scholarly journals Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 268 ◽  
Author(s):  
Javian Malcolm ◽  
Nadia Falzone ◽  
Boon Lee ◽  
Katherine Vallis
Keyword(s):  
Radionuclide Therapy ◽  
Patient Management ◽  
Radiation Treatment ◽  
External Beam Radiotherapy ◽  
Patient Treatment ◽  
Special Focus ◽  
Targeted Radionuclide Therapy ◽  
Metastatic Lesions ◽  
Prostate Cancers ◽  
Improve Patient Management

Compared to external beam radiotherapy, targeted radionuclide therapy (TRT) allows for systemic radiation treatment of metastatic lesions. Published work on recent strategies to improve patient management and response to TRT through individualising patient treatment, modifying treatment pharmacokinetics and increasing anticancer potency are discussed in this review, with a special focus on the application of clinically evaluated radiolabelled ligands and peptides in the treatment of neuroendocrine and prostate cancers.

scholarly journals Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy

Theranostics ◽  
2021 ◽  
Vol 11 (13) ◽  
pp. 6120-6137
Author(s):  
Justin C. Jagodinsky ◽  
Won Jong Jin ◽  
Amber M. Bates ◽  
Reinier Hernandez ◽  
Joseph J. Grudzinski ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Radionuclide Therapy ◽  
External Beam Radiotherapy ◽  
Temporal Analysis ◽  
External Beam ◽  
Targeted Radionuclide Therapy ◽  
Type 1 Interferon

scholarly journals Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255798
Author(s):  
Kara Magee ◽  
Ian R. Marsh ◽  
Michelle M. Turek ◽  
Joseph Grudzinski ◽  
Eduardo Aluicio-Sarduy ◽  
...  
Keyword(s):  
Radionuclide Therapy ◽  
External Beam Radiotherapy ◽  
Low Grade ◽  
External Beam ◽  
Advanced Stage ◽  
Targeted Radionuclide Therapy ◽  
Safe Delivery ◽  
Companion Dogs ◽  
Subject Specific

Rationale Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced cancer. Methods The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed. Results The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT. Conclusions The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.

scholarly journals 594 Combination of antigen-specific vaccination and targeted radionuclide therapy improves anti-tumor efficacy in a murine prostate model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A624-A624
Author(s):  
Hemanth Potluri ◽  
Carolina Ferreira ◽  
Joseph Grudzinski ◽  
Christopher Massey ◽  
Reinier Hernandez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Median Survival ◽  
Radionuclide Therapy ◽  
Low Dose ◽  
External Beam Radiotherapy ◽  
Effector Memory ◽  
High Dose ◽  
Targeted Radionuclide Therapy

BackgroundWhile checkpoint blockade has been unsuccessful in prostate cancer trials, the approval of Sipuleucel-T demonstrates the value of antigen-specific vaccination approaches for this disease. We have studied a DNA vaccine specific for the ligand-binding domain of the androgen receptor (pTVG-AR) as a more scalable vaccination approach, though its efficacy is likely limited by the immunosuppressive prostate microenvironment. External beam radiotherapy has been shown to sensitize poorly responsive tumors to immunotherapy, but is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can deliver radiation to all cancer sites simultaneously, similar to other targeted radionuclide therapy (TRT) approaches. In this study, we used TRT in combination with pTVG-AR to improve anti-tumor efficacy in a murine prostate cancer model.Methods6-week old male C57BL/6 mice were implanted subcutaneously with TRAMP-C1 cells. pTVG-AR or the empty vector were administered weekly from the day after tumor implantation. An intravenous injection was administered of 50 (”low-dose”) or 250 μCi (”high dose”) of 90Y-NM600, estimated to deliver a dose of 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. In one study, this TRT treatment was repeated once after three weeks. Groups of mice (n=5) were euthanized at several time points for flow cytometry analysis of the tumors. Separate cohorts (n=7) were followed for survival.ResultsLow-dose TRT administered once in combination with pTVG-AR (median survival 91 days) significantly improved survival more than low-dose TRT alone (median survival 59 days; p=.049) or pTVG-AR alone (median survival 59 days; p=0.01). Low-dose TRT plus pTVG-AR was also superior to high-dose TRT plus pTVG-AR (median survival 67 days; p=0.05). We next examined the effect of giving high-dose TRT twice in combination pTVG-AR. We found that the combination of fractionated TRT and pTVG-AR greatly slowed tumor growth unlike fractionated TRT alone (p=0.03). High-dose TRT + pTVG-AR caused a two-fold increase in CD86 expression on dendritic cells (p=0.0009) on Day 3 and a 10% increase in effector memory CD8+ T cells (p=0.002) on Day 1 compared to TRT alone. This combination also resulted in T cells with 3-fold lower PD-1 expression (p=4e-7) and 2-fold lower TIGIT expression (p=0.01).ConclusionsThese data suggest that the combination of antigen-specific vaccination and TRT can be an effective treatment for cancers that are refractory to immunotherapy. This combination may act through increasing co-stimulation by dendritic cells, leading to a more active cytolytic CD8+ T cell population.

