Anti-tumor efficacy of a combination therapy with PD-L1 targeted alpha therapy and adoptive cell transfer of PD-1 deficient melanoma-specific human T-lymphocytes.

The optimization of adoptive transfer approaches of anti-tumor T cells requires both the functional improvement of the injected T cells and the modulation of the tumor microenvironment, favoring the recruitment of these T cells and their activation. We have recently shown the therapeutic benefit of two approaches tested individually in a melanoma model wich were on one hand the adoptive transfer of specific T cells deficient for the expression of the inhibitory receptor PD-1, and on the other hand PD-L1 targeted alpha therapy (TAT). In this study, we sought to investigate the efficacy of these two therapies combined, compared to each monotherapy, in order to evaluate the synergy between these two approaches, in the same melanoma model. Here we used melanoma-specific T-cell clones, previously validated for the edition of PDCD1 gene and with previously demonstrated superior anti-tumor activity than their wild-type counterparts, after adoptive transfer in NSG mice engrafted with PD-L1 expressing human melanoma tumors. We also used a previously validated TAT approach, using a 213Bi-anti-human-PD-L1 mAb, alone or in combination with adoptive cell transfer, in the same mouse model. We confirmed previous results obtained with each monotherapy and documented the safety and the superior ability of a combination between the adoptive transfer of PD-1 deficient T cells and TAT targeting PD-L1 to control the growth of melanoma tumors in NSG mice. This study provides the first proof-of-concept of the efficacy of a combination therapy using TAT, adoptive cell transfer and genomic editing of IC-coding genes.

Topical niacinamide enhances hydrophobicity and resilience of corneocyte envelopes on different facial locations.

Age-related differences in maturation parameters of corneocyte envelopes (size, hydrophobicity and rigidity) were examined at several facial test sites in young and old female Caucasians. In addition, the effect of topically applied niacinamide on these parameters was evaluated in a 4-week placebo-controlled study.

Pigmentation effects of blue light irradiation on skin and how to protect against them.

BACKGROUND: Visible light, in particular blue light, has been identified as an additional contributor to cutaneous photoageing. However, clinical studies demonstrating the clear effect of blue light on photoageing are still scarce, and so far, most studies have focused on broad-spectrum visible light. Although there is evidence for increased skin pigmentation, the underlying mechanisms of photoageing in vivo are still unclear. Furthermore, there is still a need for active ingredients to significantly protect against blue light-induced hyperpigmentation in vivo. Our study had two aims: to detect visible changes in skin pigmentation following repeated irradiation of the skin with LED-based blue light and to reduce pigmentation using suitable active ingredients. METHOD: We conducted a randomized, double-blind and placebo-controlled clinical study on 33 female volunteers with skin phototypes III and IV. We used a repetitive blue light (4 × 60 J cm-2 , 450 nm) irradiation protocol on the volunteers' inner forearms. Using hyperspectral imaging, we assessed chromophore status. In addition, we took chromameter measurements and photographs to assess visible hyperpigmentation. RESULTS: We measured significant changes in chromophore status (P < 0.001 vs baseline), that is of melanin, haemoglobin and oxygen saturation, immediately after blue light irradiation. In addition, we found visible skin colour changes which were expressed by a significant decrease in ITA° values (delta ITA° = -16.89, P < 0.001 vs baseline for the placebo group) and an increase in a* (delta a* = +3.37, P < 0.001 vs baseline for the placebo group) 24 h post-irradiation. Hyperpigmentation and skin reddening were mitigated by both a formulation containing 3% of a microalgal product and a formulation containing 3% niacinamide. CONCLUSION: Our study sets out an efficient and robust protocol for investigating both blue light-induced cutaneous alterations, such as changes in skin chromophores, and signs of photoageing, such as hyperpigmentation. Moreover, we have shown evidence that both an extract of the microalga Scenedesmus rubescens and niacinamide (vitamin B3) have the potential to protect against blue light-induced hyperpigmentation.

