Future Prospects for Targeted Alpha Therapy

Current Radiopharmaceuticals, 2011, 4, 000-000

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Future Prospects for Targeted Alpha Therapy Barry J. Allen Centre for Experimental Radiation Oncology, St. George Cancer Centre, Gray St Kogarah NSW 2217 Australia Abstract: The objectives in the application of targeted alpha therapy (TAT) for cancer therapy are reviewed. These relate to elimination of isolated cancer cells, cell clusters and tumors. Requirements for isolated cancer cells are good cellular targeting, high specific activity, and very short range. The regression of cell clusters in the peri-vascular space requires high capillary permeability and short range cross fire whereas for developed tumors, good bioavailabilty and anti- capillary activity are essential. Current sources of alpha radiation are reviewed and the prospects for commercial sources for clinical application are discussed. The Ac:Bi generator is the most practical alpha source, bringing therapy to Nuclear Medicine with the same practicality as the Mo:Tc generator has for imaging. The status quo of TAT is briefly reviewed with respect to dose normalization, real time microdosimetry and biological dosimetry for deterministic and stochastic effects and toxicity. The role of Monte Carlo calculations is emphasized. The strengths and weaknesses of TAT are examined and the way forward for clinical acceptance is discussed.

Keywords: Targeted alpha therapy, alpha sources, clinical trials, radioisotopes, monoclonal antibodies, tumor vasculature, tumor anti-vascular alpha therapy, microdosimetry, biological dosimetry, Monte Carlo calculations, toxicity. 1. THE STATUS QUO

CD20 (Ibritumomab, Ofatumumab)

1.1. Monoclonal Antibodies

CD52 (Alemtuzumab)

Since the development of the hybridoma [1], monoclonal antibodies (MAb) have been raised against many antigens over-expressed by cancer and other cells [2]. Most of these MAbs are benign with little antibody-dependent cellmediated cytotoxicity (ADCC), caused by lysis of antibodycoated target cells by effector cells with cytolytic activity and Fc receptors. Cell-mediated cytotoxicity arises from cytolysis of a target cell by effector lymphocytes, such as cytotoxic T lymphocytes or NK cells and may be antibodydependent or independent. Another limitation relates to the expression of the targeted antigens being only on a subset of cancer cells. Some antibodies work by neutralizing or blocking receptors, and these tend to be the more effective.

CD33 (Gemtuzumab)

The following antigens and MAbs have been approved by FDA for clinical use:

ErbB: HER1/EGFR (Cetuximab, Panitumumab) HER2/neu (Trastuzumab) EpCAM (Catumaxomab, Edrecolomab) VEGF-A (Bevacizumab) Rituximab (Tositumomab)

*Address correspendence to this author at the Centre for Experimental Radiation Oncology, St. George Cancer Centre, Gray St Kogarah NSW 2217 Australia; E-mail: [email protected]

1874-4710/11 $58.00+.00

The major therapeutic antibodies on the market are Avastin®, Herceptin® (both oncology), Humira®, Remicade® (both Autoimmune and Infectious Disease ‘AIID’) and Rituxan® (oncology and AIID) and accounted for 80% of revenues in 2006. Benign or partial blocking MAbs that are cancer cell specific can still be effective if labeled with a toxin. Then the MAb becomes a targeting vector to take the toxin to the targeted cancer cells. In such cases, the half life of the MAb in the body should preferably match the half life of the toxin. Toxins can be chemicals or radioisotopes and are mostly chelated to the MAb to form relatively stable immunoconjugates. Chemical toxins can have long half lives in the body (e.g. ricin) which increases their toxicity for normal tissue. Radioisotopes have both a wide range of half lives and radiation decay properties. Nuclear imaging uses long lived -emitters, allowing blood clearance as the tumor increases its uptake of the conjugate over time, so improving contrast. 131I and 123I, 201Tl, 67 Ga and 111In are some reactor and cyclotron produced radioisotopes for this purpose. Beta-emitting radionuclides, predominantly 131I, are used for therapy. The radioisotopes are generally conjugated with a bi-functional chelator attached to the targeting antibody to form the radioimmunoconjugate (IC). However, the early success of emitting radioimmunotherapy has been modest [2]. © 2011 Bentham Science Publishers Ltd.

