for Cancer and TRIUMFs Role Joseph G Jurcic MD Professor of Medicine at CUIMC Director Hematologic Malignancies Columbia University Irving Medical Center Attending Physician New YorkPresbyterian Hospital ID: 1016000
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1. Targeted Radionuclide Therapy for Cancer and TRIUMF’s Role Joseph G. Jurcic, MDProfessor of Medicine at CUIMCDirector, Hematologic MalignanciesColumbia University Irving Medical CenterAttending Physician, New York-Presbyterian HospitalE-mail: jgj2110@cumc.columbia.edu
2. DisclosuresResearch FundingAbbVieActinium PharmaceuticalsArog PharmaceuticalsAstellas PharmaCelgeneDaiichi-SankyoForma TherapeuticsGenentechKura OncologyPTC TherapeuticsSyros PharmaceuticalsClinical Advisory BoardActinium PharmaceuticalsAd Hoc AdvisorAbbVieBoston BiomedicalCelgene/BMSDaiichi-SankyoConsultancyNovartis
3. Targeted radionuclide therapy backgroundβ particle-emitting isotopesα particle-emitting isotopesTargeted α-particle therapy for leukemiaMeeting demand for isotopesOutline
4. TumorTargeted Radionuclide Therapy (TaRT)Composed of:Targeting vector (antibody, peptide)Bifunctional chelateRadionuclideDelivers radiation to tumor selectivelyMinimizes toxicity to normal tissue
5. Selected β-Emitters for TaRTIsotopeHalf-lifeEnergy (keV)Range (mm)γ EmissionsIodine-1318.1 days6100.8+Yttrium-902.7 days23005.3‒Lutetium-1776.6 days2100.3+Copper-672.6 days5800.8+Rhenium-1863.7 days11001.1+Rhenium-18817 hrs21002.4+Holmium-1661.1 days19002.2+Strontium-8950.5 days15006.7‒Samarium-1531.9 days8100.5+
6. Radioimmunotherapy for Non-Hodgkin LymphomaHess C et al. Med Chem Commun 2014; 5:408-431.90Y-Ibritumomab Tiuxetan (Zevalin®)131I-Tositumomab (Bexxar®)
7. Overall SurvivalStrosberg J et al. N Engl J Med 2017;376:125-135.177Lu-Dotatate for Neuroendocrine TumorsProgression-Free Survival
8. Alpha- vs. Beta-Particle RadioimmunotherapyTumorTumorNormal EndotheliumBlood Vesselα-Particle50-80 µm range5-8 MeVβ-Particle1-10 mm range0.1-1 MeV
9. Advantages of α-Emitting IsotopesHigh energy (5-8 MeV)Short path (50-80 µm)100 times more potent than β-particlesMore selective, efficient tumor cell killingLess radiation to normal tissuesLimited ability of cells to repair DNA damageepswww.unm.eduNucleus with2 fewer protons and 2 fewerneutronsAlpha particleNucleus
10. Selected α-Emitters for TaRTIsotopeHalf-lifeEnergy (keV)Range (mm)Bismuth-2121 hr61000.04-0.1Bismuth-21346 min84000.05-0.08Actinium-22510 days6000-84000.05-0.08Astatine-2117.2 hrs75000.04-0.1Radium-22311 days60000.04-0.08Thorium-22718.7 days5900-74000.04-0.1Lead-21210.6 hrs57000.04-0.1Terbium-1494 hrs41000.04-0.08
11. 223Ra for Bone Metastatic Prostate CancerOverall SurvivalTime to 1st Symptomatic Skeletal EventParker C et al. N Engl J Med 2013; 369:213-223.
12. 225Ac-PSMA-617 for Prostate Carcinoma68Ga-PSMA-11 PET/CT Scans During and After TherapyKratochwil C et al. J Nucl Med. 2016; 57:1941-1944.