CONTEXTE: La lumière visible, en particulier la lumière bleue, a été identifiée comme un facteur supplémentaire du photo-vieillissement cutané. Cependant, les études cliniques, démontrant l'effet réel de la lumière bleue sur le photo-vieillissement, sont encore rares et jusqu'à présent, la plupart des études portaient sur l'influence de la lumière visible à large spectre. Bien qu'il y ait des preuves concernant l'effet sur la pigmentation de peau, les mécanismes sous-jacents du photo-vieillissement in vivo sont encore peu clairs. De plus, le besoin d'ingrédients actifs protégeant de manière significative en in vivo contre l'hyperpigmentation induite par la lumière bleu est toujours présent. NOTRE ÉTUDE A EU DEUX OBJECTIFS: Détecter des changements visibles dans la pigmentation de la peau à la suite d'une irradiation répétée avec de la lumière bleue à base de LED, et réduire la pigmentation à l'aide d'ingrédients actifs adaptés. MÉTHODE: Nous avons mené une étude clinique randomisée, à l'aveugle et controlée avec un placebo sur 33 volontaires féminins de phototypes de peau III et IV. Nous avons défini un protocole d'irradiation répétitif à lumière bleue (4 x 60 J cm-2, 450 nm) sur les avant-bras intérieurs des volontaires. En utilisant l'imagerie hyperspectrale nous avons évalué l'état de chromophore. En outre, nous avons pris des mesures de couleur et des photographies pour évaluer l'hyperpigmentation de manière visuelle. RÉSULTATS: Nous avons mesuré des changements significatifs dans le statut de chromophore (p<0.001 par rapport au statut initial), par exemple au niveau de la mélanine, de l'hémoglobine et de la saturation en oxygène, immédiatement après l'irradiation à lumière bleue. De plus, nous avons constaté des changements visibles de couleur de la peau qui ont été exprimés par une diminution significative des valeurs ITA° (delta ITA° valeurs = -16.89, p<0.001 par rapport au statut initial pour le groupe placebo), et une augmentation de a* (delta a* = +3.37, p <0.001 par rapport au statut initial pour le groupe placebo) 24 heures après l'irradiation. L'hyperpigmentation et les rougeurs de la peau ont été atténués par une formulation contenant 3% d'un extrait d'algue ainsi que par une formulation contenant 3% de niacinamide. CONCLUSION: Notre étude a établi un protocole efficace et robuste pour étudier à la fois les altérations cutanées induites par la lumière bleue, telles que les changements dans les chromophores de la peau, ainsi que les signes de photo-vieillissement, tels que l'hyperpigmentation. Enfin, nous avons prouvé qu'un extrait de l'algue Scenedesmus rubescens et la niacinamide (vitamine B3) avaient le potentiel de protéger contre l'hyperpigmentation induite par la lumière bleue.

An image-based mapping of significance and relevance of facial skin colour changes of females living in Thailand.

OBJECTIVE: There are methods to evaluate skin colour on defined areas over the face but no approach automatically and accurately evaluates skin colour variations on large facial areas, comparing subjects, treatments and/or time points. We propose such an image-based approach to visualize quickly the outcome of clinical studies on colour variations. METHODS: Among 54 Asian women, one group applied a vehicle twice daily, during 28 days, and the other group an anti-ageing emulsion, taking facial images at baseline and after treatment. Changes in L*a*b* values were studied on four pre-selected facial regions. We also reconstructed average facial images from which the L*a*b* parameters were extracted for every pixel, computing relevance (ΔE) and significance data. Using colour gradients, we mapped these results onto the average facial images. RESULTS: After treatment, L*a*b* parameters show no statistically relevant colour changes in the vehicle group. In the 'active' group, skin was lighter at the upper cheek and, overall, redness decreased. Relevance and significance maps confirmed no visible colour changes in the vehicle group. In the 'active' group, the mapping approach revealed colour changes and their location. Skin became lighter below the eye, cheek and forehead. It was less red below the eyes, on the cheek, jawline and forehead, and generally more yellow. CONCLUSION: Our image-based mapping approach proves to be powerful. It enables us to identify precise facial regions of relevant and statistically significant colour changes after a topical treatment, regions that would have otherwise been undetected.

