C. Bodet-Milin

FDG-PET/CT predicts outcome in patients with aggressive non-Hodgkin's lymphoma and Hodgkin's disease.

Early therapy response assessment with metabolic imaging is potentially useful to determine prognosis in aggressive lymphoma and, thus, can guide first-line therapy. Forty-eight patients with aggressive lymphoma [24 Hodgkin’s disease (HD); 24 non-Hodgkin’s lymphoma (NHL)] underwent fluoro-deoxyglucose positron emission tomography (FDG-PET) before chemotherapy (PET1) and at mid-treatment (PET2). Therapeutic response was evaluated using conventional methods at mid-treatment. PET2 results were related to event-free survival (EFS) and overall survival (OS) using Kaplan–Meier analyses. PET1 was positive in all patients. PET2 was negative in 38 patients (18 NHL-20 HD) and positive in 10 (6 NHL-4 HD). Of the PET-negative patients, 61 and 65% achieved complete remission, and only 50 and 25% of PET-positive patients, respectively, for NHL and HD, achieved complete remission. Significant associations were found between PET2 and EFS (p=0.0006) and OS (p=0.04) for NHL, and EFS (p<0.0001) for HD (but not for OS, because no HD patient died). FDG-PET at mid-treatment can predict the outcome of patients with aggressive lymphoma and should be a useful tool to modify an ineffective therapy.

Radioimmunoconjugates for the treatment of cancer.

Radioimmunotherapy (RIT) has been developed for more than 30 years. Two products targeting the CD20 antigen are approved in the treatment of non-Hodgkin B-cell lymphoma (NHBL): iodine 131-tositumomab and yttrium 90-ibritumomab tiuxetan. RIT can be integrated in clinical practice for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy. High-dose treatment, RIT in first-line treatment, fractionated RIT, and use of new humanized monoclonal antibodies (MAbs), in particular targeting CD22, showed promising results in NHBL. In other hemopathies, such as multiple myeloma, efficacy has been demonstrated in preclinical studies. In solid tumors, more resistant to radiation and less accessible to large molecules such as MAbs, clinical efficacy remains limited. However, pretargeting methods have shown clinical efficacy. Finally, new beta emitters such as lutetium 177, with better physical properties will further improve the safety of RIT and alpha emitters, such as bismuth 213 or astatine 211, offer the theoretical possibility to eradicate the last microscopic clusters of tumor cells, in the consolidation setting. Personalized treatments, based on quantitative positron emission tomography (PET), pre-therapeutic imaging, and dosimetry procedures, also could be applied to adapt injected activity to each patient.

Toxicity and efficacy of combined radioimmunotherapy and bevacizumab in a mouse model of medullary thyroid carcinoma

Significant antitumor effects were previously observed with radioimmunotherapy (RIT) using an anti‐carcinoembryonic antigen (CEA) monoclonal antibody (F6) labeled with iodine‐131 in medullary thyroid cancer (MTC)‐bearing nude mice. Nevertheless, no complete response was achieved. Because angiogenesis is critical for tumor growth, bevacizumab is used to treat solid tumor in clinical practice. The present pilot study evaluated toxicity and efficacy of RIT combined with bevacizumab in mice subcutaneously grafted with TT MTC cells.

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.

Radioimmunoconjugates for treating cancer: recent advances and current opportunities

ABSTRACT Introduction: Radioimmunoconjugates have been used for 30 years to diagnose and treat cancer. For many years, the use of these therapeutic tools has been limited to haematological disorders, such as non-Hodgkin’s lymphoma, given that they have only had a moderate effect on solid tumours. Areas covered: Recently, several strategies have revived the potential therapeutic application for radioimmunoconjugates. In this review, the authors review the advances in immunological engineering to develop new tools like monoclonal antibodies and their derivatives. Then, the authors summarize the development of radionuclides, the use of recombinant antibodies, pretargeting approaches, and dose fractionation techniques, providing opportunities for both therapeutic and diagnostic applications. Expert opinion: Radioimmunoconjugates used in nuclear medicine have entered a new era of development. These advances give rise to a variety of opportunities in the management of various cancers, where the radiolabelled antibodies may be particularly useful in immuno-specific phenotypic imaging e.g. companion diagnostics. Concerning therapeutic applications, radioimmunoconjugates have demonstrated their efficacy in the treatment of both haematological malignancies and solid tumours. Recent procedural developments are of great interest in optimising oncological targeted therapies. In the field of cancer theranostics, we believe that radioimmunoconjugated compounds are likely to play a large part in near future.

