INSTITUTE OF PHYSICS PUBLISHING PHYSICS IN MEDICINE AND BIOLOGY Phys. Med. Biol. 51 (2006) R327–R341 doi:10.1088/0031-9155/51/13/R19

REVIEW

Internal high (LET) targeted radiotherapy for cancer

Barry J Allen

Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah NSW 2217, Australia

E-mail: [email protected]

Received 6 April 2006, in final form 24 May 2006 Published 20 June 2006 Online at stacks.iop.org/PMB/51/R327

Abstract High linear energy transfer (LET) radiation for internal targeted has been a long time coming on to the medical therapy scene. While fundamental principles were established many decades ago, the clinical implementation has been slow. Localized capture therapy, and more recently systemic targeted alpha therapy, are at the clinical trial stage. What are the attributes of these that have led a band of scientists and clinicians to dedicate so much of their careers? High LET means high energy density, causing double strand breaks in DNA, and short-range radiation, sparing adjacent normal tissues. This targeted approach complements conventional radiotherapy and chemotherapy. Such therapies fail on several fronts. Foremost is the complete lack of progress for the control of primary GBM, the holy grail for cancer therapies. Next is the inability to regress metastatic cancer on a systemic basis. This has been the task of chemotherapy, but palliation is the major application. Finally, there is the inability to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. This review charts, from an Australian perspective, the developing role of local and systemic high LET, internal .

1. Introduction

1.1. Background After an earlier life as a neutron physicist, the author began in the 1980s to investigate the use of in medicine. One such project lay in cancer therapy, with emphasis on thermal and epithermal neutrons for boron neutron capture therapy (BNCT). BNCT is a localized form of targeted alpha therapy (TAT), wherein a high linear energy transfer (LET) radiation source is carried to the targeted cancer cells, the radiation released on neutron capture or by decay of the radioisotope. There are many similarities between BNCT and TAT, in that suitable targeting

0031-9155/06/130327+15$30.00 © 2006 IOP Publishing Ltd Printed in the UK R327 R328 Review molecules or vectors must access cancer cells in normal tissue or in a tumour. BNCT has an advantage in that toxicity is turned on in the targeted organ, so systemic toxicity is not the issue it could be in TAT. However, TAT has the advantage of being either a local or systemic therapy. This history covers the development of internal, high LET radiotherapy from an Australian perspective, and more compete bibliographies are available elsewhere for BNCT (Barth et al 2005) and for TAT (Hassfjell and Brechbiel 2001). Uniquely for the author, the TAT project was a spin-off from BNCT program, culminating in the discovery of the tumour anti-vascular alpha therapy (TAVAT) hypothesis, of potential importance to both therapies. As Convener of the 2003 World Congress on Medical Physics and Biomedical Engineering in Sydney (Allen et al 2004) and chair of the high LET Track, the author was able to coordinate the first combined high LET cancer therapy session at an international conference.

1.2. Boron neutron capture therapy The essential elements of BNCT are an epithermal neutron beam that induces the thermal neutron capture reaction in B-10 (2838 × 10−24 cm2) at depth in tissue. The boron is located in the tumour and surrounding tissue, by virtue of some selective uptake mechanism. This may be physiological (e.g. with BSH and the leaky blood brain barrier), metabolic (e.g. BPA) or molecular (e.g. monoclonal antibody). The boron compound should be preferentially taken up by cancer cells in tumours, and the neutron induced fission reaction of B-10 releases the high LET alpha and Li-7 particles in opposite directions, killing the targeted cancer cells. The Australian effort addressed all aspects of BNCT, save for clinical trials. In particular, different boron compounds were examined, a thermal NCT reactor facility was developed for in vitro and in vivo studies, new dosimeters were developed and applied to phantom epithermal studies to validate our in house dose planning system. Some 70 papers were published over 10 years, and as President of the International Society for Neutron capture Therapy, the author convened the Fourth International Symposium on NCT in Sydney in 1990.

1.3. Targeted alpha therapy With the collapse of the NCT program in Australia, a new research program on targeted alpha therapy for cancer was developed that progressed from ‘bench to bedside’ in one decade. Some 35 papers have been published, and two clinical trials commenced. The initial studies related to the alpha emitting radioisotope Tb-149, but the 225Ac:213Bi generator has become the workhorse for the ongoing research. The major difference between working in a national laboratory and a small research department in a local hospital was the freedom to follow your own research, but without a budget! So the TAT project existed, and continues to do so, on donations and research grants, and the goodwill of collaborating staff and PhD students. The red line hovers close by from time to time, adding another dimension to running a research group.

