Radiopharmaceutical Therapy Research Articles

Dosimetry in Clinical Radiopharmaceutical Therapy of Cancer: Practicality Versus Perfection in Current Practice.

The use of radiopharmaceutical therapies (RPTs) in the treatment of cancers is growing rapidly, with more agents becoming available for clinical use in last few years and many new RPTs being in development. Dosimetry assessment is critical for personalized RPT, insofar as administered activity should be assessed and optimized in order to maximize tumor-absorbed dose while keeping normal organs within defined safe dosages. However, many current clinical RPTs do not require patient-specific dosimetry based on current Food and Drug Administration-labeled approvals, and overall, dosimetry for RPT in clinical practice and trials is highly varied and underutilized. Several factors impede rigorous use of dosimetry, as compared with the more convenient and less resource-intensive practice of empiric dosing. We review various approaches to applying dosimetry for the assessment of activity in RPT and key clinical trials, the extent of dosimetry use, the relative pros and cons of dosimetry-based versus fixed activity, and practical limiting factors pertaining to current clinical practice.

Tumor Response to Radiopharmaceutical Therapies: The Knowns and the Unknowns.

Radiopharmaceutical therapy (RPT) is defined as the delivery of radioactive atoms to tumor-associated targets. In RPT, imaging is built into the mode of treatment since the radionuclides used in RPT often emit photons or can be imaged using a surrogate. Such imaging may be used to estimate tumor-absorbed dose. We examine and try to elucidate those factors that impact the absorbed dose-versus-response relationship for RPT agents. These include the role of inflammation- or immune-mediated effects, the significance of theranostic imaging, radiobiology, differences in dosimetry methods, pharmacokinetic differences across patients, and the impact of tumor hypoxia on response to RPT.

SNMMI Clinical Trials Network Research Series for Technologists: Introduction.

The field of nuclear medicine and molecular imaging has grown tremendously over the past several years with the approval of new imaging agents, diagnostic radiopharmaceuticals, and radiopharmaceutical therapies. Clinical research continues to expand within nuclear medicine and molecular imaging departments. Working as a nuclear medicine technologist on a clinical trial or with investigational radiopharmaceuticals can be quite different from working in an approved-drug setting in the clinic. Nuclear medicine technologists involved in clinical trials can be at the front line of following rigorous trial requirements and ensuring good-quality data. The details of working in clinical research are often not taught in nuclear medicine technologist programs. As such, there is an emerging need for education about clinical research for both experienced and new nuclear medicine technologists, particularly for those working with investigational radiopharmaceuticals. This article is an introduction to the SNMMI Clinical Trials Network Research Series for Technologists. This series of articles aims to provide education on working in the context of a clinical trial within the nuclear medicine department. The following 7 topics will be addressed in the series: ethical issues in clinical research, application of good clinical practice to clinical research in medical imaging, contract research organizations with application in clinical imaging, a clinical research primer on the regulatory process for how and when radiopharmaceuticals can be used and the role of the institutional review board, use of imaging agents in therapeutic drug development and approval, imaging agent trials, and imaging agents with radiopharmaceutical therapies in clinical trials. Other topics may be added over the course of the development of the series.

Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns.

Radiopharmaceutical therapies are gaining increasing prominence as they improve survival in patients with common diseases such as metastatic prostate cancer ([ 1 ][1],[ 2 ][2]). However, whereas sodium iodide (131I) therapy has been used for over 70 y in treating malignant and benign thyroid

Reimbursement Approaches for Radiopharmaceutical Dosimetry: Current Status and Future Opportunities.

Interest in performing dosimetry for clinical radiopharmaceutical therapy procedures has grown in recent years. Several approved therapies include dosimetry in the Food and Drug Administration-approved label instructions, and other therapies are best used under a patient-tailored paradigm. This paper, which is a product of the Society of Nuclear Medicine and Molecular Imaging Dosimetry Task Force, presents motivations and general workflows for radiopharmaceutical therapy dosimetry, as well as existing strategies for obtaining reimbursement for clinical activities related to dosimetry. Several specific patient examples are provided, including suggested codes for reimbursement. In addition to current reimbursement approaches, key dosimetry services that are not supported under the current coding structure are presented and suggested as areas of focus in the coming years.