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In recent times high linear energy transfer (LET) radiation in the form of auger electrons and alphas particles have been studied. Auger and Coster-Kronig electron transitions cause the emission of multiple low energy and very short range electrons, such that the LET can still be high. However, the short range requires access into the nucleus to cause single (SSB) and double (DSB) strand breaks in the DNA. Alpha particles have ranges up to ~80 m and the radioisotope sources can be located on cell membranes or nearby cells. The LET is typically ~100 keV/m with a high probability of causing DSBs (although the ratio SSB/DSB ~20, compared with ~60 for low LET radiation) [3]. Alpha radiation is ideal for killing isolated cancer cells in transit in the vascular and lymphatic systems and for inducing tumor regression by killing tumor capillary endothelial cells. Apoptosis [4] is the dominant form of cell death with high LET radiation. A programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area. Apoptosis plays a crucial role in developing and maintaining health by eliminating old cells, unnecessary cells, and unhealthy cells. Over the past 20 years targeted alpha therapy (TAT) has progressed from in vitro studies, through in vivo experiments and on to clinical trials. The radiobiology and microdosimetry is well understood but the key to its application is in the biological targeting. The dose to normal tissues always provides a limitation to the injected dose and that received by the tumor. It is the ability of TAT to achieve cancer regression within the maximum tolerance dose (MTD) for normal tissue. Pretargeting is one way to get round this limitation. The basis of pretargeting is the initial administration of a modified antibody that accumulates in the target tumor over 24-48 hours as it slowly clears from the circulation. A radioactive ligand is then injected which quickly binds to the antibody sequestered in the tumor, while being cleared by renal filtration. See Lindgren et al in this hot-topic issue. TAT was originally thought to be an ideal therapy for “liquid” cancers, eg leukaemia and micrometastases, as the short half lives of the radioisotopes was sufficient to target these blood borne cancer cells and the short range ensured that the targeted cancer cells received the highest radiation dose. The difficulty of proving efficacy against micrometastic disease cannot be underestimated [5] but phase 1 trials of end stage AML cancer patients have established the deterministic tolerance dose and provided evidence of efficacy. The hypothesised tumor antivascular -therapy [6] offers the potential of shutting down leaky tumor capillaries and so inhibiting tumor growth. This effect has been ascribed to tumor regressions observed in a phase 1 trial of TAT for metastatic melanoma. It is now appropriate to consider that TAT can be applied to high risk subjects in remission, for whom recurrence is likely to arise from subclinical disease, as well as end stage patients for palliative therapy. Perhaps the most appropriate application could be for post-hormonal therapy in prostate cancer, when the PSA is at its nadir. TAT could target the

Barry J. Allen

hormone insensitive cells that survive and lead to fatal outcomes. Alpha radiation is a very effective in causing DNA damage and when targeted can be highly cytotoxic to cancer cells. With energies from 2-8 MeV and ranges of 20-80 m, -emitting radioisotopes can deliver high linear energy transfer radiation with increased rates of double strand breaks that can induce apoptosis in cells within the -particle range. However, because of this, if mismatch DNA repair occurs, then -radiation has a much higher probability (~20) of causing genetic damage and secondary cancer than electrons or photons. 1.2. Alpha Sources A great deal of preclinical work paved the way for the advance to clinical trials in recent years. In the clinical setting, the Sloan Kettering Memorial Cancer Center has led the way, first with the application of 213Bi immunotherapy and more recently with 225Ac. Other laboratories have studied 149 Tb, 211At and 212Bi. The advantages of the Bi radioisotopes are that they can be generated from long lived parents, 225Ac with 10 d and 228Th with 1.91 y half lives generators can be imported from overseas production centers. The Ac-Bi generator has an additional advantage in that it decays in house and does not need long term waste disposal as is the case for 228 Th. The properties of -emitting radioisotopes and chelators for radiolabeling are reviewed by Wilbur et al in this hot-topic issue. 211

