Targeted Alpha Therapy (TAT) Articles

Articles

  • From the Desk of the Editor

    Welcome to the Center of Excellence on Castration Resistant Prostate Cancer (CRPC) with Bone Metastases. I am Dr. Neal Shore, MD, FACS, CPI, Director of the Carolina Urologic Research Center (CURC), Atlantic Urology Clinics, Myrtle Beach, South Carolina. Founded in 1998, CURC is currently supported by 13 Urologists, 3 Radiation Oncologists, 1 Pathologist, 10 Advanced Practice Providers, and a team of 10 fulltime research and administrative CURC personnel.
    Published June 30, 2017
  • TAT-10: A comparative evaluation of Ac225 and Bi213 as therapeutic radioisotopes for targeted alpha therapy

    Kanazawa, Japan (UroToday.com) This is an editorial talk on the relative advantages of Ac225 and Bi213 for targeted alpha therapy. Some factors that seem like obvious advantages for one over the other might be ameliorated by various other effects. For example, the Ac225 decay chain releases four alpha particles whereas Bi213 has only one.
    Published June 21, 2017
  • TAT-10: A Novel Micro-Actinium225-Bismuth212 Biomedical Generator System

    Kanazawa, Japan (UroToday.com) A micro-fluidic “lab-on-a-chip” was described for the separation of Bi213. Miniturization has certain advantage such as efficient use of reagents and minimizing radioactivity exposure to workers even while producing enough Bi213 for individual patient injection or lab studies.
    Published June 21, 2017
  • TAT-10: Bi-213-anti-EGFR-Mab Therapy of Recurrent Bladder Cancer - A Pilot Study

    Kanazawa, Japan (UroToday.com) Patients with non-muscle invasive bladder cancer treated with surgical resection and chemotherapy with Bacillus Calmette-Guerin (BCG) experience up to 40% relapse and require bladder removal. Following successful treatment using Bi-213 labeled Epidermal Growth Factor Reduction (EFGR) Mab in mice, a pilot study was undertaken with 12 human patients (10 male, 2 female).
    Published June 21, 2017
  • TAT-10: Changes to Alkaline Phosphatase Dynamics and Overall Survival in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Radium-223 in an International Early Access Program

    Kanazawa, Japan (UroToday.com) Identifying a reliable marker that is highly correlated with improved overall survival and reduced adverse events for Ra223 treatment would greatly aid the clinical management of metastatic castration-resistant prostate cancer (mCRPC) patients. Bone alkaline phosphate (ALP) is a marker for osteoblasts in bone tissue.
    Published June 21, 2017
  • TAT-10: Correspondence between alpha-particle emitter dosimetry and normal organ toxicity

    Kanazawa, Japan (UroToday.com) Alpha particle doses are often very non-uniform within an organ so micro-dosimetry  with good resolution is necessary. This is not possible with human subjects so this study uses mice.
    Published June 21, 2017
  • TAT-10: Development of Alpha-emitting At111-meta-astotbenzylguanidine (At211-MABG) as a Novel Therapeutic Agent for Malignant Pheochromocytoma

    Kanazawa, Japan (UroToday.com) Malignant pheochromocytoma (PCC) has previously been treated with the beta-emitter I131 conjugated to meta-iodobenzylguanidine with only limited success since complete remission was quite low. This motivates the present study with alpha-emitting At211-MABG.
    Published June 21, 2017
  • TAT-10: Development of Effective Chelators for Th227 to be Used in Targeted Thorium Conjugates

    Kanazawa, Japan (UroToday.com) Ra223 represents a breakthrough in alpha therapy after FDA approval in May 2013 of Ra223 – dichloride (XOFIGO) for the treatment of metastatic castration-resistant prostate cancer. As a calcium analog, Ra223 is well-suited for treatment of bone metastases but the absence of efficient chelators limit its use in other types of radiotherapy. The same generators used for Ra223 production can be also be used for highly purified Th-227. This study aims to produce efficient chelators for Th227.
    Published June 21, 2017
  • TAT-10: Directing Alpha-emitting Conjugates to Cancer Chromatin via PARP-1