OBJECTIF: Il existe des méthodes pour évaluer la couleur de la peau sur des zones pré-définies du visage mais aucune approche n'évalue de manière automatique et précise les variations de couleur de peaux sur de large régions du visage, en comparant les sujets, les traitements et/ou les temps d'analyse. Nous proposons une telle méthode basée sur l'analyse d'images pour visualiser de manière rapide les résultats des études cliniques portant sur des variations colorimétriques. MÉTHODES: Parmi 54 femmes d'origine asiatique, un premier groupe a appliqué un véhicule deux fois par jour, pendant 28 jours. Un deuxième groupe a, lui, appliqué une émulsion anti-âge. Des images de visage ont été réalisées avant et après traitement. Les variations des valeurs L*a*b* ont été étudiées sur quatre régions du visage pré-sélectionnées. Nous avons également reconstruit des images de visages moyens pour lesquelles les paramètres L*a*b* ont été extraits pour chaque pixel. Pour ces mêmes pixels, les valeurs de pertinence (delta E) et significativité ont été calculées. A l'aide d'un gradient de couleur, nous avons représenté ces résultats sur les images de visages moyens. RÉSULTATS: Après traitement, les paramètres L*a*b* n'ont montré aucun résultat significativement pertinent pour le groupe ayant appliqué le véhicule. Pour le groupe "actif", la peau est devenue plus claire sur la partie supérieure de la joue et globalement moins rouge. Les cartographies de pertinence et de significativité ont confirmée l'absence de variation colorimétrique sur le groupe véhicule. Sur le groupe "actif", l'approche par cartographie a révélé les changements de couleurs et leur localisation. La peau est devenue plus claire sous les yeux, sur les joue et le front. Le dessous des yeux, les joues, la mâchoire et le front sont devenues moins rouges et généralement plus jaunes. CONCLUSION: Notre approche de cartographie basé sur l'analyse d'images s'est montrée pertinente. Elle nous permet d'identifier de manière précise les régions du visage sur lesquelles des changements pertinents et significatifs de couleur ont eu lieu après l'application d'un traitement topique. Ces régions n'auraient pas été détectées sans cette technique.

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies.

In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125I and 211At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity of astatination (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields>85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75-80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.

Production and characterization of monoclonal antibodies specific for canine CD138 (syndecan-1) for nuclear medicine preclinical trials on spontaneous tumours.

We isolated 11 antibodies specific for canine CD138 (cCD138) to validate the interest of CD138 antigen targeting in dogs with spontaneous mammary carcinoma. The affinity of the monoclonal antibodies in the nanomolar range is suitable for immunohistochemistry and nuclear medicine applications. Four distinct epitopes were recognized on cCD138 by this panel of antibodies. CD138 expression in canine healthy tissues is comparable to that reported in humans. CD138 is frequently expressed in canine mammary carcinomas corresponding to the human triple negative breast cancer subtype, with cytoplasmic and membranous expression. In canine diffuse large B-cell lymphoma, CD138 expression is associated with the 'non-germinal center' phenotype corresponding to the most aggressive subtype in humans. This homology of CD138 expression between dogs and humans confirms the relevance of tumour-bearing dogs as spontaneous models for nuclear medicine applications, especially for the evaluation of new tumour targeting strategies for diagnosis by phenotypic imaging and radio-immunotherapy.

Novel approaches to characterize age-related remodelling of the dermal-epidermal junction in 2D, 3D and in vivo.

BACKGROUND/PURPOSE: The dermal-epidermal junction (DEJ) forms epidermal protrusions down into the dermis (rete ridges) and dermal projections up into the epidermis (dermal papillae). Usually visualized in two-dimensions (2D), our knowledge of how the DEJ changes with ageing is limited. We aimed to characterize how this structure exists in 3D and changes with age. METHODS: Photoprotected and photoexposed skin were imaged using reflectance confocal microscopy (RCM) in young and aged individuals. Biopsies of the imaged areas were processed for histological sectioning and for imaging using micro-computed X-ray tomography (microCT). RESULTS: Images obtained from RCM and microCT were used to 3D reconstruct the DEJ. DEJ heights obtained from microCT images showed strong correlation with histology-measured heights. We proposed a novel definition of rete ridges (RRm ) and dermal papillae (DPm ), which allowed easier automated measurement of reduced DPm and RRm volumes in aged skin from microCT reconstructions. An algorithm to map DPm connectivity showed reduced lengths of DPm branches with age. CONCLUSION: Three-dimensional images illustrated the complex topography of the DEJ and highlighted the distinct morphology of dermal papillae compared with rete ridges, which is not evident when evaluating 2D sections. Ex vivo imaging was more successful in differentiating DEJ architecture with respect to age.