New Advances in Radioimmunotherapy for the Treatment of Cancers

Radioimmunotherapy (RIT) has been in use for more than 20 years and has progressed significantly with the discovery of new molecular targets, the development of new stable chelates, the humanization of monoclonal antibodies (mAbs), and the use of pretargeting techniques. Today, two products targeting the CD20 antigen are approved in the treatment of B cell lymphoma: 131I-tositumomab (Bexxar®) and 90Y-ibritumomab tiuxetan (Zevalin®). RIT can be integrated in clinical practice for treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy in frontline treatment in FL patients. High-dose treatment, RIT as consolidation, RIT in first-line treatment, fractionated RIT, and use of new humanized mAbs, in particular targeting CD22, showed promising results in B cell lymphoma. In other hemopathies, such as multiple myeloma, efficacy has been demonstrated in preclinical studies. In solid tumors, more resistant to radiations and less accessible to large molecules such as mAbs, clinical efficacy remains limited. However, RIT used in minimal or small-size metastatic disease has shown promising clinical efficacy. Pretargeting approaches have been potential in increasing the therapeutic index of radiolabeled antibodies. Finally, new beta emitters such as lutetium-177 with better physical properties will further improve the safety of RIT. Moreover, alpha emitters such as bismuth-213 or astatine-211 offer the theoretical possibility to eradicate the last microscopic clusters of tumor cells, in the setting of consolidation. Personalized dosimetry protocols, particularly based on quantitative positron emission tomography (PET) imaging, should be developed to optimize injected activity.

Prospects for Enhancing Efficacy of Radioimmunotherapy

Radioimmunotherapy has been in use for more than 20 years and has progressed significantly since its efficacy has first been demonstrated in hematology. Yet it still has limitations that prevent its large-scale clinical use. This chapter reviews recent developments to overcome these limitations including new antibody specificities, pretargeting methods, fractionated injections, and the use of alpha emitters. Immuno-PET is also likely to assist in selecting patients for radioimmunotherapy, optimizing injected activities, and noninvasively monitoring therapy efficacy.

Immuno-TEP pré-ciblée avec l’anticorps bi-spécifique anti-ACE et le peptide IMP-288 marqué au gallium-68 pour l’imagerie des récidives de CMT

Objectifs Cette etude compare la sensibilite de l’immuno-TEP/CT (i-TEP) a celle du bilan conventionnel d’imagerie chez des pts porteurs de recidives de carcinomes medullaires de la thyroide (CMT). Patients et methodes Quatorze pts inclus dans une etude d’optimisation ont beneficie d’une i-TEP, respectivement, 1xa0h et 2xa0h apres l’injection de 150xa0MBq de 68Ga-IMP288xa0pre-ciblee par 120xa0nmoL de TF2xa0injecte 24xa0h a 42xa0h plus tot. Le bilan conventionnel d’imagerie comprenait 1xa0TDM thoraco-abdomino-pelvien, 1xa0IRM pelvi-rachidienne (PR), 1xa0IRM hepatique et 1xa0TEP a la fluoro-DOPA (DOPA-TEP). Le gold standard (GS) etait l’histologie et/ou le suivi evolutif et/ou la visualisation d’une lesion par au moins 2xa0modalites d’imagerie differentes. Resultats Cent vingt lesions ont ete detectees par l’i-TEP, 71xa0par le TDM, 12xa0par l’IRM PR, 14xa0par l’IRM hepatique et 71xa0par la DOPA-TEP. Quatre-vingt dix-huit lesions ont ete confirmees comme pathologiques par le GSxa0: ganglionsxa0: 51, poumonxa0:12, foiexa0: 18, osxa0: 16xa0et cœurxa0:1. La sensibilite globale de l’i-TEP etait de 91xa0% dont 100xa0% pour les ganglions et le foie, 88xa0% pour les os et 42xa0% pour les poumons. Les sensibilites globales du TDM, des IRM PR et hepatique, de la DOPA-TEP etaient, respectivement, de 81xa0%, 86xa0%, 78xa0% et 67xa0%. Le TDM et la DOPA-TEP avaient des sensibilites de 75xa0et 76xa0% pour les ganglions, 78xa0et 78xa0% pour le foie, 100xa0et 16xa0% pour les poumons, respectivement. La sensibilite de la DOPA-TEP pour les lesions osseuses etait de 63xa0%. La lesion cardiaque etait detectee par l’i-PET, le CT et la DOPA-TEP. Les valeurs medianes de SUV max pour l’i-TEP a 1xa0h et 2xa0h et la DOPA-TEP etaient, respectivement, 15,25 (4,09xa0a 94,14), 12,34 (5,14xa0a 100,20) et 5,69 (2,10xa0a 57,24). Aucune lesion n’etait visualisee uniquement sur l’i-TEP 2xa0h. Conclusion Ces resultats demontrent l’impact potentiel de l’i-TEP utilisant l’anticorps anti-ACE pre-cible pour le bilan d’extension des recidives de CMT, notamment pour l’extension ganglionnaire, hepatique et osseuse avec une sensibilite globale superieure a celle du TDM et de la DOPA-TEP. Le TDM reste plus efficace pour detecter les metastases pulmonaires et, pour des valeurs de sensibilite proches, l’i-TEP permet de voir des lesions osseuses dans des zones non explorees par l’IRM.