At, with a 7.2 h half life, needs to be used at or near the 30 MeV cyclotron production site. 149Tb must be produced by a GeV synchrotron. However, such accelerator facilities are quite appropriate for localised clinical trials. While the half lives of 213Bi (46 min) and 212Bi (61 min) are rather short, there is sufficient time for synthesis of the alpha-immuno-conjugates, and for vascular distribution throughout the body. Uptake data for acute myelogenous leukaemia is very fast, saturating at ~10 min post-injection. There is, however, inadequate time for infusion into tumors, which can take 24-48 hours. This is one reason for the development of the 225Ac alpha conjugate, as the 10 d half life allows plenty of time for infusion through the target tumors. Further, 225Ac decays by the emission of 4 alpha particles, producing the most toxic, short range radiation known. However, the short range of the alpha products requires a high degree of homogeneity if all tumor cells are to be neutralised. Thus a limitation will lie in the need for uniform uptake in tumors and in the tumor to tissue dose ratio, because of toxicity to normal cells within range. On the other hand, 225Ac would be very effective in tumor antivascular alpha therapy [6] by killing tumor capillary endothelial cells and depriving tumors of oxygen and nutrition. Targeting constructs must be specific for the cancers to be treated. As such, a number of constructs are being used or are to be introduced into the clinic and are reviewed by Olafsen et al in this hot-topic issue. The following monoclonal antibodies (MAb) are in use as immunoconjugates: Humanised HuM195 targets acute myelogenous leukaemia [7]

Future Prospects for Targeted Alpha Therapy

Murine 9.2.27 targets the MCSP antigen on melanoma cells and pericytes [8] Anti-CD20 for lymphoma [9] Human-mouse chimeric anti-tenascin 81C6 for glioblastoma multiforme (GBM) [10] Substance p for GBM [11] MX-35 F(ab´)2 for ovarian cancer [12] In the case of bone cancer, RaCl2 has a natural affinity for bone. It is the first alpha agent to be taken up by industry, which is funding a world wide clinical trial for palliative therapy of breast and prostate cancer in the bone.

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2. THERAPEUTIC OBJECTIVES The primary objective in immunotherapy is to increase efficacy by improving delivery and specificity. At the same time, toxicity must be reduced to allow increased doses to be delivered to control the target cancer. Cancer management begins with surgery to remove solid tumors, radiotherapy to control local tumor and reduce local recurrence (as in postlumpectomy for breast cancer) and chemotherapy to control systemic disease or for palliation. Immunotherapy is a developing approach that could make a major contribution to the management of cancer. There are three separate objectives that must be addressed:

Other proposed vectors with promising preclinical performance are:

1. Kill isolated cancer cells in transit in the lymphatic and vascular circulation.

The small protein PAI2 against uPA, which is widely expressed by many cancers at their most malignant stage [13]. However, PAI2 runs the risk of renal uptake but may have the benefit of higher permeability in leaky tumor capillaries.

2. Regress pre-vascular and lymphatic lesions.

C595 is a murine MAb against MUC-1 [13] and is also of generic nature.

These cells have special problems relating to cell cycle and bioavailability.

The polysaccharide capsule binding MAb 18 B7 is proposed for fungal infection [14].

Cells may be outside the cell cycle in the G0 phase. As such they are relatively insensitive to radiotherapy and chemotherapy.

Recent or current clinical trials include [15]:

3. Regress vasculature and tumors. Each objective requires a different approach. 2.1. Isolated Cancer Cells

Phase 1 trials of 213Bi immunoconjugates for studies in acute myelogenous leukaemia (AML) [7], melanoma [8,16], lymphoma [9] and glioma [11], as reviewed by Morgenstern et al in this hot-topic issue.

Systemic cancer targeting is required, but only a small fraction of the dose will reach its target so short range cytotoxic action is essential to reduce normal tissue damage, which will be the dose limiting factor.

Phase 2 trial of 225Ac for AML (see Scheinberg et al in this hot-topic issue)

High labeling efficiency is required to reduce saturation of targeted antigens by unlabelled MAb.

Phase 1 trial of 223Ra for bone cancer (see Vaidyanathan et al in this hot-topic issue) Phase 1 trials of 211At for GBM [10] and ovarian cancer [12] (see Zalutsky et al and Vaidyanathan et al in this hot-topic issue). The original 213Bi AML trial has been completed and the current trial is phase 2 with chemotherapy pre-treatment. The intralesional melanoma trial with 213Bi has also been completed, being followed by a systemic trial with the same alpha conjugate. Forty-two subjects were enrolled with data available for 38. While there was no evidence of adverse events, significant responses were observed as follows: 10% near complete or partial; 40% stable disease, 50% progressive disease and 13% long term survival. Survival was found to be independent of the injected activity up to 25 mCi (~0.3 mCi/kg), suggesting that a key determinant for survival had been missed. These responses were ascribed to the variable tumor capillary permeability. These activities are very much less than the MTD found for 213Bi-HuM195 conjugate of ~1 mCi/kg bodyweight.

