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Development of Targeted Alpha Particle Therapy for Solid Tumors.

Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prosta

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… Introduction Over the past two decades, radioimmunotherapy (RIT) has proven to be an effective treatment for non-solid tumors (reviewed in [ 1 , 2 ]); e.g., radiolabeled anti-CD20 monoclonal antibodies for the treatment of lymphoma. … This approach to specifically deliver ionizing radiation payloads is termed radioimmunotherapy (RIT). …

Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications.

This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At, and 149Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinica

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… Pretargeting also shows potential for both PET imaging and for reducing nonspecific toxicity and hematotoxicity in radioimmunotherapy. … An alpha-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer Cancer Res. 2000 60 6095 6100 11085533 98. Winter B.M. Von Rundstedt F.-C. Grimm M.-O. …

Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity.

The tumor-associated glycoprotein 72 (TAG-72) antigen is present on a high percentage of tumor types including ovarian carcinomas. Antibody B72.3 is a murine monoclonal recognizing the surface domain of the TAG-72 antigen and has been widely used in human clinical trials. After our initial encouraging studies (M. G. Rosenblum et al., J. Natl. Cancer Inst., 83: 1629-1636, 1991) of tissue disposition, metabolism, and pharmacokinetics in 9 patients with ovarian cancer, we designed an escalating dose, multi-arm Phase I study of 90Y-labeled B72.3 i.p. administration. In the first arm of the study,

ImmunoPET in Multiple Myeloma-What? So What? Now What?

Despite constant progress over the past three decades, multiple myeloma (MM) is still an incurable disease, and the identification of new biomarkers to better select patients and adapt therapy is more relevant than ever. Recently, the introduction of therapeutic monoclonal antibodies (mAbs) (including direct-targeting mAbs and immune checkpoint inhibitors) appears to have changed the paradigm of MM management, emphasizing the opportunity to cure MM patients through an immunotherapeutic approach. In this context, immuno-positron emission tomography (immunoPET), combining the high sensitivity an

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… ImmunoPET also opens the door to radioimmunotherapy (RIT). Indeed, it provides a useful theranostic companion for targeting assessment and for dosimetric purposes before the administration of therapeutic radioimmunoconjugates [ 7 , 79 , 82 ]. … Radioimmunotherapy of lymphoma: An underestimated therapy option Lancet Haematol. 2017 4 e6 e7 10.1016/S2352-3026(16)30188-0 27964866 107. Illidge T. Radioimmunotherapy of Lymphoma: A Treatment Approach Ahead of Its Time or Past Its Sell-By Date? J. Clin. …

Actinium-225 targeted alpha particle therapy for prostate cancer.

Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (225Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with 225Ac in PCa are PSMA-targeted TAT agents, notably [225Ac]Ac-PSMA-617, [225Ac]Ac-PSMA-I&T and [225Ac]Ac-J591. Ongoing inve

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… Antibody-based Radioimmunotherapy agents for Preclinical Tumors of PCa Radioimmunotherapy (RIT) combines the precision of monoclonal antibodies with the robust cell-destructive potential of radiation therapy. … In contrast to 223 Ra, the precursor radionuclide 227 Th demonstrates the ability to form stable chelator complexes, making it well-suited for targeted radioimmunotherapy. …

Targeted Radionuclide Therapy: Practical Applications and Future Prospects.

In recent years, there has been a proliferation in the development of targeted radionuclide cancer therapy. It is now possible to use baseline clinical and imaging assessments to determine the most effective therapy and to tailor this therapy during the course of treatment based on radiation dosimetry and tumor response. Although this personalized approach to medicine has the advantage of maximizing therapeutic effect while limiting toxicity, it can be challenging to implement and expensive. Further, in order to use targeted radionuclide therapy effectively, there is a need for multidisciplina

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… The first application in oncology was in the 1940s when physicians began imaging and treating patients with thyroid disease using radioactive iodine. 1 Radioimmunotherapy (RIT), the use of a radiolabeled monoclonal antibody for targeted therapy, is more recent than TRT, although this is also more than … for the treatment of non-Hodgkin’s lymphoma Onco Targets Ther 2009 2 229 242 20616910 10.2147/ott.s4456 PMC2886324 8 Schaefer NG Ma J Huang P Buchanan J Wahl RL Radioimmunotherapy in non-Hodgkin lymphoma: opinions of U.S. medical oncologists and hematologists J Nucl Med 2010 51 987 994 20484425 10.2967 …

Immunotherapy Strategies Against Multiple Myeloma

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… Radioimmunotherapy (RIT) selectively delivers radiation to target cells at multiple disease sites and facilitates the escalation to radiation doses not achievable through external beam therapy. … Cancer Res . 2014 ; 74 ( 4 ): 1179 – 1189 . doi:10.1158/0008-5472.CAN-13-1589 . 24371230 10.1158/0008-5472.CAN-13-1589 PMC3970848 71 Larson SM Carrasquillo JA Cheung NK Press OW Radioimmunotherapy of human tumours . …

Current landscape and future directions of targeted-alpha-therapy for glioblastoma treatment.