    Kanazawa, Japan (UroToday.com) Poly (ADP-ribose) Polymerase (PARP-1) is a very abundant nuclear protein. High risk neuroblastoma over-expresses PARP-1 and we plan to use this feature to selectively target the neuroblastoma in treating the cancer chromatin. At211-MM4 was evaluated in vitro for the pharmacology and cytotoxicity in a panel of neuroblastoma cell lines.
    Published June 21, 2017
  • TAT-10: Dosimetry and Biodistribution of Pb203-AR-RMX in Patients with Somatostatin Expressing Neuroendocrine Tumors: A Clinical Exploratory Study

    Kanazawa, Japan (UroToday.com) This is an exploratory study in patients who had received targeted beta therapy to determine the dosimetry and biodistribution using imaging agents Pb203 and Ga68 in preparation for eventual targeted alpha therapy using Pb212. Six patients with confirmed somatostatin-expressing neuroendocrine tumors were recruited.
    Published June 21, 2017
  • TAT-10: Efficacy of Actinium-225-labeled Anti-CD33 Antibody in Acute Myeloid Leukemia Correlates with Peripheral Blast Count

    Kanazawa, Japan (UroToday.com) This study was conducted in two phases. Phase one had 18 relapsed and refractory acute myeloid leukemia (AML) patients. Patients were treated with a single infusion of Actimab-A, the company’s name for Ac-225 conjugated to the anti-CD33 monoclonal antibody lintuzumab. Doses ranged from 18.5 to 148 kBq/kg and post analysis determined a maximum dose of 111 kBq/kg. In the second trial (18 newly diagnosed patients), were treated with two equal doses at 14 days and 21 days. Total doses ranged from 37 to 148 kB/kq.
    Published June 21, 2017
  • TAT-10: Experimental Alpha Microdosimetry using Fluorescent Nuclear Track Detectors

    Kanazawa, Japan (UroToday.com) This study uses a crystalline Al2O3:C,Mg Fluorescent Nuclear Track detector to measure the microdosimetry of alpha radiation to tissue.
    Published June 21, 2017
  • TAT-10: Exploration of the Chemistry of Astatine; From Basic Research Towards Applied Questions

    Kanazawa, Japan (UroToday.com) Conventional As211 labeling protocols are based on astatine as an iodine analog. These are lacking since astatbenzoate-labeled compounds are unstable when metabolized, contrary to the iodine analog. We have developed a number of both calculational and experimental tools to understand the basic chemistry of astatine.
    Published June 21, 2017
  • TAT-10: High-resolution Alpha Camera imaging as a tool for developing Targeted Alpha Therapy

    Kanazawa, Japan (UroToday.com) Alpha particle dose can be highly non-uniform within an organ so microdosimetry with high resolution imaging is required for accurate dosimetry measure. An alpha camera is described to accomplish this.
    Published June 21, 2017
  • TAT-10: Locoregional alpha-radioimmunotherapy against peritoneal metastasis of gastric cancer

    Kanazawa, Japan (UroToday.com) Patients with peritoneal metastasis of gastric cancer (PMGC) have an extremely poor prognosis as no effective therapeutics have been established. Gastric cancer overexpresses HER2 about 20% of the time. Trastuzumab is a humanized anti-HER2 monoclonal antibody so we investigate At211-trastuzumab in mice models using N87 xenografts for treatment of PMGC.
    Published June 21, 2017
  • TAT-10: Novel IgG t Melanin Show Promise for Radioimmunotherapy of Metastatic Melanoma

    Kanazawa, Japan (UroToday.com) Previous studies of treating metastatic melanoma using a murine antibody to melanin labeled with the beta-emitting isotope Re188  established safety and efficacy. However, that antibody (genotype IgM) presented obstacles to humanization. We recently identified an 8C3 murine antibody (genotype IgG) that is amenable to humanization. The purpose of the present study is evaluate 8C3 radio-labeled with Re188 and also the alpha-emitting isotope Bi213.
    Published June 21, 2017
  • TAT-10: Optimization of the patient dosimetry in alphatherapy