Short half life is preferred as cells in the vascular system can be reached quickly. The long half life of chemotoxins in the body is not indicated for such targets. As such, alpha radiation is best suited for the toxic agent. Lymphatic administration may be essential to eliminate cells in transit from primary lesions. The therapeutic response is difficult to determine. However, magnetic cell separation of cancer cells in the peripheral blood with the magnetic microspheres coated with the targeting MAb could solve this problem [17]. 2.2. Cell Clusters These occur when the cell cycle is switched on in the appropriate seed/soil environment. However, endothelial cell growth factors expressed by cancer cells are still insufficient to stimulate the vascular extensions into the lesion. Clusters can only be reached by non-vascular transport. Long range cross fire, as for betas, is not indicated but useful short range cross fire can occur for alphas [18]. Chemical toxins have no cross fire effect and would be much less effective in cell clusters with limited penetra-


tion. The long half life of chemotoxins in the body is not indicated for such targets. 2.3. Tumors Tumor capillary permeability is an important parameter that determines in part the bioavailability of the cancer cells in a tumor. Leaky neogenic capillaries allow the extravasation of the IC into the perivascular space to saturate the targeted antigens expressed by contiguous and adjacent cancer cells. Long range cross fire effect gives -radiation an important advantage and reduces the effect of heterogeneous uptake of the -IC in the tumor. Intralesional injections with -ICs can overcome this problem but may not be indicated for systemic disease. Chemotoxins will suffer from bioavailability and the lack of a cross fire effect. The potential role of the bystander effect [19] could be of benefit here. This radiation-induced phenomenon causes unirradiated cells to exhibit effects as a result of signals received from nearby irradiated cells, causing a mutation in the nucleus of the hit cells. Cells that that are not directly hit by an -particle, but are in the vicinity of one that is hit, may also contribute to the genotoxic response of the cell population. In vitro studies show that when the medium containing irradiated cells is transferred to unirradiated cells, these cells show bystander responses when assayed for clonogenic survival and oncogenic transformation. Tumor capillary permeability causes a high density of IC labeled antigens around the capillaries, with a rapid drop off with distance from the capillaries. Whereas this is a drawback for -emitting ICs, it enhances the toxicity of -ICs to the capillary endothelial cells. The short range (~80 m) of the emitted -radiation ensures a high radiation absorbed dose to the endothelial cell nucleus, inducing apoptosis. The capillary will close and if enough such capillaries close down, the tumor will regress. This process is called tumor antivascular alpha therapy (TAVAT) and explains the tumor regressions observed in the phase 1 clinical trial of systemic TAT of metastatic melanoma [6]. This process could be assisted by tumor vascular disruption agents that increase tumor capillary permeability. 3. WHAT NEEDS TO BE DONE? 3.1. Adjuvant Therapy While TAT is a nuclear medicine procedure, it is complementary to external beam radiotherapy (EBRT), for which radiation oncologists employ ever more complex and precise irradiation modalities. While management is often improved, mortality may not be changed. On the other hand, those cancers (e.g. GBM) with poor control and prognosis remain intractable to EBRT. Even in relatively simple applications as in primary prostate cancer, EBRT cannot spare the nerve bundles and incontinence and impotence are relatively common adverse events. As such, the role of TAT as an adjuvant therapy designed to spare critical tissues needs to be investigated.

