclide therapy targeting fibroblast activation protein-α in a preclinical tumor model.

α- and β-emitting radionuclides targeting human fibroblast activation protein-α (hFAP) are under investigation for cancer therapy. In prior work, analysis of the tumor microenvironment 24 h after therapy completion indicated therapy-induced immune activation. Here, we analyzed systemic immune responses at varying timepoints during treatment to further elucidate the immune-stimulating effects of the therapy.

Generic semi-automated radiofluorination strategy for single domain antibodies: [F]FB-labelled single domain antibodies for PET imaging of fibroblast activation protein-α or folate receptor-α overexpression in cancer.

Background: Radiofluorination of single domain antibodies (sdAbs) via N-succinimidyl-4-[F]fluorobenzoate ([F]SFB) has shown to be a promising strategy in the development of sdAb-based PET tracers. While automation of the prosthetic group (PG) [F]SFB production, has been successfully reported, no practical method for large scale sdAb labelling has been reported. Therefore, we optimized and automated the PG production, enabling a subsequently efficient manual conjugation reaction to an anti-fibroblast activation protein (FAP)-α sdAb (4AH29) and an anti-folate receptor (FR)-α sdAb (2BD42).

Clinicopathological and molecular predictors of [F]FDG-PET disease detection in HER2-positive early breast cancer: RESPONSE, a substudy of the randomized PHERGain trial.

Background: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [Fluorine]fluorodeoxyglucose-positron emission tomography ([F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [F]FDG-PET disease detection were evaluated.

Methods: A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.

Optimal [F]FDG PET/CT Cutoff for Pathologic Complete Response in HER2-Positive Early Breast Cancer Patients Treated with Neoadjuvant Trastuzumab and Pertuzumab in the PHERGain Trial.

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [F]FDG PET/CT. [F]FDG PET/CT responders were defined as patients with an SUV reduction (ΔSUV) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy).

Phase II Trial Assessing the Repeatability and Tumor Uptake of [Ga]Ga-HER2 Single-Domain Antibody PET/CT in Patients with Breast Carcinoma.

Human epidermal growth factor receptor 2 (HER2) status is used for decision-making in breast carcinoma treatment. The status is obtained through immunohistochemistry or in situ hybridization. These two methods have the disadvantage of necessitating tissue sampling, which is prone to error due to tumor heterogeneity or interobserver variability.

The Presence of Anti-TPO Antibodies Increase the Likelihood of Post-I131 Hypothyroidism.

The use of radioactive iodine in the treatment of hyperthyroidism is common practice. However, a standardized treatment protocol with regard to radioactive iodine treatment (RAI) remains subject to discussion. We retrospectively analyzed 100 patient records.

Nanobody-mediated SPECT/CT imaging reveals the spatiotemporal expression of programmed death-ligand 1 in response to a CD8 T cell and iNKT cell activating mRNA vaccine.

Although promising responses are obtained in patients treated with immune checkpoint inhibitors targeting programmed death ligand 1 (PD-L1) and its receptor programmed death-1 (PD-1), only a fraction of patients benefits from this immunotherapy. Cancer vaccination may be an effective approach to improve the response to immune checkpoint inhibitors anti-PD-L1/PD-1 therapy. However, there is a lack of research on the dynamics of PD-L1 expression in response to cancer vaccination.

Development and Validation of a Predictive Model for Metastatic Melanoma Patients Treated with Pembrolizumab Based on Automated Analysis of Whole-Body [F]FDG PET/CT Imaging and Clinical Features.

Background: Antibodies that inhibit the programmed cell death protein 1 (PD-1) receptor offer a significant survival benefit, potentially cure (i.e., durable disease-free survival following treatment discontinuation), a substantial proportion of patients with advanced melanoma.

Phase I Study of [Ga]Ga-Anti-CD206-sdAb for PET/CT Assessment of Protumorigenic Macrophage Presence in Solid Tumors (MMR Phase I).

Macrophages play an important role throughout the body. Antiinflammatory macrophages expressing the macrophage mannose receptor (MMR, CD206) are involved in disease development, ranging from oncology to atherosclerosis and rheumatoid arthritis. [Ga]Ga-NOTA-anti-CD206 single-domain antibody (sdAb) is a PET tracer targeting CD206.

Targeted α-Therapy Using Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment.

Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with Ac in a human CD20 and ovalbumin expressing B16-melanoma model.

Computer-aided detection and segmentation of malignant melanoma lesions on whole-body F-FDG PET/CT using an interpretable deep learning approach.

Background And Objective: In oncology, 18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) / computed tomography (CT) is widely used to identify and analyse metabolically-active tumours. The combination of the high sensitivity and specificity from F-FDG PET and the high resolution from CT makes accurate assessment of disease status and treatment response possible. Since cancer is a systemic disease, whole-body imaging is of high interest.

Targeted Radionuclide Therapy with Low and High-Dose Lutetium-177-Labeled Single Domain Antibodies Induces Distinct Immune Signatures in a Mouse Melanoma Model.

Targeted radionuclide therapy (TRT) using probes labeled with Lutetium-177 (177Lu) represents a new and growing type of cancer therapy. We studied immunologic changes in response to TRT with 177Lu labeled anti-human CD20 camelid single domain antibodies (sdAb) in a B16-melanoma model transfected to express human CD20, the target antigen, and ovalbumin, a surrogate tumor antigen. High-dose TRT induced melanoma cell death, calreticulin exposure, and ATP-release in vitro.

TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy.