Radiopharmaceutical Dosimetry for Cancer Therapy: From Theory to Practice.

This supplement to The Journal of Nuclear Medicine includes 7 articles that address several of the critical facets of the current state of radiation dosimetry in radiopharmaceutical therapy. This supplement is designed to be a snapshot in time that attempts to address both the rapid progress and the

Dosimetry for Radiopharmaceutical Therapy: Current Practices and Commercial Resources.

With the ongoing dramatic growth of radiopharmaceutical therapy, research and development in internal radiation dosimetry continue to advance both at academic medical centers and in industry. The basic paradigm for patient-specific dosimetry includes administration of a pretreatment tracer activity of the therapeutic radiopharmaceutical; measurement of its time-dependent biodistribution; definition of the pertinent anatomy; integration of the measured time-activity data to derive source-region time-integrated activities; calculation of the tumor, organ-at-risk, and/or whole-body absorbed doses; and prescription of the therapeutic administered activity. This paper provides an overview of the state of the art of patient-specific dosimetry for radiopharmaceutical therapy, including current methods and commercially available software and other resources.

Dosimetry for Radiopharmaceutical Therapy: The European Perspective.

This review presents efforts in Europe over the last few years with respect to standardization of quantitative imaging and dosimetry and comprises the results of several European research projects on practices regarding radiopharmaceutical therapies (RPTs). Because the European Union has regulatory requirements concerning dosimetry in RPTs, the European Association of Nuclear Medicine released a position paper in 2021 on the use of dosimetry under these requirements. The importance of radiobiology for RPTs is elucidated in another position paper by the European Association of Nuclear Medicine. Furthermore, how dosimetry interacts with clinical requirements is described, with several clinical examples. In the future, more efforts need to be undertaken to increase teaching and standardization efforts and to incorporate radiobiology for further individualizing patient treatment, with the aim of improving the outcome and safety of RPTs.

Abstract P169: Dynamic cell-level modeling of antibody binding and internalization for radiosensitivity assessements in alpha-emitter radiopharmaceutical therapy

Abstract The radiobiological response to alpha-emitter radiopharmaceutical therapy (αRPT) is often studied in cell monolayers. The geometric models which are currently used to estimate the relationship between isotope activity concentration and cell survival probability typically idealize cells as spheres without considering cellular biological processes. This results in inaccurate and non-generalizable results, which could hamper the rigorous study of the underlying radiobiology. The purpose of this study was to create accurate absorbed dose models by combining Monte Carlo simulations with 3D measurements of cell clustering and geometries, as well as dynamic carrier molecule binding and trafficking in individual cells of cell monolayers. This allows for a more accurate way to model cell survival in these αRPT experiments. Experimental conditions of previous cell survival experiments with 212Pb on NT2.5 HER2+ breast cancer cells were replicated. Live cells were imaged on a confocal microscope. Nuclei were stained with Hoechst and the media was stained with labelled dextran, creating a negative template of the cells. A relevant antibody (Ab) was tagged with AF488. 3D time lapses of membrane binding kinetics and internalization were recorded. Photobleaching was modelled and corrected for. All cells were segmented into nuclei, membrane and cytosol compartments using a purpose-build algorithm. The temporal antibody signals were used to fit pharmacokinetic models, which enabled interpolation and validation with experimental binding assays. The segmentations were used in a Monte Carlo code. S-values for every compartment and time frame were calculated using the Ab distribution directly, capturing the effect of Ab trafficking. Absorbed doses were calculated for each cell and were used to model previously obtained cell survival curves. Statistics were calculated for >100 cells. We observed a large range in absorbed doses (coefficient of variation 0.74). Absorbed doses to the nucleus per unit decay on the membrane, which are mainly determined by cellular geometries, agreed with the geometric model (error <6%). S-values for intercellular decays increased >50% over time, which corresponds to perinuclear trafficking of Abs. The dose contribution of neighboring cells was high (46% of total dose; 6x geometric model), highlighting the importance of cell clustering. Applying this to previous cell survival data yielded an estimated radiosensitivity kappa of 7.1 (geometric model: 2.8). Cell clustering has a larger, and cell geometry has a smaller impact than is assumed in current models. Perinuclear trafficking of internalized Ab positively impacts cell nucleus absorbed dose, which is typically ignored. Dose variability should be included in radiosensitivity modeling. We intend to use such rigorous and highly detailed, cell-level analyses to arrive at simplifications that are generalizable and whose accuracy is better understood. For example, based on our findings a better accounting of cell clustering would substantially improve geometric model calculations. Citation Format: Remco Bastiaannet, Ioanna Liatsou, Robert Hobbs, George Sgouros. Dynamic cell-level modeling of antibody binding and internalization for radiosensitivity assessements in alpha-emitter radiopharmaceutical therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P169.