Barry J. Allen

3.2. Dose Normalisation The clinical trials reviewed above are indeed very promising. However, there are already discrepancies in the normalisation of administered dose. Dose is given per unit surface area or per kg body mass. Both of these units need to be re-evaluated. MAbs are hydrophilic and, as such, relate to neither of these quantities. Rather, it is the fat free mass which could be considered to be more appropriate. This can be estimated by dual x-ray absorptiometry (DXA) or less accurately by skin fold measurements. With this normalisation of dose, obese patients will be less likely to be underdosed and lean subjects over-dosed. The concentration of Ab in the blood and tissues is determined by the volume of distribution. This is the apparent volume in which a drug is distributed immediately after it has been injected intravenously and equilibrated between plasma and the surrounding tissues to produce the concentration in plasma. The volume of distribution has nothing to do with the actual volume of the body or its fluid compartments but rather involves the distribution of the drug within the body. For drugs that are highly tissue-bound, comparatively little of a dose remains in the circulation to be measured; thus, plasma concentration is low and volume of distribution is high. Drugs, such as MAbs, that remain in the circulation tend to have a low volume of distribution. The volume of distribution provides a reference for the plasma concentration expected for a given dose but provides little information about the specific pattern of distribution. Each drug is uniquely distributed in the body. Some drugs distribute mostly into fat, others remain in the extra-cellular fluid (ECF), (i.e. the liquid containing proteins and electrolytes) and others are bound extensively to specific tissues. Many basic drugs (e.g. amphetamine, meperidine) are extensively taken up by tissues and thus have an apparent volume of distribution larger than the volume of the entire body. The extent of drug distribution into tissues depends on the extent of plasma protein and tissue binding. Many acidic drugs (e.g. warfarin, aspirin) are highly protein-bound and thus have a small apparent volume of distribution. In the bloodstream, drugs are transported partly in solution as free (unbound) drug and partly reversibly bound to blood components (e.g. plasma proteins, blood cells). Of the many plasma proteins that can interact with drugs, the most important are albumin, 1-acid glycoprotein, and lipoproteins. At high drug concentrations, the amount of bound drug approaches an upper limit determined by the number of available binding sites. Saturation of binding sites is the basis of displacement interactions among drugs. 3.3. Monte Carlo Calculations Monte Carlo calculations can be used to elicit the specific energies deposited in the nuclei of cells in organs and targeted cancers. However, the anatomical modelling of the target volume needs to precisely represent the anatomical region. A prime example would be the irradiation of the kidney cortex or glomerulus by -sources, either the radioisotopes alone or small MW (< 60 kDa) conjugates filtered out of the blood by the kidneys. Another example is the calcula-

Future Prospects for Targeted Alpha Therapy

tion of -particle absorbed dose to tumor capillary endothelial cells in the perivascular region to explain the tumor antivascular alpha therapy effect. These calculations can then provide data on cell kill and ultimately organ failure. Such calculations can also provide information on the stochastic processes that give rise to secondary cancer. These data can then support pharmacokinetic modelling to assess localized dose-rates and convert those dose-rates to integrated absorbed dose. 3.4. Alpha Dosimetry In -radiation therapy the Medical Internal Radiation Dose (MIRD) method can be used to determine the radiation absorbed doses in the target and other organs. This is not the case for -radiation as the actual location of the emitter determines the absorbed dose delivered on the microscopic scale. The short range and uncertain biodistribution of the AIC in the body presents a difficult dosimetry problem. Imaging agents cannot identify the location of the AIC at the micrometre level, as would be required for accurate dosimetry. The actual doses delivered at the micrometre scale can be much larger or much smaller than the average absorbed dose, depending on the targeting of specific receptors. Real time dosimetry may be achievable with MOSFET (metal-oxide semiconductor field-effect transistor) microdosimeters that can provide information on the millimetre scale. Such dosimeters are small enough to be placed into orifices or surgically into tissue, these applications having obvious disadvantages. 3.5. Biological Dosimetry Off line biological dosimetry can be implemented by inducing damaged lymphocytes to divide and form micronuclei in the mitotic state. These micronuclei result from DSBs in the DNA, which form discrete entities of phospholipid bilayered-enclosed DNA fragments within the lymphocyte prior to division [20]. Can the biological dose measured by the micronuclei be assumed to be the whole body dose? It is certainly the dose to the blood volume and to the vascular walls. The AIC, being a large molecule, is not expected to diffuse through the vascular walls and so the activity remains limited to the vasculature which, however, includes the bone marrow. An alternative approach is biological dosimetry. One approach is to use radiation induced micronuclei in lymphocytes as a direct measure of the biologically effective dose. Lymphocytes in the peripheral blood are exposed to background alpha and beta radiation on systemic administration of the AIC. The AIC is designed to target the cancer cells, not the lymphocytes and as such background dose levels are expected to be low. However, there will be random hits of lymphocytes by untargeted alpha decays of the radioisotope in the blood. Post-irradiation peripheral blood is taken and lymphocytes induced to divide at different times. Cells that have suffered DSBs of their chromosomes will exhibit both large and small sections, which may or may not recombine