2. Boron neutron capture therapy

2.1. Radiobiology The dose arising from BNCT is a superposition of both low and high LET radiations. When a B-10 nucleus captures a thermal neutron, the resulting compound nucleus B-11 undergoes fission to form an alpha particle and a Li-7 ion moving in opposite directions with total energy 2.79 MeV. A 478 keV gamma ray is also emitted with 94% branching ratio. The particle Review R329 energy is then 2.31 MeV, and this is expended over a combined particle range of ∼10 µm. These radiations are high LET particles, and deliver the high energy deposition rate of ∼230 keV µm−1, causing double strand breaks in cellular DNA that are difficult to repair. The localization of energy, together with the 478 keV gamma ray for imaging, means that an extremely localized cancer cell therapy could be achieved. However, the neutrons must be able to thermalize at the cancer depth in tissue so as to react with the boron-10 atoms selectively taken up by cancer cells. In addition, but with lower probability, neutrons will be captured by nitrogen and hydrogen atoms in normal tissues, the former producing a high LET alpha particle which is non-specific in its radiation damage. A 2.2 MeV gamma ray is emitted after neutron capture in hydrogen. If fast neutrons are present in the neutron beam, then proton knock-on reactions can occur, producing more non-specific high LET radiation. The relative biological effectiveness (RBE) of these reactions are 3.2 for the high LET and 1 for the low LET radiation (Barth et al 2005). The relative proportion of the different radiation types depends on the energy spectrum of the incident neutrons and the biodistribution of boron compound in tumour and normal tissue. The short range of the reaction products results in dose sparing of capillary endothelial cells (Allen and Charlton 1994, Gabel et al 1987, Kitao 1975, Rydin et al 1976). The term compound biological effectiveness (CBE) was developed to take account of these variables (Morris et al 1994). The determination of biological radiation dose is complex, with many assumptions in a patient treatment. Nevertheless, the weighted dose or photon equivalent dose (not to be confused with the equivalent dose used in radiation protection), allows some comparison of results and an understanding of the key factors involved in the dose received by the patient. Phase 1 clinical trials allow escalation of the weighted dose and determination of safe irradiation conditions.

2.2. Neutron sources

2.2.1. Moata thermal BNCT facility. A 100 kW Argonnaut reactor was available at the Australian Atomic Energy Commission Research Laboratories at Lucas Heights, and the thermal column was modified to provide an in vitro and in vivo thermal neutron capture therapy (TNCT) irradiation facility (Allen et al 1989a). The nude mouse provides a useful animal model, as human melanoma cells can be injected to grow as tumour xenografts without inducing rejection. The subcutaneous xenografts were then irradiated in the TNCT facility. Bismuth gamma ray shielding was installed to reduce the gamma dose, and mice were placed in neutron shield tubes, with the tumour open to the neutron field. We were successful in completely regressing melanoma without causing symptomatic radiation damage to the mice (Allen et al 1992). This unique facility would have allowed detailed investigations of the efficacy of BNCT to be made in different human cancers, using different boron compounds. However, this capability was lost when the Moata reactor was closed.

2.2.2. Neutron energy range. The optimal neutron energy for NCT is in the epithermal range, i.e. between 0.5 eV and 10 keV. At lower energy, neutron penetration is too poor, while at higher energy the fast neutron component increases as does the non-specific radiation damage. The early studies by Hiroshi Hatanaka (Hatanaka 1991) used an intra-operative thermal beam, such that skin dose was eliminated and neutron penetration was increased by removing part of the shielding skull and holding the tumour cavity open with the ubiquitous ping-pong ball. R330 Review

2.2.3. Heavy water. Heavy water was administered to patients in Japan to increase the thermal neutron penetration and the depth of treatment. Our quantitative investigation of this procedure used Fourier transform infra red analysis to measure heavy water concentrations in the patient’s blood (Blagojevic et al 1994). Theoretical calculations (Wallace et al 1995b)were made for thermal and epithermal beams. These results showed that significant improvements in depth-dose could be achieved at safe levels of heavy water concentration.