13. Conditioning for Hematopoietic Cell Transplant1Sandmaier BM et al. Blood 2002; 100:318-326.2Chen Y et al. Blood 2012; 119:1130-1138.211At-Anti-CD452CD3+ CellsWeeks post-transplant% Donor213Bi-Anti-CD451Granulocytes
14. Prognostic Factors for Acute Myeloid Leukemia1Juliusson G et al. Blood 2009;113:4179-4187.2Papaemmanuil E et al. N Engl J Med 2016; 2209-2221.Survival by Age1Survival by Karyotype2
15. Lintuzumab (HuM195, SGN-33)1Caron PC et al. Cancer Res 1992; 52:6761-6767.2Caron PC et al. Blood 1994; 83:1760-1768.3Raza A et al. Leuk Lymph 2009; 50:1336-1344.4Burke JM et al. Bone Marrow Transplant. 2003; 32:549-556.5Jurcic JG et al. Proc ASCO 2000; 19:8a. Humanized anti-CD33 monoclonal antibodyKills target cells by ADCC and fixes complement1Rapidly targets leukemia cells in patients without immunogenicity2Has modest activity in relapsed AML3Can eliminate large leukemic burdens when labeled with the β-emitters 131I and 90Y4,5
16. 213Bi-Lintuzumab: A 1st Generation α-Emitting Conjugateα10 days221Frα4.9 min217Atα0.032 sec213Biα46 minStableIsotopes225Ac225Ac/213Bi Generator10.36-37 MBq/kg delivered in 3-7 fractions over 2-4 daysMyelosuppression lasted 12-41 days (median, 22 days)Transient liver function abnormalities seen in 6 patientsMTD was not reached14/18 patients had reductions in marrow blastsJurcic JG et al. Blood 2002; 100:1233-1239.SCN-CHX-A-DTPANNNSCNCO2HCO2HCO2HCO2HCO2H
17. Rosenblat TL et al. Clin Cancer Res 2010; 16:5303-5311.Jurcic JG et al. Blood 2002; 100:1233-1239.Biodistribution and Dosimetry of213Bi-LintuzumabIsotopeMean Absorbed Dose (mSv/MBq)Marrow/Whole BodyRatioMarrowLiverWhole Body131I2.70.80.1614.490Y6.84.00.4913.9213Bi9.85.80.000427,300Posterior60-MinuteSummationRate/MinuteDose 1Dose 4
18. Actinium-225: An α-Particle NanogeneratorShort half-life and need for on-site generator limit use of 213Bi.225Ac can be stably conjugated to antibodies using DOTA.225Ac-labeled antibodies are 1,000-10,000 times more potent in vitro compared to 213Bi analogs.Nanocurie doses of 225Ac-labeled antibodies prolong survival of mice in xenograft models.McDevitt MR et al. Science 2001; 294:1537-1540.α10 days221Frα4.9 min217Atα0.032 sec213Biα46 minStableIsotopes225Acα10 days221Frα4.9 min217Atα0.032 sec213Biα46 minStableIsotopes225Ac
19. Phase I Trial of 225Ac-LintuzumabUpdated from Jurcic JG et al. Blood 2011; 118:768.18 patients with R/R AML received a single dose of 18.5-148 kBq/kg Dose-limiting toxicity was myelosuppressionNo renal toxicity was seenMaximum tolerated dose was 111 kBq/kgBone marrow blasts were reduced in 10/15 (67%) evaluable patients8 patients (53%) had marrow blast reductions of ≥ 50%3 patients achieved ≤ 5% marrow blasts at doses of 37, 111, and 148 kBq/kg
20. Phase II Trial of 225Ac-Lintuzumab MonotherapyStudy Design and Clinical OutcomesFinn LE et al. Blood 2017; 130:2638; Atallah EL et al. Blood 2018; 130:1457; Berger M et al. TAT 11 2019; poster 61.Day 18225Ac-Lintuzumab74 kBq/kg/fraction OR55.5 kBq/kg/fraction18SpironolactoneG-CSFDose (kBq/kg)Response RatePatients with Gr 4 Thrombocytopenia > 6 weeks Patients withGr 4 Neutropenia> 6 weeks 74 (n=13)69%1 CR, 2 CRp, 6 CRi 46%38%55.5 (n=27)22%3 CRp, 3 CRi 30%40%Abbreviations: CR, complete remission; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete blood count recovery.
21. Future Development of 225Ac-Lintuzumab in AML/MDSTailored 225Ac dose for specific clinical applicationHigh-DoseLow-DoseTargeted ConditioningCombination with CLAG-MCombination with Venetoclax Conditioning for HCT in High-Risk MDSCombination TherapySingle-AgentCombination with7+3 InductionMinimal Residual Disease in AML
22. Clinical Studies with 213Bi and 225AcDiseaseIsotope(s)RadioligandLeukemia213Bi, 225AcLintuzumabLymphoma213BiAnti-CD20 mAbMelanoma213Bi9.2.27 mAbBladder cancer213BiAnti-EGFD mAbGlioma213Bi, 225AcSubstance PNeuroendocrine tumors213Bi, 225AcDOTATOCProstate cancer225AcPSMA-617Adapted from Morgenstern A et al. Semin Nucl Med 2020; 50:119-123.
23. Anticipated Need for 225AcCurrent need for pre-clinical and clinical trials with 225Ac is < 5 Ci (185 GBq)/year.~1 mCi (37 MBq) is required for each patient.Assuming 100,000-200,000 patients/year, annual demand for 225Ac may increase to 100-200 Ci (3700-7400 GBq). Report on Joint IAEA-JRC Workshop, Supply of Actinium-225, IAEA, Vienna, October 2018.