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over time. The small sections may form as micronuclei on induction of mitosis, which can be observed by staining and counting by microscope and/or automated shape recognition programs. Results for different post-irradiation times are compared with benchmark values before exposure. Repair processes are observed to reduce the micronuclei count after a week of so. This biological dosimeter provides a direct measure of stochastic radiation damage without the need to measure absorbed dose and determine RBE factors. The relationship to genetic damage and secondary cancer needs to be investigated. Initial studies of this effect were made in mice using the 213Bi-cDTPA-9.2.27 -immunoconjugate [21]. Mice received an intraperitoneal injection of 16.65 MBq of AIC and mutant frequency and spectra were analysed for the brain, spleen and kidneys. Elevated but non-significant frequencies above background were observed for the kidneys but not for brain or spleen. Results were time dependent, returning to background 4 weeks post-irradiation but with predominant residual size mutations that could cause secondary cancer. Further research is needed to quantify these effects. The equivalent dose is defined to take into account the ICRP (International Commission on Radiological Protection) radiation weighting factor of 20 because -particles are ~20 time more likely to cause cancer and other stochastic effects for the same absorbed dose of electrons or photons. The effective dose is a weighted average of individual organ equivalent doses. Both equivalent and effective dose values are associated with the unit Sievert (Sv). However, the relevant end-points for treatment evaluation (i.e. toxicity and efficacy) are deterministic for which the end-points for -particle radiation have 3-7 times more toxicity or efficacy per unit absorbed dose than electrons or photons. The factor used to weight the absorbed dose for deterministic end-points is the relative biological efficacy (RBE). As such, the unit for the so far undefined biological absorbed dose is Gy, not the Sv. It is recommended that the absorbed dose (in Gy) should be listed separately for (electrons and photons) emissions and for -particle emissions (see Sgouros et al in this issue). 3.6. Toxicity Clinical determinations of the maximum tolerance dose (MTD) for different -emitting radioisotopes and antibodies are still insufficient to differentiate between them (Dahle et al in this issue). Bone marrow toxicity is lowest, or the MTD is the highest, for bismuth immunoconjugates, then thorium followed by astatine and actinium immunoconjugates. Note that if the -emitting radioisotopes escape from the chelator, then different dose limiting organs apply. Dose limiting organs are the liver and bone marrow for 225Ac; bone marrow for 227Th, 223Ra, kidneys for 213Bi and Thyroid, stomach, spleen, lung for 211At. How does toxicity from -immunotherapy compare to that for -immunotherapy? For such comparisons the same model and endpoint must be used. Both 213Bi-d9MAb and 177 Lu-d9MAb effectively cured peritoneal carcinomatosis in a nude mouse model following i.p. injection [22]. Treatment with therapeutically effective activities of 177Lu-d9MAb was


not free of toxic side effects. Lymphoblastic lymphoma, proliferative glomerulonephritis and hepatocarcinoma were seen in some animals but were not observed after treatment with 213Bi-d9MAb at comparable therapeutic efficacy. Intact MAbs have a long residence times (weeks) in the blood and limited penetration into tumors because of their high MW ~150 kDa. Increased uptakes into tumors might be expected with lower MW targeting constructs, e.g. MW Fab = 50 kDa and scFv = 25 kDa. However, the downside is that higher doses to the kidneys result for molecules with MW < 60 kDa because of increased renal filtering. This effect can be offset by pre-treatment with D-lysine (Olafsen et al in this hot-topic issue). The larger F(ab´)2 fragments would avoid renal toxicity because of their higher MW. Tests have been made with Iodine and Astatine, which are both halogens and have similar uptakes in many tissues. However, uptake ratios of At to I for spleen, stomach and lungs are 4-6 times. As such, 131 I should not be used as a surrogate for 211At biodistribution studies. Patient specific -particle dosimetry is reviewed by Palm et al in this hot-topic issue. The authors raise the issue of cancer risk to early stage cancer patients. In such cases, the stochastic and long term risks include secondary cancers and organ dysfunction must be included in justifying the cancer therapy.

3.7. Pros and Cons for TAT The advantages of TAT are that: Patients do not need to be isolated after treatment. For liquid cancers such as acute myeologenous leukaemia the uptake plateaus in ~5 min in the leukaemia volumes. TAVAT can be effective well below the MTD in solid tumors. The Ac generator can be readily disposed of because of its short 10 d half life. Alpha-particles have the ability to kill isolated cells. Microscopic cross fire can reduce cell clusters. Nuclear Medicine departments may be reluctant to be involved with -emitting radioisotopes, because of: Uncertainty in the dosimetry. Inability to determine whether isolated cells in transit are eliminated. Limited availability of the Ac:Bi generator. Local applicability of a 211At source. Use of low MW targeting constructs can cause renal radiation necrosis. High MW targeting constructs require a long radioisotope half life to penetrate into tumors.

