Radioinmunoterapia en el linfoma no Hodgkin, posicionamiento, seguridad y eficacia de 90Y-ibritumomab. Experiencia y seguimiento a los 10 años / Radioimmunotherapy for non-Hodgkin's lymphoma; positioning, safety, and efficacy of 90Y-Ibritumomab. 10 years of experience and follow-up

Introducción. La radioinmunoterapia (RIT) es uno de los tratamientos dirigidos contra dianas moleculares del linfoma no Hodgkin (LNH). Objetivo. Evaluar el posicionamiento de la RIT con 90Y-ibritumomab en pacientes con LNH, así como su seguridad y efectividad. Método. Estudio retrospectivo de pacientes con LNH que recibieron RIT con 90Y-ibritumomab. Se evaluaron la concordancia con las guías clínicas, la toxicidad según la clasificación Common Terminology Criteria for Adverse Events (CTCAE) y la efectividad en función de la respuesta al tratamiento y de la supervivencia global (SG) y la supervivencia libre de progresión (SLP). Resultados. Se solicitó RIT en 26 pacientes, de los que 21 (11 mujeres, edad media ± desviación estándar 56±10 años) fueron incluidos en el estudio, con la siguiente distribución: LNH folicular 67%, LNH del manto 14%, LNH difuso de células B grandes 9,5% y LNH transformado 9,5%. Se trató a 12 pacientes con LNH refractario, 7 para consolidación de respuesta y 2 para acondicionamiento a trasplante. El 71% de los pacientes presentó efectos adversos, generalmente manejables y transitorios, siendo la trombocitopenia el más frecuente. A los 3-4 meses, se obtuvo una tasa de respuesta global del 76,2% (completa en 71,4% y parcial en 4,8%) y el 19% mostró progresión de su enfermedad. Con una mediana de seguimiento de 70 meses, la SG fue 96±8 y la SLP de 54±11 meses. Conclusiones. La RIT presentó una moderada correlación con las guías clínicas y probablemente esté infrautilizada. Los efectos adversos fueron frecuentes, leves y manejables. Los datos muestran una alta tasa de respuesta completa y una prolongación de la SG y la SLP (AU)

Introduction. Radioimmunotherapy (RIT) is one of the therapies directed against molecular targets in non-Hodgkin's lymphoma (NHL). Objective. To evaluate the positioning, safety, and effectiveness of RIT with 90Y-Ibritumomab in NHL patients. Method. A retrospective study was conducted on patients with NHL who received RIT with 90Y-Ibritumomab. An evaluation was made of the concordance with clinical guidelines, toxicity as rated by the Common Terminology Criteria for Adverse Events (CTCAE), and effectiveness was assessed based on response to treatment, overall survival (OS), and progression-free survival (PFS). Results. RIT was requested in 26 patients, of whom 21 (11 women, mean age 56±10 years) were included in the study, with the following distribution: Follicular NHL, 67%, Mantle NHL, 14%, Diffuse large B-cell NHL, 9.5%, and Transformed NHL 9.5%. Twelve patients with refractory NHL, 7 for consolidation response, and 2 transplant conditioning, were treated. Adverse effects were observed in 71% of patients, which were usually manageable and transient, and with the most common being thrombocytopenia. At 3-4 months, overall response rate was 76.2% (71.4% complete and 4.8% partial response), and 19% had progression of disease. With a median follow up of 70 months, the OS was 96±8 months, and the PFS was 54±11 months. Conclusion. RIT showed a moderate correlation with clinical guidelines, and is probably underused. Adverse effects were common, mild, and manageable. The data show a high complete response rate and an increase in the OS and PFS (AU)

Monte Carlo Calculation of Radioimmunotherapy with (90)Y-, (177)Lu-, (131)I-, (124)I-, and (188)Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts.

Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like (131)I or (90)Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of (90)Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as (90)Y, (177)Lu, (131)I, (124)I, and (188)Re are used. Tumour control probability (TCP) and normal tissue complication probability (NTCP) curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody) distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC)). (90)Y and (188)Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases.