An International Study of Factors Affecting Variability of Dosimetry Calculations, Part 1: Design and Early Results of the SNMMI Dosimetry Challenge.

In this work, we present details and initial results from a 177Lu dosimetry challenge that has been designed to collect data from the global nuclear medicine community aiming at identifying, understanding, and quantitatively characterizing the consequences of the various sources of variability in dosimetry. Methods: The challenge covers different approaches to performing dosimetry: planar, hybrid, and pure SPECT. It consists of 5 different and independent tasks to measure the variability of each step in the dosimetry workflow. Each task involves the calculation of absorbed doses to organs and tumors and was meant to be performed in sequential order. The order of the tasks is such that results from a previous one would not affect subsequent ones. Different sources of variability are removed as the participants advance through the challenge by giving them the data required to begin the calculations at different steps of the dosimetry workflow. Data from 2 patients after a therapeutic administration of 177Lu-DOTATATE were used for this study. The data are hosted in Deep Blue Data, a data repository service run by the University of Michigan. Participants submit results in standardized spreadsheets and with a short description summarizing their methods. Results: In total, 178 participants have signed up for the challenge, and 119 submissions have been received. Sixty percent of submissions have used voxelized dose methods, with 47% of those using commercial software. In initial analysis, the volume of organs showed a variability of up to 49.8% whereas for lesions this was up to 176%. Variability in time-integrated activity was up to 192%. Mean absorbed doses varied up to 57.7%. Segmentation is the step that required the longest time to complete, with a median of 43 min. The median total time to perform the full calculation was 89 min. Conclusion: To advance dosimetry and encourage its routine use in radiopharmaceutical therapy applications, it is critical that dosimetry results be reproducible across centers. Our initial results provide insights into the variability associated with performing dose calculations. It is expected that this dataset, including results from future stages, will result in efforts to standardize and harmonize methods and procedures.

Technical note: A wearable radiation measurement system for collection of patient-specific time-activity data in radiopharmaceutical therapy: system design and Monte Carlo simulation results.