Immune checkpoint blockade (ICB) of the PD-1 pathway revolutionized the survival forecast for advanced non-small cell lung cancer (NSCLC). Yet, the majority of PD-L1 NSCLC patients are refractory to anti-PD-L1 therapy. Recent observations indicate a pivotal role for the PD-L1 tumor-infiltrating myeloid cells in therapy failure.

The Road to Personalized Myeloma Medicine: Patient-specific Single-domain Antibodies for Anti-idiotypic Radionuclide Therapy.

To this day, multiple myeloma remains an incurable cancer. For many patients, recurrence is unavoidably a result of lacking treatment options in the minimal residual disease stage. This is due to residual and treatment-resistant myeloma cells that can cause disease relapse.

Undetectable thyroglobulin makes I whole-body scan and stimulated thyroglobulin obsolete in follow-up care of differentiated thyroid cancer: a retrospective study.

Background: Differentiated thyroid cancer (DTC) is a common malignancy with increasing incidence. Follow-up care for DTC includes thyroglobulin (Tg) measurement and ultrasound (US) of the neck, combined with I remnant ablation when indicated. Diagnostic precision has evolved with the introduction of the new high-sensitive Tg-assays (sensitivity ≤0.

Formatting and gene-based delivery of a human PD-L1 single domain antibody for immune checkpoint blockade.

Monoclonal antibodies that target the inhibitory immune checkpoint axis consisting of programmed cell death protein 1 (PD-1) and its ligand, PD-L1, have changed the immune-oncology field. We identified K2, an anti-human PD-L1 single-domain antibody fragment, that can enhance T cell activation and tumor cell killing. In this study, the potential of different K2 formats as immune checkpoint blocking medicines was evaluated using a gene-based delivery approach.

The Prognostic Value of CD206 in Solid Malignancies: A Systematic Review and Meta-Analysis.

An increased presence of CD206-expressing tumor associated macrophages in solid cancers was proposed to be associated with worse outcomes in multiple types of malignancies, but contradictory results are published. We performed a reproducible systematic review and meta-analysis to provide increased evidence to confirm or reject this hypothesis following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The Embase, Web of Science, and MEDLINE-databases were systematically searched for eligible manuscripts.

Site-Specific Radiolabeling of a Human PD-L1 Nanobody via Maleimide-Cysteine Chemistry.

Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) and its ligand PD-L1 have proven to be efficient cancer therapies in a subset of patients. From all the patients with various cancer types, only 20% have a positive response. Being able to distinguish patients that do express PD-1/PD-L1 from patients that do not allows patients to benefit from a more personalized and efficient treatment of tumor lesion(s).

Lyophilization of NOTA-sdAbs: First step towards a cold diagnostic kit for Ga-labeling.

Unlabelled: Lyophilization is commonly used in the production of pharmaceutical compounds to increase the stability of the Active Pharmaceutical Ingredient (API) by removing solvents. This study investigates the possibility to lyophilize an anti-HER2 and an anti-MMR single-domain antibody fragment (sdAb)-based precursor as a first step in the development of a diagnostic kit for PET imaging.

Methods: NOTA-sdAb precursors have been lyophilized with the following formulation: 100 µg NOTA-sdAb in 0.

Value of [11C]-Methionine PET/CT in Preoperative Localization of Parathyroid Adenomas.

There are multiple imaging modalities in primary hyperparathyroidism. Ultrasound examination and subtraction scintigraphy are usually the first-line imaging techniques. When these results are negative or inconsistent, additional [C]-methionine PET/CT (MET-PET/CT) or 4-dimensional computed tomography can be performed.

Ga-Labeling: Laying the Foundation for an Anti-Radiolytic Formulation for NOTA-sdAb PET Tracers.

During the preparation of [Ga]Ga-NOTA-sdAb at high activity, degradation of the tracers was observed, impacting the radiochemical purity (RCP). Increasing starting activities in radiolabelings is often paired with increased degradation of the tracer due to the formation of free radical species, a process known as radiolysis. Radical scavengers and antioxidants can act as radioprotectant due to their fast interaction with formed radicals and can therefore reduce the degree of radiolysis.

Early Reassessment of Total Metabolic Tumor Volume on FDG-PET/CT in Advanced Melanoma Patients Treated with Pembrolizumab Predicts Long-Term Outcome.

PD-1 Immune checkpoint inhibitors, such as Pembrolizumab, can have a durable beneficial therapeutic effect in patients with advanced melanoma. However, not all patients will benefit equally from these therapies, and (potentially life-threatening) immune-related adverse events may occur. In this study, we investigate the value of early response assessment by FDG-PET/CT as a biomarker for predicting survival.

Immunogenicity Risk Profile of Nanobodies.

Unlabelled: Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affinity in the (sub-)nanomolar range in conjunction with an easy selection and production, which allow them to outperform conventional antibodies for imaging and radiotherapeutic purposes. As for all protein theranostics, extended safety assessment and investigation of their possible immunogenicity in particular are required.

Single-Domain Antibody Nuclear Imaging Allows Noninvasive Quantification of LAG-3 Expression by Tumor-Infiltrating Leukocytes and Predicts Response of Immune Checkpoint Blockade.

Recent advances in the field of immune-oncology led to the discovery of next-generation immune checkpoints (ICPs). Lymphocyte activation gene-3 (LAG-3), being the most widely studied among them, is being explored as a target for the treatment of cancer patients. Several antagonistic anti-LAG-3 antibodies are being developed and are prime candidates for clinical application.