Quantitative single-particle digital autoradiography with α-particle emitters for targeted radionuclide therapy using the iQID camera.

PURPOSE: Alpha-emitting radionuclides exhibit a potential advantage for cancer treatments because they release large amounts of ionizing energy over a few cell diameters (50-80 µm), causing localized, irreparable double-strand DNA breaks that lead to cell death. Radioimmunotherapy (RIT) approaches using monoclonal antibodies labeled with α emitters may thus inactivate targeted cells with minimal radiation damage to surrounding tissues. Tools are needed to visualize and quantify the radioactivity distribution and absorbed doses to targeted and nontargeted cells for accurate dosimetry of all treatment regimens utilizing α particles, including RIT and others (e.g., Ra-223), especially for organs and tumors with heterogeneous radionuclide distributions. The aim of this study was to evaluate and characterize a novel single-particle digital autoradiography imager, the ionizing-radiation quantum imaging detector (iQID) camera, for use in α-RIT experiments. METHODS: The iQID camera is a scintillator-based radiation detection system that images and identifies charged-particle and gamma-ray/x-ray emissions spatially and temporally on an event-by-event basis. It employs CCD-CMOS cameras and high-performance computing hardware for real-time imaging and activity quantification of tissue sections, approaching cellular resolutions. In this work, the authors evaluated its characteristics for α-particle imaging, including measurements of intrinsic detector spatial resolutions and background count rates at various detector configurations and quantification of activity distributions. The technique was assessed for quantitative imaging of astatine-211 ((211)At) activity distributions in cryosections of murine and canine tissue samples. RESULTS: The highest spatial resolution was measured at ∼20 µm full width at half maximum and the α-particle background was measured at a rate as low as (2.6 ± 0.5) × 10(-4) cpm/cm(2) (40 mm diameter detector area). Simultaneous imaging of multiple tissue sections was performed using a large-area iQID configuration (ø 11.5 cm). Estimation of the (211)At activity distribution was demonstrated at mBq/µg-levels. CONCLUSIONS: Single-particle digital autoradiography of α emitters has advantages over traditional film-based autoradiographic techniques that use phosphor screens, in terms of spatial resolution, sensitivity, and activity quantification capability. The system features and characterization results presented in this study show that the iQID is a promising technology for microdosimetry, because it provides necessary information for interpreting alpha-RIT outcomes and for predicting the therapeutic efficacy of cell-targeted approaches using α emitters.

Encapsulation of α-Particle-Emitting 225Ac3+ Ions Within Carbon Nanotubes.

UNLABELLED: (225)Ac(3+) is a generator of α-particle-emitting radionuclides with 4 net α-particle decays that can be used therapeutically. Targeting (225)Ac(3+) by use of ligands conjugated to traditional bifunctional chelates limits the amount of (225)Ac(3+) that can be delivered. Ultrashort, single-walled carbon nanotubes (US-tubes), previously demonstrated as sequestering agents of trivalent lanthanide ions and small molecules, also successfully incorporate (225)Ac(3+). METHODS: Aqueous loading of both (225)Ac(3+) ions and Gd(3+) ions via bath sonication was used to construct (225)Ac@gadonanotubes ((225)Ac@GNTs). The (225)Ac@GNTs were subsequently challenged with heat, time, and human serum. RESULTS: US-tubes internally loaded with both (225)Ac(3+) ions and Gd(3+) ions show 2 distinct populations of (225)Ac(3+) ions: one rapidly lost in human serum and one that remains bound to the US-tubes despite additional challenge with heat, time, and serum. The presence of the latter population depended on cosequestration of Gd(3+) and (225)Ac(3+) ions. CONCLUSION: US-tubes successfully sequester (225)Ac(3+) ions in the presence of Gd(3+) ions and retain them after a human serum challenge, rendering (225)Ac@GNTs candidates for radioimmunotherapy for delivery of (225)Ac(3+) ions at higher concentrations than is currently possible for traditional ligand carriers.