24. 225Ac Production MethodsExtraction from 233USpallation of 232ThProduction from 226RaProton cyclotronsElectron linacs Robertson AKH et al. Current Radiopharmaceuticals 2018; 11:156-172.
25. Extraction from 233U using 229Th Sources Oak Ridge National Laboratory (5.5 GBq, 150 mCi)JRC Karlsruhe (1.7 GBq, 46 mCi)Leipunskii Institute for Physics and Power Engineering (5.5 GBq, 150 mCi)233U (t½ = 1.6 x 105 y) 229Th (t½ = 7.9 x 103 y) 225Ra (t½ = 15 d) 225AcReport on Joint IAEA-JRC Workshop, Supply of Actinium-225, IAEA, Vienna, October 2018.
26. Spallation of 232Th232Th(p,x)225Ac 225Ac232Th(p,x)225Ra (t½ = 15 d) Various other products are formed, including 227Ac (T½ = 22 y).Activity ratio of 227Ac to 225Ac is ~0.2%.227Ac can increase the toxicity of the 225Ac radiopharmaceutical and creates a problem for patient waste handling.Method pursed by US DOE National Laboratories, TRIUMF, INR, CERN, and NorthStar Medical Technologies.
27. 232Th-Spallation-Produced 225Ac with Reduced 227Ac Content225Ac separated by thorium peroxide precipitation followed by cation exchange and extraction chromatography. Results in Ac product with measured 227Ac content of 0.15 ± 0.04%A second Ac product with 227Ac < 7.5 x 10-5 % was obtained by extraction chromatography on the 225Ra-containing fraction.Robertson AKH et al. Inorg Chem 2020; https://doi.org/10.1021/acs.inorgchem.0c01081.
28. Production from 226Ra226Ra(p,2n)225Ac 225Ac226Ra(γ,n)225Ra (T½ = 15 d) Advantages include:Availability of low-energy accelerators.1000 Ci of 226Ra exists in the from of radium needles used for brachytherapy.Negligible production of 227Ac.High radiotoxicity of 226Ra and decay to 222Rn gas make target manufacturing, irradiation, processing, and recycling difficult.Electron linacs for photonuclear production pursed by ANL, TRIUMF, and Niowave, Inc.Low-energy cyclotron production is also under investigation.
29. TaRT is active in a variety of cancers including prostate, neuroendocrine, lymphoma, leukemia, and gliomas.225Ac-based therapies have produced promising results in prostate carcinoma, AML, and other malignancies. 225Ac extraction from 233U stockpiles will not be sufficient be meet future needs.Novel production methods for 225Ac include spallation from 232Th and production from 226Ra using low-energy accelerators.TRIUMF has been at the forefront of development of the novel production methods.Partnerships among academic medical researchers, facilities like TRIUMF, and the pharmaceutical industry are critical for TaRT to reach its full potential.Conclusions
30. AcknowledgmentsU.S. Department of Energy John McClure Saed MizradehActinium Pharmaceuticals, Inc. Mark S. Berger Dale LudwigMulticenter Trial Investigators Ehab Atallah, Medical College of Wisconsin Kebede H. Begna, Mayo Clinic Michael Craig, West Virginia University Laura E. Finn, Ochsner Medical Center Sharif S. Khan, Bon Secours St. Francis Cancer Center M. Yair Levy, Baylor University Raya Mawah, Swedish Cancer Institute Johnnie J. Orozco, Fred Hutchinson Cancer Research Center John Pagel, Swedish Cancer Institute Jae Park, Memorial Sloan Kettering Cancer Center Alexander Perl, University of Pennsylvania Farhad Ravandi, MD Anderson Cancer Center David A. Rizzieri, Duke University Gail Roboz, Weill Cornell Medical College B. Douglas Smith, Johns Hopkins University William Tse, University of LouisvillePatients participating in these studiesColumbia University Medical Center Todd L. Rosenblat Chaitanya R. Divgi Mark Frattini Memorial Sloan-Kettering Cancer Center David A. Scheinberg Jorge Carrasquillo Suzanne Chanel Michael Curcio Dan Douer John Humm Jaspreet S. Jaggi Katherine S. Kolbert Steven M. Larson Michael R. McDevitt Neeta Pandit-Taskar Shutian RuanNational Cancer Institute Martin Brechbiel Otto GansowJohns Hopkins University George SgourosInstitute for Transuranium Elements Christos Apostolidis Roger Molinet Alfred Morgenstern