Barry J. Allen

Lack of long range cross fire to give averaging of the tumor absorbed dose. 4. QUO VADIS? These problems could be resolved with biological dosimetry and magnetic cell separation of cancer cells in the blood with magnetic microspheres coated with the targeting MAb. The limited supplies of 225Ac available at present from separation from 229Th are adequate for clinical trials. However, should TAT become a clinical procedure, then new supplies must be found. Accelerator production centers could ensure adequate supply of 225Ac for international distribution and 211At for local distribution. Alpha-particle therapy needs first to establish maximum tolerance doses for practical acceptance. This has been determined with 213Bi-IC for acute myeologenous leukaemia at ~1 mCi/kg [7]. The maximum tolerance dose has not yet been established for metastatic melanoma, but the efficacious dose for some melanomas is certainly less than 0.3 mCi/kg [14] and for intra-cavity therapy of GBM it is ~0.14 mCi/kg for 211At-IC [10]. The next stage is to determine the efficacy in phase II trials at the MTD or the effective dose. A current study of combined modalities for acute myelogenous leukaemia is ongoing at Memorial Sloan Kettering Cancer Center using chemotherapy to reduce the cancer load followed by 213Bi-IC to further reduce the cancer. The melanoma trial showed significant efficacy in the phase 1 trial achieving 10% near complete or partial response, 40% stable disease and 13% long term survival of 25 y, without any evidence of adverse events [8,14]. The GBM study at Duke University Medical Center achieved a median survival of 52 weeks for GBM [10]. While these results are relatively impressive, the potential of TAT to reduce solid tumors by tumor antivascular therapy remains just that. The demonstration of the synergy between tumor vascular disruption agents and TAVAT could bring about a sea change in cancer therapy. Alpha-particle therapy is still a work in progress, but great gains are being made in translating preclinical studies to clinical trials. Ideally suited to leukaemia, -therapy is demonstrating efficacy, but at the MTD. GBM results from intra-cavity administration are very promising, with a 52 w median survival. However, the promise of targeted alpha therapy is greatly extended by the development of TAVAT for solid tumors. Metastatic melanoma results show surprising tumor regressions at doses very much below the MTD, and if further research is successful, TAVAT could change the prognosis for end-stage cancers. REFERENCES [1] [2] [3]

Köhler. G.; Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 1975, 256, 495-497. Goldenberg, D.M. Targeted therapy of cancer with radiolabeled antibodies. J. Nucl. Med., 2002, 43, 693-713. Brons, S.; Jakob, B.; Taucher-Scholz, G.; Kraft, G. Heavy ion production of single- and double-strand breaks in plasmid DNA in aqueous solution. Phys. Med., 2001, 17, 217s-218s.

Future Prospects for Targeted Alpha Therapy [4] [5] [6]

[7]

[8]

[9]

[10]

[11]

[12]