90Sr content in 90Y-labeled SIR-spheres and Zevalin.

Three different 90Y internally administered radionuclide therapies are currently used in both standard-of-care and clinical trial procedures atMD Anderson Cancer Center. TheraSphere and SIR-Spheres therapies utilize 90Y-labeled microspheres, while Zevalin is an 90Y-labeled radioimmunotherapeutic agent. Several publications have indicated radionuclidic impurities resulting from 90Y production methods. The 90Y in SIR-Spheres and Zevalin are produced from a 90Sr/90Y generator, which leaves measurable quantities of 90Sr in the final product. TheraSphere 90Y is produced in a nuclear reactor which results in a large number of impurities, most notably 88Y and 91Y. Product information sheets reference these impurities with specific limits given. These limits represent a tiny fraction of the total product activity, and in the case of TheraSphere and SIR-Spheres gamma-emitting impurities, this has been verified in the literature. An analysis of 90Sr impurities in SIR-Spheres and Zevalin is presented in this paper. Impurity quantities were found to be within the vendors' documented limits.

213Bi (alpha-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model.

Treatment failure in breast cancer is largely the failure to control metastatic dissemination. In this study, we investigated the efficacy of an antibody against the rat variant of HER-2/neu, labeled with the alpha-particle emitter (213)Bi to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination of tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 muCi of (213)Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 muCi (213)Bi-7.16.4, (b) 90 muCi (213)Bi-7.16.4, (c) 120 muCi (213)Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 muCi (213)Bi-7.16.4 increased median survival time to 41 days compared with 28 days for the untreated controls (P < 0.0001); corresponding median survival times for groups b, c, and d were 36 (P < 0.001), 31 (P < 0.01), and 33 (P = 0.05) days, respectively. Median survival relative to controls was not significantly improved in mice injected with 10-fold less cells or with multiple courses of treatment. We concluded that alpha-emitter (213)Bi-labeled monoclonal antibody targeting the HER-2/neu antigen was effective in treating early-stage HER-2/neu--expressing micrometastases. Analysis of the results suggests that further gains in efficacy may require higher specific activity constructs or target antigens that are more highly expressed on tumor cells.

Radioimmunotherapy with radioactive nanoparticles: first results of dosimetry for vascularized and necrosed solid tumors.

Radioimmunotherapy uses monoclonal antibodies that are still labeled with only one radioactive atom. The aim of this paper is to assess, by means of MCNPX simulations, the doses delivered around and throughout a solid tumor when the radioactive atom linked to each antibody is replaced by a 5 nm diameter nanoparticle composed of numerous radionuclides. A new model for a spherical vascularized tumor has been developed in which the antibody distributions inside the tumor can be uniform or heterogeneous. It is also possible to simulate a central necrotic core inside the tumor where the concentration of radiolabeled antibodies is assumed to be zero. Dosimetry calculations have been performed for the beta-emitting radionuclide (90)Y2O3. Preliminary results show that the irregularity of vasculature and the presence of a necrotic core have a noticeable influence on the deposited dose profiles. Moreover, with a total activity of 5 and 34 MBq for tumor radii of 0.5 and 1.0 cm, respectively, viable tumor cells can receive doses of up to 50 Gy, even if high nonuniformity of the total activity is observed in the tumor. These simulations still require accurate information about antibody characteristics and necrosis sizes but clearly confirm that the use of monoclonal antibodies conjugated to nanoparticles could lead to a considerable enhancement of treatment efficacy against cancer.

Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down.

Radioimmunotherapy using 131I-A5B7, an anti-CEA antibody, in combination with the vascular disrupting agent, combretastatin A4-phosphate (CA-4-P, 200 mg/kg), has produced tumor cures in SW1222 colorectal xenografts. CA-4-P causes acute tumor blood vessel shutdown, which can be monitored in clinical trials using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The purpose of this study was to determine the magnitude of the anti-vascular effect of CA-4-P in the SW1222 tumor, at 200 mg/kg and at lower, more clinically relevant doses, using conventional assays; relate effects to changes in DCE-MRI parameters and determine the corresponding effects on tumor retention of 131I-A5B7. The tumor vascular effects of 30, 100 and 200 mg/kg CA-4-P were determined, at 4- and 24-h post-treatment, using DCE-MRI, uptake of Hoechst 33342 for tumor vascular volume and conventional histology for necrosis. The effect of CA-4-P on tumor and normal tissue 131I-A5B7 retention was also determined. A significant reduction in tumor DCE-MRI kinetic parameters, the initial area under the contrast agent concentration time curve (IAUGC) and the transfer constant (Ktrans), was demonstrated at 4 h after CA-4-P, for all dose levels. These effects persisted for at least 24 h for the 200 mg/kg group but not for lower doses. A similar pattern was seen for vascular volume and necrosis. Despite this dose response, all three dose levels increased tumor retention of radio labeled antibody to a similar degree. These results demonstrate that moderate tumor blood flow reduction following antibody administration is sufficient to improve tumor antibody retention. This is encouraging for the combination of CA-4-P and 131I-A5B7 in clinical trials.

Phase I study of 131I-chimeric(ch) TNT-1/B monoclonal antibody for the treatment of advanced colon cancer.

PURPOSE: The primary aim of this study was to evaluate the biodistribution and toxicity of 131I-chimeric(ch) TNT-1/B monoclonal antibody (MAB), which binds to intracellular antigens of necrotic regions within tumors, in patients with advanced colon or colorectal cancer. The rationale for targeting areas of tumor necrosis is the observation that necrotic lesions are more abundant in cancer lesions than in surrounding tissues. PATIENTS AND METHODS: Cohorts of patients with advanced colon or colorectal cancer were administered a one-time 30-60-minute intravenous (i.v.) infusion of 131I-chTNT-1/B at doses ranging from 12.95 to 66.23 MBq/kg (0.35-1.79 mCi/kg). RESULTS: The dose-limiting toxicity, experienced at 66.23 MBq/kg (1.79 mCi/kg) 131I-chTNT-1/B MAB, was myelosuppression. Two (2) patients at the 66.23-MBq/kg (1.79 mCi/kg) dose level had both grade 3 thrombocytopenia and grade 3 neutropenia that persisted for at least 2 weeks but were reversible. The maximum tolerated dose was 58.09 MBq/kg (1.57 mCi/kg) 131I-chTNT-1/B MAB. Of the 21 patients, one developed a moderate human antichimeric antibody (HACA) response and 6 developed low HACA responses. CONCLUSIONS: The infusion of 131I-chTNT-1/B MAB was well tolerated, without significant nonhematological toxicity. No patient obtained a complete or partial response, based on tumor cross-product response criteria. Tumor localization was seen in patients with dose levels at, and exceeding, 50.23 MBq/kg (1.36 mCi/kg) 131I-chTNT-1/B MAB.

Copper-67 as a therapeutic nuclide for radioimmunotherapy.