Purpose: A high level of personalization in Molecular Radiotherapy (MRT) could bring advantages in terms of treatment effectiveness and toxicity reduction. Individual organ‐level dosimetry is crucial to describe the radiopharmaceutical biodistribution expressed by the patient, to estimate absorbed doses to normal organs and target tissue(s). This paper presents a proof‐of‐concept Monte Carlo simulation study of “WIDMApp” (Wearable Individual Dose Monitoring Apparatus), a multi‐channel radiation detector and data processing system for in vivo patient measurement and collection of radiopharmaceutical biokinetic data (i.e., time‐activity data). Potentially, such a system can increase the amount of such data that can be collected while reducing the need to derive it via nuclear medicine imaging. Methods: a male anthropomorphic MIRD phantom was used to simulate photons (i.e., gamma‐rays) propagation in a patient undergoing a 131I thyroid treatment. The administered activity was set to the amount usually administered for the treatment of differentiated carcinoma while its initial distribution in different organs was assigned following the ICRP indications for the 131I biokinetics. Using this information, the simulation computes the Time‐dependent Counts Curves (TCCs) that would have been measured by seven WIDMApp‐like sensors placed and oriented to face each one of five emitting organs plus two thyroid lobes. A deconvolution algorithm was then applied on this simulated data set to reconstruct the Time‐Activity Curve (TAC) of each organ. Deviations of the reconstructed TACs parameters from values used to generate them were studied as a function of the deconvolution algorithm initialization parameters and assuming non‐Poisson fluctuation of the TCCs data points. Results: This study demonstrates that it is possible, at least in the simple simulated scenario, to reconstruct the organ cumulated activity by measuring the time dependence of counts recorded by several detectors placed at selected positions on the patient's body. The ability to perform in vivo sampling more frequently than conventional biokinetic studies increases the number of time points and therefore the accuracy in TAC estimates. In this study, an accuracy on cumulated activity of 5% is obtained even with a 20% error on the TCC data points and a 50% error on the initial guess on the parameters of the deconvolution algorithm. Conclusions: the WIDMApp approach could provide an effective tool to characterize more accurately the radiopharmaceutical biokinetics in MRT patients, reducing the need of resources of nuclear medicine departments, such as technologist and scanner time, to perform individualized biokinetics studies. The relatively simple hardware for the approach proposed would allow its application to large numbers of patients. The results obtained justify development of an actual prototype system to characterize this technique under realistic conditions.

Radioembolization Dosimetry with Total-Body 90Y PET.

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive 90Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. 90Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging 90Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE 90Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose-volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body 90Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

Imaging and dosimetry for alpha-particle emitter radiopharmaceutical therapy: improving radiopharmaceutical therapy by looking into the black box.

Radiopharmaceutical therapy using α-particle emitting radionuclides (αRPT) is a novel treatment modality that delivers highly potent alpha-particles to cancer cells or their environment. We review the advantages and challenges of imaging and dosimetry in implementing αRPT for cancer patients.

A 3-dimensional stationary cascade gamma-ray coincidence imager

Objective. For certain radionuclides that decay through emitting two or more gamma photons consecutively within a short time interval—called cascade gamma-rays, the location where a radiopharmaceutical molecule emits cascade gamma-rays can be identified through coincidence detection of the photons. If each cascade photon is detected through a collimation mechanism, the location of the molecule can be inferred from the intersection of the back-projections of the two photons. Approach. In this work, we report the design and evaluation of a three-dimensional stationary imager based on this concept for imaging distributions of cascade-emitting radionuclides in radiopharmaceutical therapy. The imager was composed of two gamma-ray cameras assembled in an L-shape. Both cameras were NaI(Tl) scintillator based, one with a multi-slit collimator, the other with a multi-pinhole collimator. The field of view (FOV) was 100 mm (∅) × 100 mm (L). Based on the unique characteristics of the cascade coincidence events, we used a direct back-projection algorithm to reconstruct point source images for assessing the imager’s intrinsic spatial resolution and the standard maximum likelihood expectation maximization algorithm for reconstructing phantom images. Main results. We evaluated the performance of the imager in both simulated and prototype form with radionuclide 177Lu (cascade photon emitter). On the simulated imager, the coincidence detection efficiency at the center of FOV was 3.85 × 10−6, the spatial resolution was 7.0 mm. On the prototype imager, the corresponding values were 3.20 × 10−6 and 6.7 mm, respectively. Simulated hot-rod and experimental cardiac phantom studies demonstrate the first three-dimensional cascade gamma coincidence imager is fully functional.