New beam monitoring tool for radiobiology experiments at the cyclotron ARRONAX.

The ARRONAX cyclotron is able to deliver alpha particles at 68 MeV. In the frame of radiological research, a new method is studied to infer in situ the deposited dose: it is based on the online measurement of the bremsstrahlung (>1 keV) produced by the interaction of the incident particle with the medium. Experiments are made using bombarded poly(methyl methacrylate) (PMMA)-equivalent water targets in order to characterise this continuous X-ray spectrum. The intensity of the bremsstrahlung spectrum allows for the beam monitoring. A simulation code of the bremsstrahlung has been built, and a good agreement is found with the experimental spectra. With this simulation, it is possible to predict the sensibility of this method: it varies with the target thickness, showing a good sensibility for thin target (<1000 µm) and saturation for thicker ones. Bremsstrahlung spectrum also shows a sensibility on the target's chemical composition.

Assessment of a fully 3D Monte Carlo reconstruction method for preclinical PET with iodine-124.

Iodine-124 is a radionuclide well suited to the labeling of intact monoclonal antibodies. Yet, accurate quantification in preclinical imaging with I-124 is challenging due to the large positron range and a complex decay scheme including high-energy gammas. The aim of this work was to assess the quantitative performance of a fully 3D Monte Carlo (MC) reconstruction for preclinical I-124 PET. The high-resolution small animal PET Inveon (Siemens) was simulated using GATE 6.1. Three system matrices (SM) of different complexity were calculated in addition to a Siddon-based ray tracing approach for comparison purpose. Each system matrix accounted for a more or less complete description of the physics processes both in the scanned object and in the PET scanner. One homogeneous water phantom and three heterogeneous phantoms including water, lungs and bones were simulated, where hot and cold regions were used to assess activity recovery as well as the trade-off between contrast recovery and noise in different regions. The benefit of accounting for scatter, attenuation, positron range and spurious coincidences occurring in the object when calculating the system matrix used to reconstruct I-124 PET images was highlighted. We found that the use of an MC SM including a thorough modelling of the detector response and physical effects in a uniform water-equivalent phantom was efficient to get reasonable quantitative accuracy in homogeneous and heterogeneous phantoms. Modelling the phantom heterogeneities in the SM did not necessarily yield the most accurate estimate of the activity distribution, due to the high variance affecting many SM elements in the most sophisticated SM.

Which radionuclide, carrier molecule and clinical indication for alpha-immunotherapy?

Beta-emitting radionuclides are not able to kill isolated tumor cells disseminated in the body, even if a high density of radiolabeled molecules can be targeted at the surface of these cells because the vast majority of emitted electrons deliver their energy outside the targeted cells. Alpha-particle emitting radionuclides may overcome this limitation. It is thus of primary importance to test and validate the radionuclide of choice, the most appropriate carrier molecule and the most promising clinical indication. Four α-particle emitting radionuclides have been or are clinically tested in phase I studies namely 213Bi, 225Ac, 212Pb and 211At. Clinical safety has been documented and encouraging efficacy has been shown for some of them (213Bi and 211At). 211At has been the most studied and could be the most promising radionuclide but 225Ac and 212Pb are also of potential great interest. Any carrier molecule that has been labeled with ß-emitting radionuclides could be labeled with alpha particle-emitting radionuclide using, for some of them, the same chelating agents. However, the physical half-life of the radionuclide should match the biological half-life of the radioconjugate or its catabolites. Finally everybody agrees, based on the quite short range of alpha particles, on the fact that the clinical indications for alpha-immunotherapy should be limited to the situation of disseminated minimal residual diseases made of small clusters of malignant cells or isolated tumor cells.

EBT2 films response to alpha radiation at 48.3 MeV.