scholarly journals Targeting Radiotherapy to Cancer by Gene Transfer

2003 ◽  
Vol 2003 (2) ◽  
pp. 102-109 ◽  
Author(s):  
R. J. Mairs ◽  
M. Boyd
Keyword(s):  
Experimental Data ◽  
Gene Transfer ◽  
Radionuclide Therapy ◽  
Radiation Treatment ◽  
The Body ◽  
Recent Experimental Data ◽  
Low Molecular Weight ◽  
Targeted Radionuclide Therapy ◽  
Targeted Radiotherapy ◽  
Radioactive Atom

Targeted radionuclide therapy is an alternative method of radiation treatment which uses a tumor-seeking agent carrying a radioactive atom to deposits of tumor, wherever in the body they may be located. Recent experimental data signifies promise for the amalgamation of gene transfer with radionuclide targeting. This review encompasses aspects of the integration of gene manipulation and targeted radiotherapy, highlighting the possibilities of gene transfer to assist the targeting of cancer with low molecular weight radiopharmaceuticals.

scholarly journals Targeted Radionuclide Therapy: Practical Applications and Future Prospects

2016 ◽  
Vol 8s2 ◽  
pp. BIC.S31804 ◽  
Author(s):  
Katherine Zukotynski ◽  
Hossein Jadvar ◽  
Jacek Capala ◽  
Frederic Fahey
Keyword(s):  
Radionuclide Therapy ◽  
Therapeutic Response ◽  
Tumor Response ◽  
External Beam Radiotherapy ◽  
Targeted Radionuclide Therapy ◽  
Practical Applications ◽  
Patient Morbidity ◽  
Personalized Approach ◽  
Post Therapy

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 multidisciplinary awareness, education, and collaboration across the scientific, industrial, and medical communities. Even more important, there is a growing understanding that combining radiopharmaceuticals with conventional treatment such as chemotherapy and external beam radiotherapy may limit patient morbidity while improving survival. Developments in radiopharmaceuticals as biomarkers capable of predicting therapeutic response and targeting disease are playing a central role in medical research. Adoption of a practical approach to manufacturing and delivering radiopharmaceuticals, assessing patient eligibility, optimizing post-therapy follow-up, and addressing reimbursement issues will be essential for their success.

scholarly journals Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade

2021 ◽  
Vol 13 (602) ◽  
pp. eabb3631
Author(s):  
Ravi B. Patel ◽  
Reinier Hernandez ◽  
Peter Carlson ◽  
Joseph Grudzinski ◽  
Amber M. Bates ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Radionuclide Therapy ◽  
Low Dose ◽  
Checkpoint Inhibitors ◽  
External Beam Radiotherapy ◽  
Combined Treatment ◽  
Optimal Dose ◽  
Immune Checkpoint Blockade ◽  
Targeted Radionuclide Therapy ◽  
Tumor Types

Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.

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