    Kanazawa, Japan (UroToday.com) Accurate dosimetry is essential in order to deliver maximum dosage to the tumor site while minimizing the dose to other organs at risk. This study develops tools for measuring the dose from Ra223. The range of alphas is to too short to image directly in humans but the decay of Ra223 also emits gamma rays as the daughter nuclei de-excite to their ground state. These gammas can be detected. SPECT imaging of the gammas was investigated for the first time.
    Published June 21, 2017
  • TAT-10: Pharmacokinetic Profiling and Therapeutic Efficacy of Alpha-emitter Labeled Ant-PD1.1 Antibodies in an Immune Competent Transgenic Breast Cancer Model

    Kanazawa, Japan (UroToday.com) Normally tumors are vulnerable from T cells in the body’s  immune system. Some tumors have the ability to express Programed cell Death Ligand 1 (PD-L1) which inactivates the T cells allowing the tumor to survive. Previous studies have shown that treatment with anti-PD-1 antibodies have been effective in reducing many cancers including breast cancer. The aim of this study is to investigate if the anti-PD-1 immunotherapy can be enhanced when combined Ac225 targeted alpha therapy.
    Published June 21, 2017
  • TAT-10: Preclinical Evaluation of Anti-HER2 2Rs15d Nanobody Labeled with Ac225

    Kanazawa, Japan (UroToday.com) Human Epidermal Growth Factor Receptor type 2 (HER2) is over expressed in many types of human cancer such as breast, ovarian, and colorectal cancers. Whole monoclonal antibodies targeted to HER2 might seem like powerful vectors for radioimmunotherapy but their slow pharmacokinetics and normal tissue clearance are significant disadvantages.
    Published June 21, 2017
  • TAT-10: Preclinical Evaluation of Astatinated Nanobodies for Targeted Alpha Therapy

    Kanazawa, Japan (UroToday.com) This study has some similarities to the previous paper in that the nanobody (Nb) 2Rs15d-Nb is employed to target HER2+ SKOV-3 cells. The radioisotope is different with present study using the alpha-emitter At211 instead of Ac225.
    Published June 21, 2017
  • TAT-10: Production of a Thorium/Actinium Generator at the Canadian Nuclear Laboratories

    Kanazawa, Japan (UroToday.com) The Canadian Nuclear Laboratory (CNL) at Chalk River, Ontario has a stockpile of U233 which is used to construct a Thorium/Actinium generator for the production of Ac225. A Thorium fraction containing most the desired isotope Th229 has been isolated with anion exchange and chromatographic techniques.
    Published June 21, 2017
  • TAT-10: Progress in the [At211]-Astatination of Antibodies by Nuclephilic Approaches Using Aryliodonium Salts Precursors

    Kanazawa, Japan (UroToday.com) In this study, we develop a method for At211 radio-labeling based on aryliodonium salts and compare with the more conventional approach using arylstannane chemistry. We find improved yields of 43 +/- 2 % for aryliodonium compared with 20 +/- 5% for arylstannane.
    Published June 21, 2017
  • TAT-10: Progress Toward an Alternate Method for Production of Ac-225

    Kanazawa, Japan (Urotoday.com) Northstar Medical Radioisotopes, LLC is a commercial supplier of  Mo99/Tc99m and is looking at potential procedures for large-scale production of Ac225. After examining several possible production paths, high-energy proton spallation was chosen for Th229 production. A  proof-of-concept experiment was carried out using spare protons from Fermilab’s 8 GeV Booster accelerator. The company envisions banks of redundant Thorium/Actinium generators to reach commercial scale supplies of Ac225.
    Published June 21, 2017
  • TAT-10: Quality Assurance and Labeling Chemistry Qualification for cGMP Production of Astatine-211-labeled anti-CD45 Antibodies