Unsealed Source: Scope of Practice for Radiopharmaceuticals Among United States Radiation Oncologists

PurposeOur purpose was to determine the utilization of and barriers to implementation of radiopharmaceutical therapy (RPT) among U.S. radiation oncologists. Methods and MaterialsAn anonymous, voluntary 21-item survey directed toward attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, Facebook, Student Doctor Network). Questions assessed practice characteristics, specific RPT prescribing patterns, RPT prescribing interest, and perceived barriers to RPT implementation. Nonparametric χ2 test was used for correlation statistics. ResultsOf the 142 respondents, 131 (92.3%) practiced in the United States and were included for this analysis. Respondents were well balanced in terms of practicing region, population size served, practice setting, and years in practice. Forty-eight percent (n = 63) reported prescribing at least 1 RPT. An additional 7% (n = 8) participate in RPT administration without billing themselves. Among those that actively prescribed RPT, the mean cumulative cases per month was 4.2 (range, 1-5). The most commonly prescribed radionuclides were radium-223 (40%; mean 2.8 cases/mo), iodine-131 (18%; mean 2.3 cases/mo), yttrium-90 (13%; mean 3.4 cases/mo), “other” (8%), samarium-153 (6%; mean 1.0 cases/mo), and strontrium-89 and phosphorous-32 (2% each; mean 1.8 and 0.4 cases/mo, respectively). Of those who answered “other,” lutetium-177 dotatate was most commonly prescribed (8%). No significant (P < .05) association was noted between practice type, practice location, years of practice, or practice volume with utilization of any RPTs. Most radiation oncologists (56%, n = 74) responded they would like to actively prescribe more RPT, although 27% (n = 35) were indifferent, and 17% (n = 22) said they would not like to prescribe more RPT. Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (44%, n = 57), interspecialty relations (41%, n = 53), lack of training (23%, n = 30), and financial considerations (16%, n = 21). ConclusionsAmong surveyed U.S. radiation oncologists, a significant number reported prescribing at least 1 RPT. The majority expressed interest in prescribing additional RPT. Wide-ranging barriers to implementation exist, most commonly interspecialty relations, treatment infrastructure, lack of training, and financial considerations.

Embracing Inpatient Radiopharmaceutical Therapies in Radiation Oncology: An Example With Commissioning Pediatric I-131 MIBG Therapy

<h3>Purpose/Objective(s)</h3> Radiopharmaceutical therapy is rapidly expanding in radiation oncology and nuclear medicine. Iodine-131 metaiodobenzylguanidine (I-131 MIBG) is an inpatient therapy involving long infusion times and special consideration for radiation exposure and contamination control. In this study, we outline our process for commissioning pediatric I-131 MIBG therapy with a multidisciplinary team and perform a failure modes and effects analysis to assess the robustness of our procedures. <h3>Materials/Methods</h3> To commission pediatric I-131 MIBG therapy, we (1) created a multidisciplinary team with the appropriate skills, (2) located a space that met the needs of this intensive inpatient therapy, and (3) developed procedures that maximized safety. We identified failure modes (FM) from room design to patient/room release and scored them (1-10) according to their risk for occurrence (O), severity (S), and lack of detectability (D), per AAPM Task Group 100. The risk-priority number (RPN) is the product of these scores and identifies the FMs with the greatest risk. <h3>Results</h3> Our multidisciplinary team includes an authorized user (radiation oncologist/nuclear medicine physician), pediatric oncologists, radiation therapists, nurses, therapy medical physicists, and radiation safety staff. The space has a dedicated restroom and shower with appropriate plumbing, shielding built into the patient room/restroom construction, appropriate ventilation/filtration, and enough space for the patient, the infusion team (3-5), equipment, and mobile shields. The procedures meet regulatory and institutional safety standards and allow for appropriate radiation exposure and contamination control. 149 FMs were identified. The FMs with the greatest RPN were related to training deficiencies: (1) training of staff was inadequate (O = 5, S = 8, D = 4, RPN = 160), (2) caregivers did not understand radiation safety training (O = 5, S = 7, D = 4, RPN = 140), and (3) saline bag line and other dose lines (if multiple vials) were not clamped properly during dose infusion (O = 4, S = 8, D = 4, RPN = 128). 36/149 (24%) FMs had a high severity (S≥7). Of those, 11 (7% of all FMs) had a moderate risk of occurrence or going undetected (O or D > 3 but < 7) and none had a high risk of occurrence or going undetected (O or D ≥7). The remaining 25 high severity FMs were associated with commissioning, training, and room design/construction (14/25); drug ordering and patient preparation (7/25); and dose infusion (4/25). We attribute these FMs' relatively low risk of occurrence or going undetected to extensive checklists and redundant procedures. <h3>Conclusion</h3> Pediatric I-131 MIBG therapy is a complex treatment that requires careful consideration during commissioning. With a properly trained multidisciplinary team, robust procedures and checklists, and appropriate resources, it can be implemented safely and effectively.