The application of the beta particle-emitting nuclide 67Cu in radioimmunotherapy is reviewed. The production of the nuclide is outlined, and different production modes are discussed with an emphasis on cyclotron production. A short survey of copper chelators currently used for antibody labelling and their impact on the pharmacokinetics of 67Cu-labelled immunoconjugates is provided. Protocols for antibody labelling with 67Cu as well as quality control procedures for 67Cu-labelled antibodies are described. Preclinical data on the biological properties of 67Cu-labelled immunoconjugates are reported and discussed. 67Cu-labelled antibodies show higher and more persistent tumour uptake than their radioiodinated counterparts due to accumulation of labelled metabolites in tumour cells. Biodistribution of 67Cu-labelled antibody fragments has been improved by selection of negatively charged chelators and peptide linkers. Pharmacokinetic analysis of the accumulated dose in tumour and critical organs such as the kidney and liver indicates that, despite this improvement, intact 67Cu-labelled antibodies achieve higher tumour uptake and better therapeutic ratios than 67Cu-labelled antibody fragments and that they are at present the logical choice for clinical studies. Clinical studies using 67Cu-labelled antibodies in lymphoma, colon carcinoma and bladder cancer patients are reviewed. Some of the advantages over radioiodinated antibodies found in the preclinical work, such as higher tumour uptake and better tumour/blood ratios, have also been found with systemic application in lymphoma and colon carcinoma. However, in both lymphoma and colon carcinoma patients, the radiation dose to the liver has been found to be higher from 67Cu- than from 131I-labelled antibodies. The intravesical application of 67Cu-labelled antibody has been shown to be a promising approach for targetting cytotoxic radiation to superficial bladder tumours, without detectable systemic absorption. Given the favourable properties of 67Cu-labelled antibodies, it is the reliable availability of the 67Cu nuclide which is the limiting factor for their more widespread evaluation in radioimmunotherapy trials.

Reproducibility of operator processing for radiation dosimetry.

Reproducibility of operator processing for radiation dose and biological half-life was assessed for radioimmunotherapy. Mean coefficient of variation for intra-operator consecutive processing and for inter-operator processing was less than 15% for all tissues. The mean coefficient of variation for intraoperator processing over 2 wk or inter-operator processing comparing an experienced and less experienced operator was generally greater, and particularly so for tumors. Satisfactory reproducibility was achievable using visual determination of regions of interests after 80 h of training.

Improved conjugate view quantitation of I-131 by subtraction of scatter and septal penetration events with a triple energy window method.

The majority of radiation absorbed dose estimates for radioimmunotherapy (RIT) with I-131 labeled antibodies have been calculated based on in vivo quantitation of activity using the conjugate view approach with planar Anger camera images. Scatter and septal penetration events contributed by a small fraction of high-energy photons emitted by I-131 with an energy exceeding 600 KeV lead to a significant degradation of I-131 images acquired with an Anger camera, which blurs the images of uptake sites and complicates the definition of background regions. The objective of this study was to evaluate a triple energy window (TEW) subtraction method that has been used to remove these interfering events from I-131 images. In the method, a primary photopeak image for I-131 is obtained after sequential subtraction of septal penetration and scatter events by using scatter multipliers derived from a photopeak window and two adjacent scatter window images. Qualitative improvement in image contrast was demonstrated with this technique, together with more accurate and reproducible quantitation for I-131 in the organs of an abdominal phantom. This TEW scatter subtraction method can be used to provide more precise dosimetry estimates for radionuclide therapy and RIT with I-131.

A sensitivity study of micro-TLDs for in vivo dosimetry of radioimmunotherapy.

The sensitivity and precision of teflon-imbedded CaSO4:Dy microthermoluminescent dosimeters (micro-TLDs) were determined. The micro-TLDs were sectioned from miniature TLDs (200 microns x 400 microns x 5 mm) that were fabricated using standard techniques. In order to measure absorbed dose, the miniature TLDs can be implanted directly into tissues (e.g., tumor xenografts) that have received injections of radiolabeled monoclonal antibodies. Micro-TLDs recovered from tissue sections cut with a microtome can be read out to determine local absorbed dose. The precision of dose estimation was quantified for uniformly irradiated 32-, 96-, and 192-microns TLD chips; coefficients of variation ranged from 22% to 41%, depending on chip size. The coefficients of variation were reduced to less than 12% using individual relative sensitivity factors for each micro-TLD. The spatial resolution of the micro-TLDs was studied by placing miniature TLDs across the sharp penumbral region of a linear accelerator x-ray field. TLDs were sectioned into 32-microns chips which were read out to determine the relative absorbed dose. The sharpness of the penumbra was readily quantified by the micro-TLDs.