Glioblastoma (GB) is the most aggressive malignancy of the central nervous system. Despite two decades of intensive research since the establishment of the standard of care, emerging strategies have yet to produce consistent satisfactory outcomes. Because of its specific localisation and intricate characteristics, GB is a uniquely regulated solid tumour with a strong resistance to therapy. Advances in targeted radionuclide therapy (TRT), particularly with the introduction of a-emitting radionuclides, have unveiled potential avenues for the management of GB. Recent preclinical and clinical stud

Radiometals in Imaging and Therapy: Highlighting Two Decades of Research.

The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for

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… avg = 278 keV) vs. 68 Ga (E β + avg = 829 keV) and the longer half-life (12.7 h) of 64 Cu allow its distribution and use as [ 64 Cu]Cu-PSMA-617 at various clinical PET centers with no sophisticated onsite radiotracer production facility [ 53 ]. 67 Cu is one of the most promising radionuclides for radioimmunotherapy … tumor Pb | = | Lead PCa | = | Prostate cancer PDL-1 | = | Programmed cell death ligand-1 PET | = | Positron emission tomography PRRT | = | Peptide receptor radionuclide therapy PSA | = | Prostate-specific antigen PSMA | = | Prostate-specific membrane antigen Ra | = | Radium Re | = | Rhenium RIT | = | Radioimmunotherapy …

Radiolabeled Peptides and Antibodies in Medicine.

Radiolabeled peptides are a relatively new, very specific radiotracer group, which is still expanding. This group is very diverse in terms of peptide size. It contains very small structures containing several amino acids and whole antibodies. Moreover, radiolabeled peptides are diverse in terms of the binding aim and therapeutic or diagnostic applications. The majority of this class of radiotracers is utilized in oncology, where the same structure can be used in therapy and diagnostic imaging by varying the radionuclide. In this study, we collected new reports of radiolabeled peptide applicati

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… For example, it may be applied for the selection of targeted therapies or to choose the appropriate dose of radioimmunotherapy. … C. ( 2004 ) Optimization of radioimmunotherapy of renal cell carcinoma: Labeling of monoclonal antibody cG250 with I-131, Y-90, Lu-177, or Re-186 . J. Nucl. …

Current and upcoming radionuclide therapies in the direction of precision oncology: A narrative review.

As new molecular tracers are identified to target specific receptors, tissue, and tumor types, opportunities arise for the development of both diagnostic tracers and their therapeutic counterparts, termed "theranostics." While diagnostic tracers utilize positron emitters or gamma-emitting radionuclides, their theranostic counterparts are typically bound to beta and alpha emitters, which can deliver specific and localized radiation to targets with minimal collateral damage to uninvolved surrounding structures. This is an exciting time in molecular imaging and therapy and a step towards personal

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… Despite the advantageous therapy profile of the two currently approved radioimmunotherapy drugs under the trade name Zevalin and Bexxar. These have been under-researched and underutilized. … Table 8 Anti CD20 radioimmunotherapies for lymphoma treatment. …

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas.

Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of "old" cytostatic

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… Radioimmunotherapy (RIT) Even though a plethora of theranostic pairs have been tested preclinically, the number of approved clinical applications remain limited. The concept of radioimmunotherapy (RIT) represents an example of a successful theranostics application in hematology. … Radioimmunotherapy in mantle cell lymphoma. Best Pract. Res. Clin. Haematol. 2012;25:201–210. doi: 10.1016/j.beha.2012.04.004. 109. …

Targeted Therapies for the Treatment of Pediatric Non-Hodgkin Lymphomas: Present and Future.

Pediatric Non-Hodgkin Lymphomas (NHL) are a diverse group of malignancies and as such treatment can vary based on the different biological characteristics of each malignancy. Significant advancements are being made in the treatment and outcomes of this group of malignancies. This is in large part due to novel targeted drug therapies that are being used in combination with traditional chemotherapy. Here, we discuss several new lines of therapy that are being developed or are in current use for pediatric patients with NHL.

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… Anti-CD20 Monoclonal Antibodies for Radioimmunotherapy: 90 Yttrium-Ibritumomab Tiuxetan 90 Yttrium-Ibrutumomab tiuxetan is a monoclonal antibody for radioimmunotherapy. … Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J. Clin. Oncol. 2002;20:3262–3269. doi: 10.1200/JCO.2002.11.017. 26. …

Tackling mantle cell lymphoma (MCL): Potential benefit of allogeneic stem cell transplantation.

Mantle cell lymphoma (MCL) is a type of non-Hodgkins lymphoma (NHL) associated with poor progression-free and overall survival. There is a high relapse rate with conventional cytotoxic chemotherapy. Intensive combination chemotherapy including rituximab, dose intense CHOP- (cyclophosphamide-doxorubicin-vincristine-prednisone) like regimens, high dose cytarabine, and/or consolidation with autologous stem cell transplant (autoSCT) have shown promise in significantly prolonging remissions. Data from phase II studies show that even in patients with chemotherapy refractory MCL, allogeneic stem cell

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… This is now complicated by the many new agents available for trial including bendamustine, bortezomib, lenalidomide, and radioimmunotherapy. The evolving approach is to have separate trials for older, more frail patients that incorporate novel agents. … High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood. 2002;99:3158–3162. doi: 10.1182/blood.v99.9.3158. 28. Geisler CH, Kolstad A, Laurell A, et al. …

Antibodies to watch in 2025.