Bone Metastases: State of the Art in Minimally Invasive Interventional Oncology.

Bone is the third most common site involved by cancer metastases, and skeleton-related events such as intractable pain due to direct osseous tumor involvement, pathologic fracture, and neurologic deficits as a consequence of nerve or spinal cord compression often affect patients' functional independence and quality of life unfavorably. The annual medical-economic burden related to bone metastases is a substantial component of the total direct medical cost estimated by the National Institutes of Health. There have been substantial recent advances in percutaneous image-guided minimally invasive musculoskeletal oncologic interventions for the management of patients with osseous metastatic disease. These advances include thermal ablation, cementation with or without osseous reinforcement with implants, osteosynthesis, thermal and chemical neurolyses, and palliative injections, which are progressively incorporated into the management paradigm for such patients. These interventions are performed in conjunction with or are supplemented by adjuvant radiation therapy, systemic therapy, surgery, or analgesic agents to achieve durable pain palliation, local tumor control, or cure, and they provide a robust armamentarium for interventional radiologists to achieve safe and effective treatment in a multidisciplinary setting. In addition, these procedures are shifting the patient management paradigm in modern-era practice. The authors detail the state of the art in minimally invasive percutaneous image-guided musculoskeletal oncologic interventions and the role of radiologists in managing patients with skeletal metastases. ©RSNA, 2021.

Novel theranostic agent for PET imaging and targeted radiopharmaceutical therapy of tumour-infiltrating immune cells in glioma.

BackgroundMalignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment.MethodsUtilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT.Findings89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy.Interpretation89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Dosimetric impact of Ac-227 in accelerator-produced Ac-225 for alpha-emitter radiopharmaceutical therapy of patients with hematological malignancies: a pharmacokinetic modeling analysis

BackgroundActinium-225 is an alpha-particle emitter under investigation for use in radiopharmaceutical therapy. To address limited supply, accelerator-produced 225Ac has been recently made available. Accelerator-produced 225Ac via 232Th irradiation (denoted 225/7Ac) contains a low percentage (0.1–0.3%) of 227Ac (21.77-year half-life) activity at end of bombardment. Using pharmacokinetic modeling, we have examined the dosimetric impact of 227Ac on the use of accelerator-produced 225Ac for radiopharmaceutical therapy. We examine the contribution of 227Ac and its daughters to tissue absorbed doses. The dosimetric analysis was performed for antibody-conjugated 225/7Ac administered intravenously to treat patients with hematological cancers. Published pharmacokinetic models are used to obtain the distribution of 225/7Ac-labeled antibody and also the distribution of either free or antibody-conjugated 227Th.ResultsBased on our modeling, the tissue specific absorbed dose from 227Ac would be negligible in the context of therapy, less than 0.02 mGy/MBq for the top 6 highest absorbed tissues and less than 0.007 mGy/MBq for all other tissues. Compared to that from 225Ac, the absorbed dose from 227Ac makes up a very small component (less than 0.04%) of the total absorbed dose delivered to the 6 highest dose tissues: red marrow, spleen, endosteal cells, liver, lungs and kidneys when accelerator produced 225/7Ac-conjugated anti-CD33 antibody is used to treat leukemia patients. For all tissues, the dominant contributor to the absorbed dose arising from the 227Ac is 227Th, the first daughter of 227Ac which has the potential to deliver absorbed dose both while it is antibody-bound and while it is free. CONCLUSIONS: These results suggest that the absorbed dose arising from 227Ac to normal organs would be negligible for an 225/7Ac-labeled antibody that targets hematological cancer.

Abstract 1395: Humanized GD2 antibody for targeted radiopharmaceutical therapy of human and canine osteosarcoma

Abstract Osteosarcoma (OS) is the most frequently diagnosed bone tumor in children in the United States. The prognosis for metastatic or recurrent OS has remained poor (5-year survival&amp;lt;30%) with no new effective therapies developed during the past 30 years. The high expression of tumor antigen, ganglioside GD2, on a variety of tumors, including OS, with its restricted expression on normal tissue makes GD2 an ideal target for anti-OS radiopharmaceutical therapy. Since human and canine OS shares many biological and molecular features and the prevalence of OS in dogs is 27 times higher than that in humans, spontaneously occurring OS in dogs has been shown to be an ideal model for testing new treatments for human translation. In this study, we evaluated a humanized GD2 antibody, hu3F8, that was developed for neuroblastoma therapy, as a potential delivery vector for targeted radiopharmaceutical therapy of human and canine OS.The cross immunoreactivity of hu3F8 with canine OS cells (OSCA78) and tissue, and human OS cells was confirmed by immunohistochemistry staining and flow cytometry. The binding affinity of hu3F8 to GD2 was assessed in vitro in OSCA78 and IMR32 (a human neuroblastoma cell line known expressing GD2) cell lines using 111In-DTPA-hu3F8. The dissociation constant Kd was 7.4 ± 1.0 nM for OSCA78, and 6.2 ± 1.9 nM for IMR32. Biodistribution study was performed in Nu/Nu mice bearing either OSCA78 tumor or IMR32 tumor. At 24 h after 111In-DTPA-hu3F8 injection, the highest uptake was observed in the tumor, followed by the blood, spleen, lung, and kidneys. The mean tumor uptake was 12.0% ID/g for OSCA78 tumors and 15.0% ID/g for IMR32 tumors, with a tumor-to-muscle ratio of 10.6 and 21.1, and a tumor-to-blood ratio of 1.1 and 2.4, for OSCA78 and IMR32 tumors, respectively. The 72 h biodistribution study revealed the highest uptake of 111In-DTPA-hu3F8 in both OSCA78 (28.0% ID/g) and IMR32 (51.6% ID/g ) tumors, with a tumor-to-muscle ratio of 93.3 and 206.6, and a tumor-to-blood ratio of 6.7 and 8.4, for OSCA78 tumors and IMR32 tumors, respectively. The improved uptake of 111In-DTPA-hu3F8 in tumors at 72 h was indicative of selective binding of 111In-DTPA-hu3F8 to GD2 expressing tumors. SPECT imaging showed that both OSCA78 and IMR32 tumors with 111In-DTPA-hu3F8 had superior contrast to the background, while 111In-DTPA-Rituximab (an irrelevant antibody) injected OSCA78-bearing mouse only showed moderate contrast to the background in the kidney.The cross immunoreactivity and high binding affinity of hu3F8 to canine OS cells/tissue and its ability to deliver an imaging payload (111In) suggest that conjugating hu3F8 with a radionuclide, such as alpha-emitter, 225Ac, may provide a potent radiopharmaceutical therapy for human and canine OS. Citation Format: Yingli Fu, Jing Yu, Ioanna Liatsou, Anders Josefsson, Yong Du, Jeffrey Bryan, Dara L. Kraitchman, George Sgouros. Humanized GD2 antibody for targeted radiopharmaceutical therapy of human and canine osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1395.