2.2.4. Epithermal neutron beams. Epithermal reactor beams were first developed by Idaho National Engineering Laboratory (INEL) and installed at the Brookhaven Medical Research Reactor (BMRR) (Coderre et al 1997, Fairchild et al 1989, 1990). A patient facility and epithermal beam was installed at the Petten JRC reactor. Other reactors and proposals in Sweden (Capala et al 2003), Finland (Joensuu et al 2003), the Czech Republic (Burian et al 2002), Japan (Hatanaka 1991, Hatanaka and Nakagawa 1994, Kobayashi et al 2000, Yamamoto et al 2000), Argentina (Blaumann et al 2001) and USA (Nigg 2002) followed. The Massachusetts Institute of Technology Reactor (MITR), site of one of the first thermal BNCT trials (Godwin et al 1955), was upgraded with the installation of a fission converter plate to produce the best epithermal beam for BNCT (Riley et al 2003). Performance specifications are: epithermal flux of 4.6 × 109 ncm−2 s−1 for 0.5–10 keV; fast neutron flux of 1.4 × 10−13 Gy cm2 (>0.5 eV); gamma dose rate 3.5 × 10−13 Gy cm2 to deliver 1.7 RBE Gy min−1 at an advantage depth of 9.7 cm for a B-10 uptake of 65 µgg−1 of BPA in the tumour and 18 µgg−1 in normal tissue. Australia had its own epithermal R&D program at Lucas Heights, based on the Hiflux Australian Reactor (HIFAR), developing the AlF3 filter concept (Harrington 1987). Harry Meriaty and others with Geoff Constantine, our BNCT refugee from the Harwell Reactor Centre, carried out beam filter studies with liquid nitrogen cooling of liquid argon on the top plate of HIFAR. This experiment was noted for a gas bubble belch in the liquid nitrogen that sprayed over Harry’s hair, probably speeding up his genetic hair loss. These studies paved the way for our phantom measurements in the Petten epithermal beam. Accelerator neutron sources have been investigated by several groups (Blackburn et al 1998, Blue and Yanch 2003,Burlonet al 2002,Giusti2002,Hawket al 2002,Hawket al 2002, Kononov et al 2002, Sakurai et al 2002, Zimin and Allen 1998, Zimin and Allen 2000) and developed and implemented at the University of Birmingham (Beynon et al 2002, Culbertson et al 2004). The Birmingham project should be the first facility of its kind to undertake clinical trials of BNCT using an accelerator as the , but will only be able to treat a small number of patients. However, the ability to deliver such treatments using an accelerator located in a radiation oncology department would open up the potential for future expansion of this technique. An alternative to an accelerator source is the Cf-252 radioactive neutron source with half-life of 2.645 years. The neutrons (average neutron energy of 2.14 MeV) are moderated in tissue, and B-10 augmented was shown to provide clinically useful increases in tumour dose at 5–15 cm from the source (Yanch et al 1990). B-10 enhancement of fast neutron therapy beams has also been investigated and found to give an effective boost to tumour dose (Wootton et al 1992).

2.2.5. Treatment planning programs. Monte Carlo dose calculations are needed because of the different LET components of radiation involved in the BNCT reaction in tissue. Neutrons are slowed down by interactions with hydrogen atoms, and alpha, beta and gamma rays emitted. The situation is much more complicated than for external beam radiotherapy, for which Monte Review R331

Carlo dose calculations are now just beginning to be performed in the clinical setting. The dose planning programs were first developed at INEL, Idaho Falls (Nigg et al 1997), MIT at Cambridge, Massachusetts (Zamenhof et al 1996) and at ANSTO, Lucas Heights (Wallace et al 1994). The ANSTO program was thoroughly tested in phantoms at the Petten epithermal beam facility (Carolan et al 1994). These experiments used the first MOSFET detectors in BNCT, developed by Anatoly Rosenfeld at the University of Wollongong.

2.3. Compounds 2.3.1. Boron analysis. Prompt boron gamma ray spectroscopy, using the 10B(n, αγ) reaction and detecting the 478 keV gamma rays, was developed by a number of laboratories, perhaps the most advanced facility being established at MIT (Rogus et al 1990). This method has the advantage of being used online to determine delivered dose. However, much higher sensitivity and resolution can be achieved off-line using inductively coupled plasma atomic emission spectrometry (ICPAES), first applied in Sydney (Tamat et al 1987, 1989a). Other boron analysis techniques developed in Sydney (Moore et al 1990) included FTIR analysis (Setiawan et al 1994), the first studies of a boronated monoclonal antibody in a melanoma section and boron energy loss spectroscopy (BEELS). BEELS is based on the detection of that have lost a discrete amount of energy following interaction with specific atoms in the sample. Elemental mapping can be performed with extremely high resolution (∼10 nm) in the scanning (STEM) or energy-filtering transmission electron microscope (EFTEM). Boron to carbon ratios of ∼3 × 10−3 have been achieved in calibration studies.