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025. In pa

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… Overall, bispecific antibodies have the highest approval success rate, while radioimmunotherapy has the lowest (32% and 0%, respectively). … The Radioimmunotherapy group currently has the lowest rate (0%). …

Radionuclide-labelled nanoparticles for cancer combination therapy: a review.

Radionuclide therapy (RT) is widely used to advanced local cancers. However, its therapeutic efficacy is limited to the radiation resistance of cancer cells. Combination therapy aims to circumvent tumor resistance, and the combination of RT with photothermal therapy (PTT), photodynamic therapy (PDT), chemotherapy (CMT), and immunotherapy has shown promising treatment outcomes. Nanotechnology holds promise in advancing combination therapy by integrating multiple therapies on a nanostructure platform. This is due to the increased surface area, passive/active targeting capabilities, high payload

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… It could stimulate dendritic cell maturation and generate anti-tumor cytokines, strengthen the systemic immune memory effects induced by radioimmunotherapy and inhibit tumor invasion. … Alpha radionuclide-chelated radioimmunotherapy promoters enable local radiotherapy/chemodynamic therapy to discourage cancer progression. Biomater Res. 2022;26(1):44. …

Evolving role of biomaterials in diagnostic and therapeutic radiation oncology.

Radiation therapy to treat cancer has evolved significantly since the discovery of x-rays. Yet, radiation therapy still has room for improvement in reducing side effects and improving control of cancer. Safer and more effective delivery of radiation has led us to novel techniques and use of biomaterials. Biomaterials in combination with radiation and chemotherapy have started to appear in pre-clinical explorations and clinical applications, with many more on the horizon. Biomaterials have revolutionized the field of diagnostic imaging, and now are being cultivated into the field of theranostic

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… Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma J. Clin. Oncol. Off. J. Am. Soc. Clin. … Phase I/II 90 Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin’s lymphoma Eur. J. Nucl. Med. 27 2000 766 777 10952488 10.1007/s002590000276 37 Fang J. Nakamura H. Maeda H. …

Therapy of newly diagnosed follicular lymphoma.

Newly diagnosed follicular lymphoma is relatively common and can be effectively treated with several differing approaches. Although the disease is often considered incurable, it is highly responsive to therapy when indicated. This review discusses the indications for treatment, risk stratification systems, treatment options with supporting clinical trial data, and expected therapeutic outcomes in newly diagnosed follicular lymphoma.

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… ORR, overall response rate; CR, complete response; PFS, progression free survival; RIT, radioimmunotherapy. … An ongoing trial of R-CHOP followed by radioimmunotherapy consolidation and MR aims to determine if efficacy can be further improved by combining multiple anti-CD20 therapeutic modalities. …

Recent Innovations and Nano-Delivery of Actinium-225: A Narrative Review.

The actinium-225 (225Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities

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… Borchardt et al. (2003) investigated intraperitoneal radioimmunotherapy in a mouse model of human ovarian cancer using a targeted 225 Ac in vivo particle generator with robust selective cytotoxicity while providing a feasible half-life for tumour delivery [ 36 ]. … Randomized Controlled Trial of Yttrium-90–Labeled Ibritumomab Tiuxetan Radioimmunotherapy Versus Rituximab Immunotherapy for Patients with Relapsed or Refractory Low-Grade, Follicular, or Transformed B-Cell Non-Hodgkin’s Lymphoma J. Clin. …

CD70-targeted platform for diagnosing and treating multiple myeloma.

BackgroundCD70, overexpressed in multiple myeloma (MM), is a promising target for theranostics. This study developed a CD70-targeted theranostic pair: the immuno-positron emission tomography tracer [89Zr]Zr-DFO-ABDB6 and the therapeutic agent [177Lu]Lu-DOTA-ABDB6, aiming to combine imaging and radiotherapy for MM.MethodsCD70 expression was confirmed in patients with MM samples (positivity rate, 66.7%) and RPMI-8226 xenografts. The nanobody derivative ABDB6 was conjugated to DFO or DOTA and radiolabeled with 89Zr or 177Lu. Pharmacokinetics, biodistribution, and toxicity were evaluated in NCG an

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… Positron emission tomography (PET)-CT effectively evaluates the distribution and metabolic activity of lesions in both intraosseous and extraosseous manifestations of multiple myeloma. 10 11 Concurrently, targeted radioimmunotherapy (RIT) demonstrates promising potential in the treatment of myeloma … Alpha radionuclide-labeled radioimmunotherapy agents could have unique value for treating minimal residual disease. 38 Despite the relatively complex procedures of pretargeted radioimmunotherapy, 38 39 it remains a promising platform for enhancing the therapeutic index and minimizing adverse toxicities …