Improvement of Radioimmunotherapy Using Pretargeting

During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA, and bispecific antibody-hapten bindings. pRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta, and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT

Interest of FDG-PET in the Management of Mantle Cell Lymphoma

FDG-PET changed response assessment and therapy strategy in diffuse large B-cell lymphoma and Hodgkin disease lymphoma. The value of FDG-PET evaluation in MCL has not been extensively studied and a recent expert consensus highlighted the need for more studies addressing this question. Data of the literature show the value of FDG-PET at baseline in patients with MCL, underlining the good sensitivity of this examination for the initial staging of this pathology, but also the potential impact of semi-quantitative analysis in this indication. The determination of SUVmax at diagnosis might indeed provide important prognostic information. Some studies also suggest the potential value of early and end-of-treatment metabolic assessment in MCL, but these results need to be validated in standardized prospective studies. These results also underlie the need to integrate FDG-PET results into MCL treatment strategy to improve disease management in identifying patients who might benefit from more intensive therapy

Graph-based multimodal multi-lesion DLBCL treatment response prediction from PET images

Diffuse Large B-cell Lymphoma (DLBCL) is a lymphatic cancer involving one or more lymph nodes and extranodal sites. Its diagnostic and follow-up rely on Positron Emission Tomography (PET) and Computed Tomography (CT). After diagnosis, the number of nonresponding patients to standard front-line therapy remains significant (30-40%). This work aims to develop a computer-aided approach to identify high-risk patients requiring adapted treatment by efficiently exploiting all the information available for each patient, including both clinical and image data. We propose a method based on recent graph neural networks that combine imaging information from multiple lesions, and a cross-attention module to integrate different data modalities efficiently. The model is trained and evaluated on a private prospective multicentric dataset of 583 patients. Experimental results show that our proposed method outperforms classical supervised methods based on either clinical, imaging or both clinical and imaging data for the 2-year progression-free survival (PFS) classification accuracy

Interest of Pet Imaging in Multiple Myeloma

The interest of 18Fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging in the management of patients with multiple myeloma (MM) for the workup at diagnosis and for therapeutic evaluation has recently been demonstrated. FDG-PET is a powerful imaging tool for bone lesions detection at initial diagnosis with high sensitivity and specificity values. The independent pejorative prognostic value on progression-free survival (PFS) and overall survival (OS) of baseline PET-derived parameters (presence of extra-medullary disease (EMD), number of focal bone lesions (FLs), and maximum standardized uptake values [SUVmax]) has been reported in several large independent prospective studies. During therapeutic evaluation, FDG-PET is considered as the reference imaging technique, because it can be performed much earlier than MRI which lacks specificity. Persistence of significant FDG uptake after treatment, notably before maintenance therapy, is an independent pejorative prognostic factor, especially for patients with a complete biological response. So FDG-PET and medullary flow cytometry are complementary tools for detection of minimal residual disease before maintenance therapy. However, the definition of PET metabolic complete response should be standardized. In patients with smoldering multiple myeloma, the presence of at least one hyper-metabolic lytic lesions on FDG-PET may be considered as a criterion for initiating therapy. FDG-PET is also indicated for initial staging of a solitary plasmacytoma so as to not disregard other bone or extra-medullary localizations. Development of nuclear medicine offer new perspectives for MM imaging. Recent PET tracers are willing to overcome limitations of FDG. (11)C-Methionine, which uptake reflects the increased protein synthesis of malignant cells seems to correlate well with bone marrow infiltration. Lipid tracers, such as Choline or acetate, and some peptide tracers, such as (68) Ga-Pentixafor, that targets CXCR4 (chemokine receptor-4, which is often expressed with high density by myeloma cells), are other promising PET ligands. 18F-fludarabine and immuno-PET targeting CD138 and CD38 also showed promising results in preclinical models

Apport de la 18F-FDG TEP/TDM dans le diagnostic précoce de la réaction du greffon contre l'hôte digestive aiguë chez les patients aux antécédents d'allogreffe de cellules souches hématopoïétiques

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Intérêt de la TEP au 18-FDG dans l'évaluation de la réponse à la radioimmunothérapie des patients porteurs de lymphomes malins non hodgkiniens traités par Yttrium-90 Epratuzumab