To advance the development of a radiobiological experimental set-up for alpha particle irradiations at the Arronax cyclotron, experiments were performed to get the dose response of Gafchomic EBT2 films for alpha particles at 48.3 MeV. A system has been developed using a thin monitor copper foil and an X-ray spectrometer to measure the beam intensity and to calculate the delivered dose. On the other hand, the authors have irradiated EBT2 films, with 6-MV X rays, to get the dose response of EBT2 films for photons. The dose response curve for alpha particles shows an effect of polymerisation saturation compared with the dose response curve for photons.

Comparative analysis of multiple myeloma treatment by CD138 antigen targeting with bismuth-213 and Melphalan chemotherapy.

INTRODUCTION: Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a MM model. In order to define where alpha-RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha-RIT using a [213Bi]-anti-mCD138 antibody in a syngeneic MM mouse model. METHODS: C57BL/KaLwRij mice were grafted with 1 × 10(6) 5T33 murine MM cells. Luciferase transfected 5T33 cells were used for in vivo localization. The first step of the study was to assess the dose-response of Melphalan 21 days after engraftment. The second step consisted in therapeutic combination: Melphalan followed by RIT at day 22 or day 25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone, RIT alone at day 22 or day 25 (3.7 MBq of [213Bi]-anti-CD138) and Melphalan combined with alpha-RIT. RESULTS: Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with Melphalan alone, only the 200 µg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25 days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, and results in increased leukocyte and red blood cell toxicity. CONCLUSIONS: Alpha-RIT seems to be a good alternative to Melphalan. Association of these two treatments provides no benefit. The perspectives of this work would be to evaluate RIT impact on the regimens incorporating the novel agents bortezomide, thalidomide and lenalidomide.

Characterization of At- species in simple and biological media by high performance anion exchange chromatography coupled to gamma detector.

Astatine is a rare radioelement belonging to the halogen group. Considering the trace amounts of astatine produced in cyclotrons, its chemistry cannot be evaluated by spectroscopic tools. Analytical tools, provided that they are coupled with a radioactive detection system, may be an alternative way to study its chemistry. In this research work, high performance anion exchange chromatography (HPAEC) coupled to a gamma detector (γ) was used to evaluate astatine species under reducing conditions. Also, to strengthen the reliability of the experiments, a quantitative analysis using a reactive transport model has been done. The results confirm the existence of one species bearing one negative charge in the pH range 2-7.5. With respect to the other halogens, its behavior indicates the existence of negative ion, astatide At(-). The methodology was successfully applied to the speciation of the astatine in human serum. Under fixed experimental conditions (pH 7.4-7.5 and redox potential of 250 mV) astatine exists mainly as astatide At(-) and does not interact with the major serum components. Also, the method might be useful for the in vitro stability assessment of (211)At-labeled molecules potentially applicable in nuclear medicine.

The cytotoxic effect of combined hyperthermia and taxane chemotherapy on ovarian cancer cells: results of an in vitro study.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) is under continuous evaluation as a potential treatment for ovarian cancer. The purpose of this study was to evaluate the effect of chemotherapy, drug concentration and temperature. MATERIALS AND METHODS: We examined the combined effects of hyperthermia and taxane chemotherapy on the clonogenic survival of the human ovarian carcinoma SHIN-3 cell line in vitro. RESULTS: When hyperthermia was combined with chemotherapy, the median lethal dose (LD50) was equivalent regardless of the duration of exposure, and was independent of the exposure temperature. Taxanes showed a similar LD50 over the temperature range tested. CONCLUSIONS: In our study, hyperthermia does not increase the cytotoxic effects of taxanes, at least for the concentrations and durations tested.

Astatine standard redox potentials and speciation in acidic medium.

A combined experimental and theoretical approach is used to define astatine (At) speciation in acidic aqueous solution and to answer the two main questions raised from literature data: does At(0) exist in aqueous solution and what is the chemical form of At(+III), if it exists. The experimental approach considers that a given species is characterized by its distribution coefficient (D) experimentally determined in a biphasic system. The change in speciation arising from a change in experimental conditions is observed by a change in D value. The theoretical approach involves quasi-relativistic quantum chemistry calculations. The results show that At at the oxidation state 0 cannot exist in aqueous solution. The three oxidation states present in the range of water stability are At(-I), At(+I), and At(+III) and exist as At(-), At(+), and AtO(+), respectively, in the 1-2 pH range. The standard redox potentials of the At(+)/At(-) and AtO(+)/At(+) couples have been determined, the respective values being 0.36 +/- 0.01 and 0.74 +/- 0.01 V vs NHE.

Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. I. Presentation and validation of a microdosimetric model.

A microdosimetric model that makes it possible to consider the numerous biological and physical parameters of cellular alpha-particle irradiation by radiolabeled mAbs was developed. It allows for the calculation of single-hit and multi-hit distributions of specific energy within a cell nucleus or a whole cell in any irradiation configuration. Cells are considered either to be isolated or to be packed in a monolayer or a spheroid. The method of calculating energy deposits is analytical and is based on the continuous-slowing-down approximation. A model of cell survival, calculated from the microdosimetric spectra and the microdosimetric radiosensitivity, z(0), was also developed. The algorithm of calculations was validated by comparison with two general Monte Carlo codes: MCNPX and Geant4. Microdosimetric spectra determined by these three codes showed good agreement for numerous geometrical configurations. The analytical method was far more efficient in terms of calculation time: A gain of more than 1000 was observed when using our model compared with Monte Carlo calculations. Good agreements were also observed with previously published results.

Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. II. Application of the microdosimetric model to experimental results.

A microdosimetric model was used to analyze the results of experimental studies on cells of two lymphoid cell lines (T2 and Ada) irradiated with (213)Bi-radiolabeled antibodies. These antibodies targeted MHC/peptide complexes. The density of target antigen could be modulated by varying the concentration of the peptide loaded onto the cells. This offered the possibility of changing the ratio of specific (from cell-bound antibody) to non-specific (from antibody present in the supernatant) irradiation. For both cell lines, survival plotted as a function of the mean absorbed dose was a decreasing exponential. For the T2 cells, the microdosimetric sensitivity calculated for the whole cell was equal whether the irradiation was non-specific (z(0) = 0.12 +/- 0.02 Gy) or specific (z(0) = 0.12 +/- 0.09 Gy). Similar results were obtained for Ada cells. These results constitute a biological validation of the microdosimetric model. For both cells, the measured cell mortality was greater than the percentage of hit cells calculated with the model at low mean absorbed doses. This observation thus suggests bystander effects. It poses the question of the relevance of the mean absorbed dose to the cell nuclei. A new concept in cellular dosimetry taking into account cytoplasm or membrane irradiation and bystander modeling appears to be needed.

[Alpha-radioimmunotherapy: a review of recent developments]. / Le point sur les avancées récentes de la radio-immunothérapie alpha.

The use of heavy particles in the treatment of cancer is increasing remarkably, whether with external radiation or using a vector such as an antibody in radioimmunotherapy. Recent pre-clinical and clinical developments of alpha-radioimmunotherapy have provided more interesting information in parallel of the use of high Linear Energy Transfer (LET) external irradiation. This review aims at presenting recent advances of this therapeutic approach, and at detailing the biological specificities of this kind of radiation.

Current status and perspectives in alpha radioimmunotherapy.

Systemic administration of radiolabeled antibody directed against tumor antigens in radioimmunotherapy (RIT) enables to specifically target the cancer cells and to destroy them. So far, this strategy has proven its efficiency in the treatment of some hematological cancers with antibodies labeled with beta emitting radionuclides. In the last 2 decades, availability of short half life alpha emitters prompted to consider their use in RIT. Contrary to beta particles, alpha particles have a short path length and display a high lineic energy transfer. Those physical characteristics open new fields of clinical applications complementary to beta-RIT. To date, alpha-RIT is still at a preclinical stage of development: the radiolabeling methods need to be optimized to ensure in vivo stability of the radiopharmaceuticals. Some radionuclides have complex decay schemes with daughters emitting further alpha particles whose toxicity needs to be investigated. The modalities of administration of radiolabeled antibodies in animal models require also to be improved for delivering higher doses to tumor targets. A comprehensive analysis of the specific events occurring at cell or tissue level in response to alpha irradiation would be of great interest in order to define the best therapeutic association for residual disease or consolidation treatments. This approach has been proven to be efficient in increasing antitumor response either by using high doses with organ protection (kidney, bone marrow) or by a synergistic effect between alpha-RIT and associated treatments, such as chemotherapy.