Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors

Confino, Hila; Hochman, Ilan; Efrati, Margalit; Schmidt, Michael; Umansky, Viktor; Kelson, I.; Keisari, Yona

doi:10.1007/s00262-014-1626-8

Cited by 32 publications

(32 citation statements)

References 28 publications

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“…The current study represents an excellent example of successful recapitulation and validation of preclinical studies that demonstrated impressive tumor responses. [1][2][3][4][8][9][10][11][12] The innovative development of a brachytherapy dose delivery that takes advantage of short-range diffusion of alpha particles is unique and could potentially be paradigm changing. Brachytherapy has relied on radioactive beta and gamma sources for many years, and new, radio-biologically more potent sources could provide great benefit for patients with other solid tumors whose prognosis is poor.…”

Section: Months After Dart Insertionmentioning

confidence: 99%

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

Popovtzer

Rosenfeld

Mizrachi

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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Purpose: Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. Methods and Materials: This prospective first-inhuman , multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. Results: Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI,

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Section: Months After Dart Insertionmentioning

confidence: 99%

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

Popovtzer

Rosenfeld

Mizrachi

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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“…Their efficacy was attributed to the diffusion of the α-particle-emitting daughters of implanted 224 Ra in the tumor region surrounding the wire (114). An interesting future direction in this particular type of brachytherapy would be stimulation of specific antitumor immunity by the tumor antigens originating from the destroyed tumor (115). Studies on the effects of α-particle radiation (via radioimmunotherapy, for example), when combined with adoptive T cell transfer to induce immune responses that better control tumor growth (116), may help determine the direction of the next type of immunotherapies.…”

Section: Preclinical α-Particle Therapy Delivered By Nanometer-sizmentioning

confidence: 99%

Targeted and Nontargeted α-Particle Therapies

McDevitt

Sgouros

Sofou

2018

Annu. Rev. Biomed. Eng.

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α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease.

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“…Le propre de cette méthode, développée pour le traitement des tumeurs solides, est d'insérer la source radioactive (le radium-224) directement au niveau de la tumeur, ce qui libère continuellement les atomes émetteurs de particules α in situ. Les analyses effectuées à la suite de ce traitement à base de rayonnements α, pour évaluer la réponse immunitaire antitumorale, ont montré : (1) une plus grande résistance à la ré-inoculation d'une même souche tumorale (c'est-à-dire : l'inhibition de la croissance tumorale), (2) une diminution des métastases pulmonaires, et (3) un effet renforcé lorsque ces radiations sont combinées avec un immunostimulant, le CpG 4 [39,40,54] …”

Section: Le Cas Des Particules Alphaunclassified

Radio-immunothérapie alpha

Ménager¹,

Gorin²,

Fichou³

et al. 2016

Med Sci (Paris)

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> La radioimmunothérapie alpha (RITα) est une thérapie anticancéreuse vectorisée utilisant généralement un anticorps monoclonal spécifique d'un antigène tumoral couplé à un émetteur de particules α. Les émetteurs α représentent un outil idéal pour éradiquer les tumeurs disséminées ou les métastases. De récentes données démontrent que les rayonnements ionisants, en plus de leur cytotoxicité directe, peuvent aussi induire une immunité antitumorale efficace. Les effets biologiques de l'irradiation pourraient donc être utilisés pour potentialiser la réponse à différents types d'immunothérapie, et ainsi ouvrir la voie au développement de nouvelles thérapies combinant RITα et immunothérapies. < radionucléide. Le choix du radionucléide repose sur des considérations pratiques (le coût, la disponibilité, le type de techniques de radiomarquage et la facilité d'utilisation), le type d'émission du radioélément, le transfert d'énergie linéique (TEL : quantité d'énergie transférée au milieu par la particule incidente, par unité de longueur de la trajectoire en keV 1 /µm) et la demi-vie physique du radioisotope (durée nécessaire pour que la moitié des noyaux radioactifs d'une source se soient désintégrés) [2]. Cette dernière doit être, autant que possible, en adéquation avec la pharmacocinétique du vecteur utilisé, afin de délivrer la plus grande dose possible de radioactivité à la tumeur après l'injection. Une demi-vie trop courte entraînera un nombre élevé de désintégrations avant d'atteindre la cible. À l'inverse, une demi-vie trop longue engendrera un grand nombre de désintégrations du radionucléide pendant la phase d'éli-mination du vecteur, rendant le radioimmunoconjugué plus toxique. La demi-vie doit également être compatible avec les applications cliniques et la prise en charge du patient. Ainsi, le temps nécessaire au transfert du radionucléide du site de production jusqu'à l'hôpital, 1 1 keV (kiloélectronvolts) = 10 3 eV ; 1 MeV (megaélectonvolts) = 10 6 eV.

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Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors

Cited by 32 publications

References 28 publications

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

Initial Safety and Tumor Control Results From a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck

Targeted and Nontargeted α-Particle Therapies

Radio-immunothérapie alpha

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