Objectif : Apprécier l'intérêt de la FDG-TEP dans l'évaluation de la réponse à la radioimmunothérapie de patients traités par 90Y epratuzumab dans un protocole de phase I/II. Matériels et méthodes : Des scanners thoraco-abdomino-pelviens et des TEP ont été réalisés lors de l'évaluation pré-thérapeutique, à 6 semaines, 3, 6, 9 , 12 et 18 mois après chaque cure de RIT. La réponse tumorale était évaluée par la TDM selon les recommandations internationales et comparée à l'analyse qualitative et quantitative des images TEP classées en 3 types de réponse: réponse complète (RC) ou incomplète (RI), et progression (PM). Résultats : La réponse thérapeutique à 13 cures de RIT a été évaluée par 36 procédures d'examen (FDG-TEP et scanners). Les patients répondeurs à la RIT pouvaient être identifiés par la FDG-TEP dès 6 semaines après le traitement. Les valeurs de sensibilités de la FDG-TEP étaient meilleures que celles du scanner pour le staging initial comme pour la détection des récidives (95 et 98% versus 54 et 36%). La FDG-TEP avait une meilleure valeur prédictive positive que le scanner pour l'évaluation des masses résiduelles. Conclusion : Cette étude montre l'intérêt de la FDG-TEP dans l'évaluation de la réponse à la RIT. Si ces données étaient confirmées sur une population plus importante, la FDG-TEP pourrait être incluse dans le bilan standard d'évaluation de la réponse à la RIT, thérapeutique encore en cours d'optimisation.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

L'imagerie phénotypique du cancer du sein

Congrès sous l’égide de la Société Française de Génie Biologique et Médical (SFGBM)National audience

Therapeutic Immunoconjugates. Which Cytotoxic Payload: Chemotherapeutic Drug (ADC) or Radionuclide (ARC) ?

International audienceOver the last decade, Antibody Drug Conjugates (ADCs) have gained a great success due to their documented clinical efficacy and manageable toxicity. Generally the word "drug" is associated with a che-motherapeutic drug, however "drug" can also be associated with other cy-totoxic payloads such as radionuclides, termed more specifically, Anti-body Radionuclide Conjugates (ARCs) for radioimmunotherapy (RIT). A large number of clinical studies have evaluated both ADCs and ARCs in varied indications. This review collected the clinical results of 11 studies including 598 patients treated with 6 ADCs and 9 studies including 377 patients treated with 5 ARCs. Toxicity was generally less frequent with ADCs than with ARCs but often led to more uncomfortable side effects. Hematological toxicity was higher with ARCs than with ADCs regardless of the ra-dionuclide used (90 Y, 131 I or 177 Lu). For radiosensitive hematological malignancies overall response rates varied from 7 to 86% (median: 50%) with ADCs and from 31 to 95% (median: 83%) with ARCs. Two studies including 135 patients were performed with ARCs in the most favorable situation of front-line therapy which can favor global efficacy. Median progression free survival (PFS) varied between 5.6 and 13.3 months (median: 7.8) with ADCs and between 6 and 25.9 months (median: 9.4) with ARCs, once again focusing on the most favorable situation of ARCs in frontline therapy. For solid tumors overall response rates varied from 6 to 34.5% (median: 15%) with ADCs and from 8 to 15% (median: 7.5%) with ARCs. Both ADCs and ARCs have shown clinical efficacy with acceptable and manageable toxicity

[18F]-Fludarabine for haematological malignancies.

LDM TEPInternational audienc

Pretargeting for imaging and therapy in oncological nuclear medicine

International audienceBackground: Oncological pretargeting has been implemented and tested in several different ways in preclinical models and clinical trials over more than 30 years. Despite highly promising results, pretargeting has not achieved market approval even though it could be considered the ultimate theranostic, combining PET imaging with short-lived positron emitters and therapy with radionuclides emitting beta or alpha particles.Results: We have reviewed the pretargeting approaches proposed over the years, discussing their suitability for imaging, particularly PET imaging, and therapy, as well as their limitations. The reviewed pretargeting modalities are the avidin-biotin system, bispecific anti-tumour x anti-hapten antibodies and bivalent haptens, antibodyoligonucleotide conjugates and radiolabelled complementary oligonucleotides, and approaches using click chemistry. Finally, we discuss recent developments, such as the use of small binding proteins for pretargeting that may offer new perspectives to cancer pretargeting.Conclusions: While pretargeting has shown promise and demonstrated preclinical and clinical proof of principle, full-scale clinical development programs are needed to translate pretargeting into a clinical reality that could ideally fit into current theranostic and precision medicine perspectives