2.3.2. Boron compounds. The boron-10 concentration in tumour needs to reach at least 20 ppm, or 109 atoms per cell, to achieve an adequate reaction rate. Two 10B compounds are currently under test in clinical trials. Sodium mercaptoundecahydro-closo-dodecaborate (BSH), originally developed at MIT (Soloway et al 1967) and used by Hatanaka in Japan, is being tested at Petten for epithermal BNCT of GBM. BSH has no intrinsic cellular selectivity, and achieves enhanced tumour uptake by virtue of the breakdown of the blood brain barrier (BBB) in the tumour. Neogenic tumour capillaries have leaky endothelial cell junctions, and large molecules can diffuse into surrounding tissue through capillary fenestrations. This is not the case in mature capillaries in normal organs. The effect of inducing breakdown of the BBB in animal brain tumours shows improved efficacy for BNCT (Barth et al 1997). The second compound is L-4-dihydroxy-borylphenylalanine (BPA), developed at BNL (Snyder et al 1958). This compound is an analogue of a metabolic agent and cellular uptake can be achieved for selected cancers. BPA.fructose (Yoshina et al 1989) was developed to reduce acidity of the BPA.HCl injection in the melanoma trials in Japan (Mishima 1996). As BPA can pass the BBB, there is potential to cause serious radiation damage to normal brain in BNCT. The effect of BPA on mouse dopaminergic neurons was investigated in a unique Australian study (Setiawan et al 1995). The administration of L-10BPA had no permanent effect on dopaminergic tracts in the brains of injected mice. Neutron capture therapy in the mouse brain with L-10BPA caused a reduction in tyrosine hydroxylase immunohistochemical activity within 4 h of irradiation, but by 48 h, this reduction reversed. No damage was observed at 120 h post-irradiation. These results suggest that potential radiation damage may not be a problem should long term survivals be achieved. Uptake of BPA.fructose after iv bolus injection was studied in patients after resection of GBM and melanoma metastatic to the brain, tumour sections being analysed by inductively coupled plasma-atomic emission spectrometry (Mallesch et al 1994). Average tumour to blood ratios were 4.4(3.2), (maximum value 10) for 12 patients with melanoma metastatic R332 Review to the brain and 2.2 (1.2) for 6 GBM patients, the latter being too low to expect successful therapy. New boronated compounds and carriers were derived and investigated, including lipoproteins (Setiawan et al 1994) and thiouracil (Wilson 1990). Liposomal entrapped DBTU- 1 attained therapeutic concentrations in a melanoma xenograft (Allen et al 1992). Other agents have been investigated as boron carriers, such as monoclonal antibodies associated with cancer antigens (Tamat et al 1989b, Stretch et al 1992) and carboranyl and dihydroxycarboranyl phenylalanine (Prashar et al 1993a, 1993b). Other low and high molecular weight boron compounds have been reviewed elsewhere (Barth et al 2005). Boronated porphyrin derivatives were developed (Kahl et al 1996). The tetra- closocarboranyl derivative of protoporphyrin IX (BOPP) showed a lot of promise (Hill et al 1995) but on occasion proved to be toxic. BOPP was eventually produced in Melbourne and tested in photodynamic therapy of high grade brain tumour patients in a phase 1 trial (Rosenthal et al 2001). It was found to be safe at 4 mg kg−1, rather lower than required for BNCT. Promising efficacy against recurrent GBM at this dose was demonstrated using BOPP as a photodynamic therapy agent (Rosenthal et al 2003).

2.3.3. Gd-157. The rare earth isotope Gd-157 has a very large thermal neutron capture cross section (242 000 barns) leading to the emission of gamma rays, conversion electrons and Auger and Koster-Kronig electrons. As such, it can be used as an in situ internal gamma ray source for large tumours and a β-ray source for smaller tumours. If Gd-157 penetrates the nucleus, it can act as a high LET intra-nuclear source by virtue of the short range electron showers. Studies of thermal neutron capture in Gd-157 at the Lucas Heights reactor Moata demonstrated the generation of double strand breaks detected by agarose gel electrophoresis (Martin et al 1988), and corresponding dose distributions in tissue were calculated (Allen et al 1989c).

2.4. Clinical trials Phase I clinical trials are designed to determine the maximum safe dose of a therapy, while phase II trials test the efficacy. Clinical BNCT studies have tended to be in the phase I & II category, with great care being exercised not to approach the maximum tolerance dose too closely. However, if the patient survival is short (less than 12 months), then long-term effects may not be discovered. Should the therapy be effective in prolonging survival in phase II trials, then patients may be compromised by delayed radiation effects. Ultimately, there is a need for randomized clinical trials (Perry et al 1997), but these may be a long time coming. While Australian efforts to include an epithermal beam facility at the New Research Reactor at Lucas Heights (Allen 1993) were thwarted by a myopic neutron beam committee at ANSTO, there is now no shortage of clinical trials worldwide, with past and ongoing studies in the USA (Busse et al 2003,Diaz2003), Japan (Mishima 1996), (Kato et al 2004), The Netherlands (Moss et al 1990, Wittig et al 2002), Czech Republic (Burian et al 2002), Finland (Joensuu et al 2003), Sweden (Capala et al 2003), Italy (Pinelli 2002) and Argentina. BNCT has generally been directed against inoperable cancers, so GBM continues to be the targeted cancer (Barth 2003), although melanoma has been shown to be responsive to BNCT (Busse et al 2003,Mishima1996), as has extra-corporeal BNCT of colorectal cancer metastases in the liver (Pinelli 2002) and other cancers (Kato 2002). Results of BNCT clinical trials have recently been reviewed in detail, the best survival data from these trials being at least comparable to that for conventional therapy. Perhaps more importantly, the safety of epithermal BNCT has been established in several phase I trials (Barth et al 2005). However, Review R333 such progress is not enough to develop the required support from the radiotherapy community, for which substantial improvements in median survival would be needed, as well as hospital based treatment. On the other hand, even at this stage of its development, patients would benefit from the much shorter treatment time (1–2 dose fractions compared with 10–20 fractions for radiotherapy) and the non-invasive nature of palliative epithermal BNCT. It is often stated that to control tumours, every clonogenic cell must be killed. This is indeed a big ask for BNCT, because the range of the reaction products is about one cell diameter, so even microscopic cross fire will be ineffective for adjacent cells. Contiguous cells, however, are not spared as the alpha and Li-7 ions move in opposite directions. So does every tumour cell have to be reached by the targeting vector? If this is the case, then BNCT is unlikely to succeed in achieving complete responses. But anti-angiogenic therapy requires only the shutdown of capillaries, starving clonogenic cells and indirectly causing cancer cell death. Is this possible in BNCT? Can a tumour anti-vascular effect be present? A s f o r TAVAT ( s e e s e c t i o n 3.3), leaky neogenic tumour capillaries allow the extra-vascular diffusion of the boron agent to reach contiguous tumour cells. Then the thermalized neutron beam induces boron-10 fission and one of the two reaction products reach back to the capillary endothelial cells. A TAVAT effect could occur, but only with the nearest neighbour cancer cells in contact with the endothelial cells. Thus tumour anti-vascular NCT (TAVNCT) could cause the regression of tumours by regression of tumour capillaries, without the need to target and directly kill every clonogenic cancer cell in the lesion.

2.5. Japan-Australia workshops on NCT These workshops arose out of the common interest in the two countries in the treatment of melanoma by BNCT. Yutaka Mishima and the author organized workshops alternating between Kobe and Sydney (Allen et al 1989b). While Australia has the highest incidence of melanoma in the world, the type of melanoma arising in Japan was highly lethal. Subungual melanoma occurs under the finger nails and soles of feet. Professor Mishima, being a dermatologist extraordinaire, took up the challenge and led a very successful, multidisciplinary team in Japan to develop thermal NCT for subcutaneous melanoma. While BNCT is clearly a core application of in medicine, there was a lack of medical support at the Board level of the AAEC. This was despite a close encounter with Mishima’s famous Duroc pig, which not only survived BNCT, but also demonstrated complete regression of a 12 cm diameter skin melanoma (Mishima et al 1989).

3. Targeted alpha therapy

3.1. Background While BNCT was running strongly, with one 2 year conference after the other, a new high LET systemic therapeutic approach was slowly evolving. This approach, called targeted alpha therapy (TAT), incorporates the essential elements of cancer therapy, a targeting molecule that fixes to membrane bound molecules on the surface of cancer cells, and a toxic radiation that deposits a large fraction of energy into the targeted cell. There has been a slow but steady rate of alpha publications through the late 20th century, which clearly demonstrated the potential superiority of this therapeutic approach. One paper that stands out was the in vivo mouse study (Bloomer et al 1984) for mice with peritoneal ascites, which showed that only alpha radiation could lead to regression of the ascites, whereas beta emitters could not. This and other papers were the foundations for our extensive alpha research, which first began with R334 Review

Tb-149, the only lanthanide with a significant alpha decay branching ratio (Allen et al 2001a). The author presented this work at the Memorial Sloan Kettering Cancer Center (MSKCC), and received polite applause. Unknown to the author, MSK was already well down the track with the Ac:Bi generator, which has transformed the practicality of TAT. Tb-149 was later produced in clinical quantities at the ISOLDE facility, CERN (Beyer et al 2002)but,aswas evident in BNCT, it is not enough to have a superior idea if it is not eminently practical in its implementation. The MSK story is well worth telling. Westerners often believe that they live in organized societies where things are done on a rational basis according to need. In research, as distinct from development, this is far from the case. Many great discoveries have been made only because of the incredible drive and motivation of the inventors. There are indeed many great development stories, where almost unlimited funds are allocated in the perceived national interest, e.g. the Manhattan project for the A-Bomb, the Lunar space race and most recently the mapping of the genome. But not with alpha therapy. Even BNCT looks good compared with this. The interaction between principals in the Ac:Bi generator story shows that it is still necessary to outflank the opposition if success is to be achieved. So, David Scheinberg at MSK, having failed to control acute myeloid leukaemia (AML) with beta-emitting radiolabelled monoclonal antibodies, decided that alphas should be used. Failing to achieve support in the USA, Scheinberg approached the Institute for Transuranium Elements (ITU) in Germany, which agreed to import waste sludge from the U-233 enrichment program at ORNL, and separate out the Ac-225. This was sent back to MSK for the world first phase 1 clinical trial of TAT for AML. Since then, Ac-225 has become readily available in the USA, but recently at a price that severely inhibits R&D. ITU has continued to collaborate with research groups, and is a vital partner in the Australian story. Several private companies are now supplying alpha generators as well. No one in Australia, save for the author (Allen 1999b), has debated the need for TAT, but this is not now the case in the US and Europe where workshops and collective recommendations have been made that are influencing the development of the field.

3.2. In vitro and in vivo studies The properties of useful alpha-emitting radioisotopes have been reviewed (Zalutsky and Bigner 1996). Our effort is now based on Bi-213, which is eluted from the Ac-225 generator (Finn et al 1997). The short half life of Bi-213, being 46 min, precludes consideration of biological lifetimes of targeting vectors. Stable alpha conjugates were synthesized in our laboratory by labelling chelated monoclonal antibodies with Bi-213 to form the alpha immuno-conjugates (AIC). These were tested in vitro and in vivo for melanoma (Allen et al 2001b, Rizvi et al 2000), leukaemia (Rizvi et al 2002), colorectal (Rizvi et al 2001), prostate (Li et al 2004), ovarian (Song et al 2005) and pancreatic cancers (Qu et al 2005). The human recombinant PAI-2 protein was successfully tested in breast (Allen et al 2003), ovarian (Qu et al 2005), prostate (Li et al 2002) and pancreatic (Qu et al 2005) cancers. These conjugates are highly selective of and cytotoxic to targeted cancer cells. In vitro cytotoxicity of alpha conjugates is very much greater than beta conjugates, non-specific alpha conjugates and free alpha isotope. The lethal pathway for alpha therapy is predominantly apoptosis (Li et al 2004). The short range of alpha particles, and the short half life of useful alpha emitting radioisotopes argue against TAT being at all effective in regressing tumours (Allen 1999a). Consequently, our studies related to the killing of isolated cancer cells and cell clusters and the inhibition of tumour growth. To this end we developed the 2 day mouse model, where treatment followed 2 days post-inoculation of cancer cells. Mice were then followed until tumours reached ∼1cm3. In all cases, complete inhibition of tumour development was Review R335 achieved with 75–100 µCi local sc injection (i.e. in the same location as the cell inoculation). Higher activities were required for systemic (tail vein or intraperitoneal) injection of the AIC. However, efficacy decreases for longer growth times and larger tumours, but can be partially offset by multiple dosing. Mice were allowed to grow melanomas and these were then injected with the AIC for melanoma. Intralesional alpha therapy was performed on these human melanoma xenografts in nude mice (Allen et al 2001b), and showed complete tumour regression over 4–8 weeks. Intralesional TAT of melanoma with 300 µCi gave complete regression of melanoma xenografts in nude mice, but was far less successful in breast and prostate tumours. These results paved the way for the intralesional phase 1 clinical trial (Allen et al 2006), wherein the mouse host for the human melanoma was simply exchanged for a human host. Activity tolerances are in the region of 24–36 mCi kg−1 for systemic (ip) injections. However, long term toxicity (∼6 months in mice) in the form of delayed radiation nephrosis, reduces the MTD to ∼9mCikg−1 in mice and between 3 and 9 mCi kg−1 in rabbits. Note that the measured gamma decay rate was reported in our earlier papers, whereas here the actual activity, which is also the alpha activity, is reported here. While kinetics and bio-distributions will depend on the type of vector used, the melanoma trial provided the basic data to determine specific organ doses for comparison with threshold dose levels and the probability of induced secondary cancer. These data are of considerable value in ensuring patient safety in further systemic phase 1 clinical trials.

3.3. Clinical trials The advantage of internal alpha radiation has been known for some time now, but only in recent years has targeted alpha therapy achieved clinical trial status. Even so, there are few completed and current trials; namely a completed phase I study for AML (Jurcic et al 2002) and an ongoing phase II study for post-chemotherapy TAT of AML at MSK; a completed phase 1 trial for intralesional melanoma (Allen et al 2006) and a current systemic melanoma at SGH; glioblastoma at Duke University (Zalutsky 2005), a completed trial for bone metastases in Norway (Nilsson et al 2005) and a current trial for lymphoma at Dusseldorf (Miederer et al 2003). While solid tumours have never been envisaged as suitable targets for TAT, in contrast with liquid cancers and micrometastases (Allen 1999a), stage 4 advanced cancer patients are used in phase 1 trials for toxicity studies. Intralesional TAT for melanoma in human patients was found to be safe and effective to 1350 µCi (Allen et al 2006). Tumours were resected at 8 weeks post-ITAT, to show massive cell debris in the injected volume, but no effect in untreated tumour or in the antibody alone tumour in the same patient. Tumour to kidney activity ratios were ∼3000. As such, intralesional TAT for inoperable ocular melanoma and brain metastases could be indicated. The intralesional melanoma trial and our current systemic melanoma trial use the 9.2.29 mab to target the melanoma-associated chondroitin sulfate proteoglycan (MCSP) receptor expressed by lesions of more than 90% of melanoma patients. This antigen is the same as the HMWMAA and thought to be similar to the NG2 murine antigen. The antibody is covalently coupled to the cDTPA chelator, and labelled with the Bi-213 alpha emitting radioisotope. The objective of these phase 1 trials with stage 4 melanoma patients was to determine the safety of the AIC, and so far complications of any type or level have not been observed up to 25 mCi. However, unexpected tumour regressions have been observed at quite low doses, such that a new concept was introduced to explain the clinical responses observed after systemic alpha therapy, called tumour anti-vascular alpha therapy (TAVAT). Leaky neogenic capillaries allow extra-vascular diffusion of the AIC to target antigens on R336 Review contiguous pericytes and cancer cells. Alpha emission kills the capillary endothelial cells, shutting down the capillaries with subsequent starvation of the tumour.

4. Conclusions

BNCT is alive and well, with results comparable to conventional therapy. From the patient point of view, palliative treatment could be considered to be preferable because of its short duration and low toxicity. The epithermal beam is now well established and adequate for the task, but new boron compounds are needed to improve selective uptake in cancers. The TAVNCT concept opens a new direction for further research. Accelerator neutron sources would help the introduction of BNCT in the hospital environment. TAT is progressing well with an ongoing phase 2 trial for AML at MSK, and the first indications of tumour regression by TAT have been observed in the phase 1 melanoma trial at SGH. Such successes have withstood serious setbacks on the local and international stage. BNL, the most successful BNCT laboratory, ran foul of tritium in the ground water and politics and the BMRR was closed. The INEL effort, of fundamental importance to the development of the epithermal beam and dose planning, was unsuccessful in implementing its own therapy program. The UKAEA shut down its DIDO reactors, curtailing the British effort in the field. In TAT, MSKCC had to obtain its first supply of Ac-225 via Germany, and later the US Government put the price of Ac up by a factor of 3. The role of the individual scientist has never been so important in overcoming the many obstacles that impede progress.

Acknowledgments

This review covers some 25 years of R&D from an Australian perspective. Apart from the stimulating interactions and friendships with many overseas scientists and clinicians, there have been many essential Australian collaborations. NCT is a multi-disciplinary science, and I am grateful to Douglas Moore and Gerald Wilson in chemistry, Roger Martin and Keith Brown in radiobiology, Baiba Harrington and Greg Storr in neutronics, Anatoly Rosenfeld and Harry Meriaty in and Ned Blagojevic in body composition. Of special importance were our dedicated and talented PhD students Swasano Tamat, Yohanes Setiawan, Julia Mallesch, Steven Wallace and Martin Carolan. In addition, I am grateful to the many co-authors of our BNCT papers who contributed their specialist knowledge to our collective endeavours. The TAT project needs the skills of many colleagues; Syed Rizvi in radiochemistry, Chand Raja in clinical trials, Yong Li in immunology and past and present PhD students Syed Rizvi, Chang Fa Qu and Emma Yanjun Song. Clinical collaborators are Peter Graham and John Kearsley at St George Hospital, Ross Smith at Royal North Shore Hospital and John Thompson at Royal Prince Alfred Hospital. Our project depends heavily on support from Alfred Morgenstern and Christos Apostolidis at the Institute for Transuranium Elements (ITU), Germany. The acknowledgements would not be complete without noting the extensive grant support for our TAT program by the USDOD, which has complemented the lack of support from Australian funding agencies. In particular, antisense acknowledgements are due to ANSTO for shutting down the unique Moata reactor thermal neutron source, and failing to implement an epithermal beam facility for the new research reactor. ANSTO also failed to support the development of TAT for cancer, neglecting core activities in nuclear applications to medicine. That we were able to go from test tube to bedside is in no small measure a result of tenacity and good luck rather than scientific virtue. Finally, I would like to acknowledge the contributions of Ralph Review R337

Fairchild, Hiroshi Hatanaka and Borje Larson, all giants in the NCT field, whose research contributions and leadership roles were cut far too short.

References

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Kitao K 1975 A method for calculating the absorbed dose near the interface from 10B(n,alpha)7Li reaction Radiat. Res. 61 304–15 Kobayashi T, Sakurai Y, Kanda K, Fujita Y and Ono K 2000 The remodeling and basic characteristics of the heavy water neutron irradiation facility of the Kyoto University Research Reactor, mainly for neutron capture therapy Nucl. Technol. 131 354–78 Kononov O et al 2002 Investigations of using near-threshold 7Li(p.n)7Be reaction for NCT based on in-phantom dose distribution Research and Development in Neutron Capture Therapy ed M W Sauerwein, R Moss and A Wittig (Bologna: Monduzzi Editore, International Proceedings Division) pp 241–6 Li Y, Cozzi P J, Qu C F, Zhang D Y, Abbas Rizvi S M, Raja C and Allen B J 2004 Cytotoxicity of human cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate Cancer Lett. 205 161–71 Li Y, Rizvi S M A, Ranson M and Allen B J 2002 213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model Br. J. Cancer 86 1197–203 Mallesch J L, Moore D E, Allen B J, McCarthy W H, Jones R and Stening W A 1994 The pharmacokinetics of p-Boronophenylalanine.fructose in human patients with glioma and metastatic melanoma Int. J. Radiat. Oncol. Biol. Phys. 28 1183–8 Martin R F, D’Cunha G, Pardee M and Allen B J 1988 Induction of double-strand breaks following neutron capture by DNA-bound 157Gd Int. J. Radiat. Biol. 54 205–8 Miederer M et al 2003 Comparison of the radiotoxicity of two alpha-particle-emitting immunoconjugates, terbium- 149 and bismuth-213, directed against a tumor-specific, exon 9 deleted (d9) E-cadherin adhesion protein Radiat. Res. 159 612–20 Mishima Y 1996 Selective thermal neutron capture therapy of cancer cells using their specific metabolic activities— melanoma as prototype Cancer Neutron Capture Therapy (New York: Plenum) pp 1–26 Mishima Y, Ichihashi M, Hatta S, Honda C, Yamamura K and Nakagawa T 1989 New thermal neutron capture therapy for malignant melanoma: melanogenesis-seeking 10B molecule-melanoma cell interaction from in vitro to first clinical trial Proc. 2nd Japan-Australia International Workshop on Thermal Neutron Capture Therapy for Malignant Melanoma (Kobe, 1987) Pigment Cell Research vol 2 pp 226–34 Moore D E, Stretch J R, Dawes A C, Cockayne D, Allen B J and Constantine G 1990 Uptake of boronated monoclonal antibodies by melanoma cells visualised by track etch autoradiography and electron energy loss spectroscopy Progress in Neutron Capture Therapy for Cancer ed B J Allen, D E Moore and B V Harrington (Sydney: Plenum) pp 335–8 Morris G M, Coderre J A, Hopewell J W, Micca P L and Rezvani M 1994 Response of rat skin to boron neutron capture therapy with p-boronophenylalanine or borocaptate sodium Radiother. Oncol. 32 144–53 Moss R, Stecher-Rasmussen F, Ravensburg K, Constantine G and Watkins P 1990 Design, construction and installation of an epithermal neutron beam for BNCT at the high flux reactor Petten Progress in Neutron Capture Therapy ed B J Allen, D E Moore and B V Harrington (New York: Plenum) pp 63–6 Nigg D, Wheeler F J, Wessol D E, Capala J and Chadha M 1997 Computational dosimetry and treatment planning for boron neutron capture therapy of glioblastoma multiforme J. Neurooncol. 33 93–104 Nigg D et al 2002 Initial neutronic performance assessment of an epithermal neutron beam for neutron capture therapy research at Washington State University Research and Development in Neutron Capture Therapy ed M W Sauerwein, R Moss and A Wittig (Bologna: Monduzzi Editore, International Proceedings Division) pp 135–9 Nilsson S, Larsen R H, Fosså S D, Balteskard L, Borch K W, Westlin J E, Salberg G and Bruland O S 2005 First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases Clin. Cancer Res. 11 4451–59 Perry J et al 1997 Challenges in the design and conduct of phase III brain tumor therapy trials Neurology 49 912–17 Pinelli T et al 2002 TAOrMINA: from the first idea to the application to the human liver Research and Development in Neutron Capture Therapy ed W Sauerwein, R Moss and A Wittig (Bologna: Monduzzi) pp 1065–72 Prashar J K and Moore D E 1993a Synthesis of carboranyl phenylalanine for potential use in neutron capture therapy of melanoma J. Chem. Soc. Perkin Trans. 1 1051–3 Prashar J K, Lama D and Moore D E 1993b Synthesis of dihydroxycarboranyl phenylalanine for potential use in neutron capture therapy of melanoma Tetrahedron Lett. 34 6799–800 Qu C F, Song E Y, Li Y, Rizvi S M, Raja C, Smith R, Morgenstern A, Apostolidis C and Allen B J 2005 Pre-clinical study of 213Bi Labeled PAI2 for the control of micrometastatic pancreatic cancer Clin. Exp. Metastasis 22 575–86 Riley K, Binns P and Harling O 2003 Performance characteristics of the MIT fission converter based epithermal neutron beam Phys. Med. Biol. 48 943–58 R340 Review

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Biography

Barry Allen is the Director, Centre for Experimental Radiation Oncology at St George Cancer Care Centre and Conjoint Professor at the Clinical School, UNSW. Previously, he worked at ANSTO as a Chief Research Scientist, investigating neutron capture mechanisms and their relationship to stellar nucleosynthesis and cross section data for fast reactors. In the early 1980s Professor Allen turned his attention to the application of neutrons in medicine. He began R&D programs in boron neutron capture therapy (BNCT) for cancer and in vivo body composition (IVBC) for medicine, and assembled multidisciplinary teams that made major contributions to both these fields. Professor Allen made the first human body protein measurements in Australia, in collaboration with Sydney hospitals, and the prototype Body Protein Monitor was installed at RNSH, where it continues to operate today. He was elected President of the International Society for Neutron Capture Therapy and convened the Fourth International Symposium in Sydney in 1990. The targeted alpha therapy (TAT) project was started at St George Hospital, where Professor Allen put together a small multidisciplinary team with US funding. This program was particularly successful in developing new therapeutic agents for the treatment of melanoma, leukaemia, breast, prostate and colorectal cancer. Some 35 papers have now been published in international journals on this topic, including the world first trial of intralesional TAT for melanoma. A phase 1 trial in of systemic TAT for melanoma began in 2004. Professor Allen has published some 300 papers in neutron capture gamma rays, resonance cross sections, stellar nucleosynthesis, in vivo body composition, boron neutron capture therapy, macro and micro-dosimetry, microbeams and targeted alpha therapy. Successful collaborative grant applications total some $4.4 million. He is a Fellow of the ACPSEM (1992) and of the Institute of Physics (1999). He convened the International Congress on Medical Physics and Biomedical Engineering in 2003 at Sydney, is President of the Asia Oceania Federation of Medical Physics and President-Elect of the International Organisation of Medical Physics.