    Kanazawa, Japan (UroToday.com) For a drug to be used on humans the US Food and Drug Administration requires current Good Manufacturing Practice (cGMP), a set of regulations that assure proper design, monitoring,  and control of manufacturing, process, and facilities. The objective of research reported here is to set up procedures to translate the production of At211-labeled anti-CD45 antibodies from benchtop to cGMP-compliant results. This requires demonstration of purity, safety, and sterility of compound produced under cGMP conditions.
    Published June 21, 2017
  • TAT-10: Radium 223 from Bench to Bedside, and Future Directions for Targeted Alpha Therapy

    Kanazawa, Japan (UroToday.com) Dr. Joe O’Sullivan, a Professor of Radiation Oncology at Queen’s College, briefly reviewed the history of radiation treatment of cancer (and prostate cancer in particular) beginning with Radium treatment only eight years after its discovery by the Curies. A landmark paper on radioactive phosphorous treatment of bone-metastatic prostate cancer was published in the journal Lancet in 1964. More recent internal treatments have concentrated on calcium analogs that are directly absorbed in the bone tumor, starting with Sr98, a beta emitter. Single agent beta emitters showed some (~50 %) palliative response but no benefit for overall survival.
    Published June 21, 2017
  • TAT-10: Reduction of Radiation Exposure to the Large Intestine During Ra223 Alpha Therapy with Oral Administration of Barium Sulfate

    Kanazawa, Japan (UroToday.com) Ra223 alpha therapy has been shown to be effective in treating bone metastases of metastatic castration-resistant prostate cancer patients. However, some patients have shown gastrointestinal side effects such as nausea and diarrhea. In this mouse study, we investigate whether these side effects may be reduced by oral administration of barium sulfate (BaSO4), a co-precipitating agent of Ra. 
    Published June 21, 2017
  • TAT-10: Session IV: Nanocarriers

    Kanazawa, Japan (UroToday.com) There is a substantial problem with binding the radioisotope to a molecular structure. Isotopes like Ra223 and Ac225 have decay chains that emit a total of four alphas. When the first decay occurs, the recoil of the daughter nucleus is sometimes sufficient to break the molecular bond holding the radioisotope. For the isotopes above, one of the daughter nuclei has a long enough half-life to travel through the body. This is doubly bad since not only is the alpha lost to the tumor site but the free isotope may damage healthy organs, especially the liver and kidneys.
    Published June 21, 2017
  • TAT-10: Spectroscopic and Computational Studies of Actinium Coordination Chemistry

    Kanazawa, Japan (UroToday.com) Ac225 is a very promising isotope for targeted alpha therapy. Production of efficient, pure conjugates would benefit from a better understanding of the basic actinium chemistry. In contrast to the tracer-level quantities of Ac225, Ac227 (half-life 22y) is available in microgram quantities which enables traditional chemical techniques. Using our stock of 150 mg (10 mCi) of Ac227, we have developed multiple spectroscopic and theoretical approaches to understand Ac coordination chemistry.
    Published June 21, 2017
  • TAT-10: Targeted Alpha Therapy of Glioblastoma Multiforme: Clinical Experience with Bi213 and Ac225-Substance P

    Kanazawa, Japan (UroToday.com) Glioblastoma multiforme (GBM) is a common brain tumor in young men with a poor prognosis of 15 months even with aggressive treatment of surgery, chemotherapy, and external radiation. In this study, the radionuclide is bound in DOTA and linked to Substance P which targets NK1 receptors expressed by GBM. The  dose was administered by 1 or 2 catheters into  either the tumor or the cranial cavity through the scull penetration remaining from the surgical treatment. PET scan imaging from Ga68-SubstanceP co-injected into the tumor site verified high retention of the radio-isotope. 
    Published June 21, 2017
  • TAT-10: US DOE Tri-Lab Research Effort to Provide Accelerator produced Ac225 for radiotherapy: 2017 Update

    Kanazawa, Japan (UroToday.com) The US DOE’s isotope program at three of its national labs (LANL, Oak Ridge, and BNL) is an on-going program to produce Ac225 isotopes for research and patient treatment. The BNL Brookhaven Linear Isotope Producer (BLIP) uses excess pulses diverted from the primary proton linac serving the BNL accelerator complex.
    Published June 21, 2017