Kerr, J.F. A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J. Path. Bact., 1965, 90, 419-435. Sgouros, G. Radioimmunotherapy of micrometastases: sidestepping the solid tumor hurdle. J. Nucl. Med., 1995, 36, 19101912. Allen, B.J.; Raja, C.; Abbas Rizvi, S.M.; Song, E.Y.; Graham, P. Tumour anti-vascular alpha therapy: a mechanism for the regression of solid tumours in metastatic cancer. Phys. Med. Biol., 2007, 52, 15-19. Jurcic, G.J.; Larson, S.M.; Sgouros, G.; McDevitt, M.R.; Finn, R.D.; Divgi, C.R.; Ballangrud, A.M.; Hamacher, K.A.; Ma, D.; Humm, J.L.; Brechbiel, M.W.; Molinet, R.; Scheinberg, D.A. Targeted alpha particle immunotherapy for myeloid leukaemia. Blood, 2002, 100, 1233-1239. Raja, C.; Graham, P.; Abbas Rizvi, S.M.; Song, E.; Goldsmith, H.; Thompson, J.; Bosserhoff, A.; Morgenstern, A.; Apostolidis, C.; Kearsley, J.H.; Reisfeld, R.; Allen, B.J. Interim analysis of toxicity and response in Phase 1 trial of systemic targeted alpha therapy for metastatic melanoma. Cancer Biol. Ther., 2007, 6, 846-852. Schmidt, D.; Neumann, F.; Antke, C. Phase 1 clinical study on alpha-therapy for non-Hodgkin’s lymphoma. In: 4th AlphaImmunotherapy Symposium; Morgenstern, A., Ed.; Institute for Transuranium Elements: Dusseldorf, Germany, 2004; pp. 12. Zalutsky, M.R.; Reardon, D.A.; Akabani, G.; Coleman, R.E.; Friedman, A.H.; Friedman, H.S.; McLendon, R.E.; Wong, T.Z.; Bigner, D.D. Clinical experience with the alpha-particle emitting 211 At: treatment of recurrent brain tumours patients with 211Atlabeled chimeric anti-tenascin monoclonal antibody 81C6. J. Nucl. Med., 2008, 49(1), 30-38. Cordier, D.; Forrer, F.; Bruchertseifer, F.; Morgenstern, A.; Apostolidis, C.; Good, S.; Müller-Brand, J.; Mäcke, H.; Reubi, J.C.; Merlo, A. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]substance P: a pilot trial. Eur. J. Nucl. Med. Mol. Imaging, 2010, 37, 1335–1344. Andersson, H.; Cederkrantz, E.; Bäck, T.; Divgi, C.; Elgqvist, J.; Himmelman, J.; Horvath, G.; Jacobsson, L.; Jensen, H.; Lindegren, S.; Palm, S.; Hultborn, R. Intraperitoneal alpha-particle radioim-

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[13] [14] [15] [16] [17]

[18]

[19] [20]

[21]

[22]

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munotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of 211At-MX35 F(ab´)2 – a phase 1 study. J. Nucl. Med., 2009, 50(7), 1153-1160. Allen BJ, Abbas Rizvi SM, Qu CF, Smith RC. Targeted alpha therapy approach to the management of pancreatic cancer. Cancers 2011, 3, 1821-1843 Dadechova E, Nakouzi A, Bryan R, Casadevill A. Ionising radiation delivered by a specific antibody is therapeutic against a fungal infection. Proc Nat Acad Sci USA, 2003, 100, 10942-10947 Allen, B.J. Clinical trials of targeted alpha therapy for cancer. Rev. Rec. Clin. Trials, 2008, 3, 185-191. Allen, B.J.; Raja, C.; Abbas Rizvi, S.M.; Graham, P.; Kearsley, J.H. New directions for clinical trials of targeted alpha therapy for metastatic melanoma. Curr. Radiopharm., 2008, 1, 240-250. Martin, V.M.; Sieqwert, C.; Scharl, A.; Harms, T.; Heinze, R.; Ohl, S.; Radbruch, A.; Miltenyi, S.; Schmitz, J. Immunomagnetic enrichment of disseminated epithelial tumour cells from peripheral blood by MACs. Exp. Haem., 1998, 26, 252-264. Wang, J.; Abbas Rizvi, S.M.; Madigan, M.C.; Cozzi, P.J.; Power, C.A.; Qu, C.F.; Morgenstern, A.; Apostolidis, C.; Russell, P.J.; Allen, B.J. Control of prostate cancer spheroid growth using 213Bilabeled multiple targeted alpha immuno-conjugates. Prostate, 2006, 66, 1753-1767. Azzam, E.I.; Little, J.B. The radiation-induced bystander effect: evidence and significance. Hum. Exp. Toxicol., 2004, 23, 61–65. Song, E.Y.; Abbas Rizvi, S.M.; Raja, C.; Qu, C.F.; Yuen, J.; Morgenstern, A.; Apostolidis, C.; Allen, B.J. The cytokinesis– block assay as a biological dosimeter for targeted alpha therapy. Phys. Med. Biol., 2008, 53, 319-328. Allen, B.J.; So, T.; Abbas Rizvi, S.M.; Song, E.Y.; Fernandez, H.R.; Lutz-Mann, L. Mutagenesis induced by targeted alpha therapy using 213Bi-cDTPA-9.2.27 in lacZ transgenic mice. Cancer Biol. Ther., 2009, 8(9), 777-781. Seidl, C.; Zöckler, C.; Beck, R.; Quintanilla-Martinez, L.; 177 Bruchertseifer, F.; Senekowitsch-Schmidtke, R. Luimmunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi. Eur. J. Nucl. Med. Mol. Imaging, 2011, 38(2), 312-322.

Accepted: 00 00, 2011