Dataset Information

Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model.

ABSTRACT: OBJECTIVES:Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to (213)Bi, an ?-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with ?-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with (213)Bi for ?-RIT or (177)Lu for ?-RIT. METHODS:A new monoclonal anti-CD138 antibody, 9E7.4, was generated by immunizing a rat with a murine CD138-derived peptide. Antibody specificity was validated by flow cytometry, biodistribution, and ?-RIT studies. Then, a ?-RIT dose-escalation assay with the (177)Lu-radiolabeled 9E7.4 mAb was performed in KalwRij C57/BL6 mice 10?days after i.v. engraftment with 5T33 MM cells. Animal survival and toxicological parameters were assessed to define the optimal activity. RESULTS:?-RIT performed with 3.7?MBq of (213)Bi-labeled 9E7.4 anti-CD138 mAb increased median survival to 80?days compared to 37?days for the untreated control and effected cure in 45% of animals. ?-RIT performed with 18.5?MBq of (177)Lu-labeled 9E7.4 mAb was well tolerated and significantly increased mouse survival (54 vs. 37?days in the control group); however, no mice were cured with this treatment. CONCLUSION:This study revealed the advantages of ?-RIT in the treatment of MM in a preclinical model where ?-RIT shows almost no efficacy.

SUBMITTER: Fichou N

PROVIDER: S-EPMC4631990 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model.

Fichou Nolwenn N Gouard Sébastien S Maurel Catherine C Barbet Jacques J Ferrer Ludovic L Morgenstern Alfred A Bruchertseifer Frank F Faivre-Chauvet Alain A Bigot-Corbel Edith E Davodeau François F Gaschet Joëlle J Chérel Michel M

Frontiers in medicine 20151104

<h4>Objectives</h4>Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to (213)Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic ...[more]

PMID: 26582128

Similar Datasets

Project description:Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer.

Project description:BackgroundMetastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.MethodsWe conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.ResultsFrom June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.ConclusionsRadioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.).

Project description:BackgroundLutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited.Case descriptionA 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.SummaryWe report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland.ConclusionsThyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.

Project description:PurposeIncreased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy.MethodsThe anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177Lu only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low-dose, and 177Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177Lu-DTPA-TRC105.ResultsBiodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses.Conclusion177Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.

Project description:BackgroundQuantitative SPECT imaging in targeted radionuclide therapy with lutetium-177 holds great potential for individualized treatment based on dose assessment. The establishment of dose-effect relations requires a standardized method for SPECT quantification. The purpose of this multi-center study is to evaluate quantitative accuracy and inter-system variations of different SPECT/CT systems with corresponding commercially available quantitative reconstruction algorithms. This is an important step towards a vendor-independent standard for quantitative lutetium-177 SPECT.MethodsFour state-of-the-art SPECT/CT systems were included: Discovery™ NM/CT 670Pro (GE Healthcare), Symbia Intevo™, and two Symbia™ T16 (Siemens Healthineers). Quantitative accuracy and inter-system variations were evaluated by repeatedly scanning a cylindrical phantom with 6 spherical inserts (0.5 - 113 ml). A sphere-to-background activity concentration ratio of 10:1 was used. Acquisition settings were standardized: medium energy collimator, body contour trajectory, photon energy window of 208 keV (± 10%), adjacent 20% lower scatter window, 2 × 64 projections, 128 × 128 matrix size, and 40 s projection time. Reconstructions were performed using GE Evolution with Q.Metrix™, Siemens xSPECT Quant™, Siemens Broad Quantification™ or Siemens Flash3D™ algorithms using vendor recommended settings. In addition, projection data were reconstructed using Hermes SUV SPECT™ with standardized reconstruction settings to obtain a vendor-neutral quantitative reconstruction for all systems. Volumes of interest (VOI) for the spheres were obtained by applying a 50% threshold of the sphere maximum voxel value corrected for background activity. For each sphere, the mean and maximum recovery coefficient (RCmean and RCmax) of three repeated measurements was calculated, defined as the imaged activity concentration divided by the actual activity concentration. Inter-system variations were defined as the range of RC over all systems.ResultsRC decreased with decreasing sphere volume. Inter-system variations with vendor-specific reconstructions were between 0.06 and 0.41 for RCmean depending on sphere size (maximum 118% quantification difference), and improved to 0.02-0.19 with vendor-neutral reconstructions (maximum 38% quantification difference).ConclusionThis study shows that eliminating sources of possible variation drastically reduces inter-system variation in quantification. This means that absolute SPECT quantification for 177Lu is feasible in a multi-center and multi-vendor setting; however, close agreement between vendors and sites is key for multi-center dosimetry and quantitative biomarker studies.

Dataset Information

Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model.

Publications

Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets