10 radionuclides for therapy

8/4/2019 10 Radionuclides for Therapy

1/27

USE OFRADIONUCLIDE

THERAPY:

ACTUAL CLINICALAPPLICATIONS?

J. Boratynski

R. KristensenF. BruchertseiferZurich, 2010


2/27

Outline1. Aim of radionuclide therapy2. Radionuclides for therapy parameters and

characteristics.

3. Linkers parameters and characteristics.4. Carriers parameters and characteristics.

5. Examples.6. Future/Clinical Trials.

7. Summary.


3/27

Aim of radionuclide therapyThe fundamental objectives for radionuclide therapy are:

1. To achieve appropriate treatment of the disease through

delivery of a radiation dose at the desired cytotoxic levelwith the defined endpoints being cure, disease control(stabilization) or palliation.

2. To avoid or minimize toxic effects (spare normal organs),both in the acute time frame and as long termcomplications. The goal of radionuclide therapy is tomaximize the therapeutic index as represented by the

ratio of the radiationdose delivered to the tumor to thatdelivered to normal tissue.

S.R. Thomas, Cancer Biotherapy & Radiopharmaceuticals, 2002, 17, 1, p.71


4/27

Target

Structure

Carrier RadionuclideLinker

Carriers:

Monoclonal antibodies, Peptides (somastotatin analogues), Small

molecules (sugars, amino acids), Liposomes, Microspheres, Particles

Linkers:

DOTA, NOTA, TRITA, DTPA

Radionuclides:

90Y, 177Lu, 186Re, 131I, 153Sm 211At, 212Bi 193mPt Auger


5/27

Radionuclides for therapy

parameters and characteristics

- stable daugher isotope

- a proper type of radiation (, Auger electrons, )

- apropriate physical half-life time (hours, days)

- radiation energy + high LET (effective cell irradiation~300 keV)

- range of radiation:Auger electrons ~ nm

~ m

~ mm


6/27

Linkers parameters and

characteristics

- conjugate metal and carrier bifunctional

- chelate metal

- couple with carrier

- stable in-vivoconditions (kinetically inert)


7/27

Carriers parameters and

characteristics

- reach matastases via blood stream- relatively long biological half-life time

- stable in-vivo


8/27

non-Hodgkins lymphoma (NHL)

Target: CD20 receptor on mature b-cells

Pre-treatment: rituxan (naked antibody)clearing the majority of normal b-cells - the therapeutic radiolabeledantibody is more focused on tumor cells.

Mechanism: the monoclonal antibody recognizes and attaches to theCD20 antigen, allowing radiation emitted by radioisotope to

penetrate and damage the B-cell as well as neighboring cells.

Zevalin: 90YT1/2=2.7 d

Energy: 2,28 MeV

Bexxar: 131IT1/2=8 d

Energy: 600 keV , 364 keV

[http://www.lymphomation.org/compare-bexxar-zevalin.htm]


9/27

ZevalinBexxar


10/27

Neuroendocrine tumours

177Lu-DOTATATE, 177Lu-DOTATOC 90Y-DOTATATE, 90Y-DOTATOC

Target: somatostatin receptors. The somatostatinreceptor is strongly over-expressed in most tumours,resulting in high tumour-to-background ratios.

25% of patietns achieving objective tumour shrinkage

>50%. Serious side-effects have been rare.90YT1/2=2.7 dEnergy: 2,28 MeV

177LuT1/2=6,7 d

Energy: 497 keV

, 208 keV

F. Forrer et al., Best Practice & Research Clinical Endocrinology & Metabolism, 2007, 21,1, p. 111-129


11/27

Thyroid carcinoma

Na131I

in capsules and i.v. (also diagnosis) target: thyroid

mechanism: thyroids iodine uptake

the oldest and most succesful radiopharmaceutical

since: 40

T1/2=8 d

Energy: 600 keV , 364 keV


12/27

Phaeochromacytoma & Neoblastoma

131I-mIBG

Similar tonorepinephrine

Uptake by adrenergicreceptors

123I 159 keV & 27 keV 131I 606 keV 89% IncidencePhaeochromacytoma

2-8/106 pr. Year

Neoblastoma 2/106 pr.

Year

norepinephrine

I-mIBG


13/27

Phaeochromacytoma & Neoblastoma

40 patients received 131I-MIBGtherapy. May 1996 to May 2006

Strong uptake of 123I-MIBG, byScintigraphy.

7.4 GBq pr. treatment cycle.Average 1.8 cycles.

11 patients showed reduction intumour size post-therapy.

27 patients reported improvedsymptoms after 131I-MIBG therapy.

11 patients required hospitalisationas a consequence of complications(bone marrow suppression).

Median survival increased by 37months (symptomatic responders).

norepinephrine

I-mIBG

Nwosu et al. British Journal of Cancer (2008) 98, 1053 1058


14/27

Synoviorthesis

Hydroxyapatite particles (HA)

90YCI3

90Y-Colloid

For Rheumatoid Arthritis,Osteoarthritis and others.

Mainly used in knee's. In practice since the 60's.

Principle:The colloidal particles arephagocytized by the synovial liningcells. The energy released effects a

therapeutically active irradiation of thesurrounding synovial tissue, resultingin a fibrotic and sclerosed synovialmembrane.The inflammatory and destructive

processes is stopped, which leads toan alleviation of the pain and effision,followed by an occlusion of superficialcapillaries.

90Y citrate or silicate colloid 111-

222MBq.


15/27

Synoviorthesis

Review of articles from 1975-2006. (Medline, Embase,Biosis, Derwent Drug file,SciSearch)

Conclusions:

Minimally invasive therapy.

Treatment is efficacious

In view of benefits, tolerabilityand safety are very good

Important!

Post-treatment immobilizationand the co-administration ofcorticoids, to minimize the riskof leakage and of efflux through

the puncture channel.Review article by Kampen et al.,Rheumatology 2007;46:1624

90YCI390YCI3

Hydroxyapatite particles (HA)


16/27

Hepatoma

Sirtex particles

Gastric Mucosa

90Y- micro Particle

TheraSphere - Glass particles

Sirtex - Polymer particles

Principle:Solid particles are inserted into the

hepatic artery of the tumor,cause embolisation in the

tumor microvasculature andtumor irradiation.

Normal liver parenchyma ispredominantly supplied with

blood from the portal vein.


17/27

Hepatoma

Sirtex particles

Gastric Mucosa

Lim et al. BMC Cancer 2005, 5:132 doi:10.1186/1471-2407-5-132

30 patients Jan 2002-Mar 2004

Hepatic metastasis

from colorectal cancer


18/27

Bone Metastasis

153Sm-EDTMP

Ethylenediaminetetra(methylenephosphonic acid)

Approved for palliativetreatment in the USAsince 1998

Standard palliativedose 1mCi/kg

T=46,27h

Bind to Ca2+


19/27

Bone Metastasis

Review of:Three randomized phase III trials,Two randomized phase II trials

Metastatic Breast prostate and

lung cancer. Conclusion: Samarium-153

should be considered as apossible optionfor the palliationof multiple sites of bone pain frommetastatic cancerwherepain

controlwith conventionalanalgesic regimens isunsatisfactoryand where activityon a bone scan of thepainfullesionsisdemonstrated. Ongoingclinical research should seek toestablish the benefit of newerradiopharmaceuticals andradiopharmaceuticals incombination with other systemictherapies

Bauman et al. Radiotherapy and Oncology 75 (2005) 258.e1258.e13


20/27

clinical trials - At-211-MX35 F(ab)2 [phase I]

Aim:- to determine the relevant pharmacokinetics for assessing absorbed dose tonormal tissues and investigating the toxicity

Methods:

-appr. 500 MBq of 211At was labeled to 0.7 mg of MX35 F(ab)2 using the reagentN-succinimidyl 3(trimethylstannyl) benzoate

- 50 MBq (3 patients) or 100200 MBq (6 patients) in 12 L of Extraneal was infusedvia the peritoneal catheter

Results:

- At-211 was found peritoneal fluid, serum (to 6% IC after 30 h) and thyroid to127 63% at 20 h without blocking < 20% IC with blocking

- no other organ uptakes could be detected

- estimated absorbed dose to the peritoneum was 15.6 1.0 mGy/(MBq/L)

- no adverse effects were observed either subjectively or in laboratory parameters

Conclusion:- intraperitoneal administration of 211At-MX35 F(ab)2 it is possible to achieve

therapeutic absorbed doses in microscopic tumor clusters without significant toxicity

Andersson et al, Journal of Nuclear Medicine 2009;50:11531160


21/27

clinical trials - I-131-Labetuzumab [phase I/II]

Liersch T, et al Ann Surg Oncol 2007;14:2577

Aim:- RIT using I-131 labetuzumab (anti-CEA) after the salvage resection ofcolorectal (CRC) liver metastases (LMs)

- liver is the only metastatic site in 30%40% of CRC patients

- 5-year survival rate is 0%3%

Method:-40-60 mCi/m

I-131 labetuzumab-2x40-50 mCi/mI-131 labetuzumab

Outcome:Safe, feasible, well acceptedProloged survival time

Phase III


22/27

clinical trials - Lu-177/Y-90 PRRT

http://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdfD. J. Kwekkeboom et al, Eur. J. Nucl. Med. Mol. Imag. 30/2003, 417-22Waldherr C et al, Ann Oncol. 2001 Jul;12(7):941-5

Frilling et al, Surgery, 2006, 140(6), 969

Aim:- peptide radioreceptor therapy (PRRT) with Lu-177/Y-90 for neuroendocrine tumors- peptide [DOTA0,Tyr3]octreotide (DOTATOC) and [DOTA0,Tyr3]octreotate(DOTATATE), specific for somastotatine receptors

Method:- 3 +/- 2 GBq Y-90 peptide- 7 +/- 3 GBq Lu-177 peptide

Outcome:According WHO criteria- CR 2%- PR (more 50%) 22%- PR (25% - 50%) 12%- SD 49%
http://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdfhttp://upload.wikimedia.org/wikipedia/commons/2/2b/DOTATOC.pnghttp://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdf


23/27

clinical trials - Ac-225/Bi-213 CD33 [phase I/II]

Phase I:

18 patients with relapsed and refractory AML (acute myelogenousleukemia) or CML (chronic myelomonocytic leukemia)

0.3 - 1.0 mCi/kg body weight of 213Bi-HuM195 (anti-CD33) no significant toxicity 14/18 patients responded

Phase I/II (ongoing):

elimination of residual disease after partial cytoreduction using cytarabine > 30 AML patients treated so far 0.5 1.25 mCi/kg body weight of 213Bi-HuM195

MTD 1 mCi/kg 24% of patients receiving 1 mCi/kg (n=25) responded (2 CR, 2 CRp, 2PR)

T. Rosenblatt et.al. submitted

J. Jurcic, Blood 2002


24/27

clinical trials - Glioma/Glioblastoma [phase I]

At-211-labeled chimericantitenascin antibody, 81C6

Outcome:

- 97% of At-211 occurred in thesurgical resection cavity

- survival increased to 52 weeks inglioblastomas and 97 weeks innonglioblastoma tumors 77

- historic control of 31 weeks

- limitation in the specific activity

Zalutsky et al J Nucl Med 2008;49:30

Substance P labelled with Lu-177/Bi-213

(Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH-R)Outcome:

- only transient toxicity was seen as symptomatic radiogenic edema in one patient

- disease stabilization and/or improved neurologic status was observed in 13 of 20 patients- resection disclosed widespread radiation necrosis with improved demarcation

TAT with diffusible peptidic vectors for local control of malignant gliomas

Kneifel et al Clin Cancer Res. 2006 Jun 15;12(12):3843-50


25/27

clinical trials - melanoma [preclinical/phase I]

Rhenium-188

- Re-188 sulfur colloid, tin colloid or microspheres on carrier e.g. filter paper, emulsion- doses appliceted 50 to 100 Gy

Jeong et al, Appl RadiatIsot 2003;58:551

Bismuth-213

- Phase I study on grade IV malignant melanoma / in-transit metastases usingBi-213 labelled mAb 9.2.27

Results: 48 patients treated with 1.5 to 27 mCi Bi-213-9.2.27

- 12% partial response

- 50% stable disease- 38% progressive disease- no signs of adverse effects

C. Raja et al, Cancer Biology & Therapy 6:6, 846-852; 2007


26/27

Summary

- long tradition of radionuclide therapy- radionuclide therapy especially the radioimmunonuclide therapy large potential

- use of beta and alpha emmiting radionuclidese.g. Y-90, I-131, Sm-153, Lu-177, Re-186/188, At-211, Bi-213 etc.

-commercially used vectorse.g. Zevalin, Bexxar, EDTMP, HDEP

-Variety of clinical trials with further AB and peptidese.g. CD33, Labetuzumab, Substance P, DOTATOC, DOTATATE

Outlook

- more specific targeting- use of alternative radionuclides specifically for the type of tumors (

or Auger-

emiters)

- combination of antibodies and peptides (pre-targeting)

e.g. modified CD22 with IMP-288 (B-cell cancer)


27/27

THANK YOU FOR YOUR

ATTENTION

ESPECIALLY OUR ORGANIZERSFOR TWO NICE WEEKS

SEE YOU IN LEIPZIG/LIPSK

10 radionuclides for therapy

Documents