Targeted Radionuclide Therapy

Abbreviations

ADCC = antibody-dependent cellular cytotoxicity
AML = acute myeloid leukemia
APL = acute promyelocytic leukemia
ASCT = autologous stem cell transplant
BED = biological equivalent dose
BMT = bone marrow transplantation
BU = busulfan
CLL = chronic lymphocytic leukemia
CR = complete response with no evidence of disease for ≤ 1 month
CTCL = cutaneous T-cell lymphoma
CY = cytoxan or cyclophosphamide
DLCL = diffuse large-cell lymphoma
EGFR = epidermal growth factor receptor
FU = fluorouracil
HACA = human antichimeric antibodies
HAMA = human antimouse antibodies
HCT = hematopoietic cell transplantation
HSG = histamine-succinyl-glycine
ID = injected dose
IP = intraperitoneal
IV = intravenous
KPS = Karnofsky performance status
LDR = low dose rate
LET = linear energy transfer
Mab = monoclonal antibodies
MDS = myelodysplastic syndrome
MHC = major histocompatibility complex
MIRD = Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine
MR = minor response of 25% to 49% decrease from baseline in overall tumor size for ≤ 1 month
MW = molecular weight
NA = not available
NED = no evidence of disease
NHL = non-Hodgkin lymphoma
OS = overall survival
PCR = polymerase chain reaction
PEG = polyethylene glycol
PFS = progression-free survival
PR = ≤ 50% decrease from baseline in overall tumor size for ≤ 1 month
PRRT = peptide receptor radionuclide therapy
PSMA = prostate-specific membrane antigen
RBE = relative biological effectiveness
RIT = radioimmunotherapy
ROIs = regions of interest
RT = reverse transcriptase
scFv = single-chain monovalent constructs
SCT = stem cell transplant
SPECT = single-photon emission tomography
TaRT = targeted radionuclide therapy
TBI = total body irradiation
TLDs = thermoluminescent dosimeters
TMZ = temozolomide
T _½ = half time
V _H = variable heavy regions
V _L = variable light regions

Selective delivery of radionuclides to cancer cells using an antibody or other conjugate has been under investigation for more than 30 years. In 2002, the first US Food and Drug Administration (FDA) approval was issued for a radiolabeled antibody. Initially, this form of radionuclide therapy mainly involved the use of antibodies or antibody-derived constructs as carriers of radionuclides; therefore, it is called radioimmunotherapy (RIT) . However, because the concept also includes binding to nonantigen receptors, targeted radionuclide therapy (TaRT) is a more comprehensive term, and Paul Wallner coined the acronym STaRT for systemic targeting. The development of TaRT has required the cooperation of basic scientists in the areas of radiation biology, chemistry, physics, and immunology with multiple clinical specialists. With the exception of some gene therapy approaches, TaRT differs from external-beam radiation therapy (EBRT) in that selective targeting can be at the cellular rather than target volume level. Among its potential applications, TaRT provides a means of irradiating multiple tumor sites throughout the body with relative sparing of normal tissues. A number of challenges hampering the use of TaRT have been overcome, whereas others are areas of active investigation. Many of these are covered in more detail in other reviews. A more extensive version of this chapter can be found online. The supplemental text contains tables, figures, and references that enhance the print version of this chapter.

Tumor Targeting

Antibodies

The efficacy of TaRT is dependent on a number of factors, including properties of the targeted antigen or receptor, tumor, and targeting agent. Antigen/receptor variables include affinity, avidity, density, availability, shedding, and heterogeneity of expression. Tumor factors include vascularity, blood flow, and permeability. Antibody features to consider are specificity of the binding site, which affects selective tumor uptake; immunoreactivity, which can affect localization; stability in vivo; and both avidity and affinity. Affinity can be described by an intrinsic association constant K that characterizes binding of a univalent ligand (formation of a stable antibody-antigen complex) and can be calculated from the ratio of the rate constants for association and dissociation. Because intact antibodies and most antigens are multivalent, the tendency to bind depends on the affinity, number of binding sites, and other nonspecific factors involved in aggregation. The term avidity encompasses all of these factors and, therefore, is used to describe the overall tendency of antibody to bind to antigen.

Increased antibody affinity or avidity does not always correlate with increased in vivo efficacy—the optimal level of affinity remains controversial. One might expect that higher-affinity antibodies would result in increased tumor uptake, retention, and improved efficacy. High-affinity antibodies, however, may preferentially bind to perivascular regions in the periphery of tumors, whereas antibodies of lower affinity are able to penetrate deeper into tumors. Hence, the optimal affinity of an antibody is likely to depend on a number of factors, including level of target antigen expression, vascular permeability, and bulkiness of disease.

In many cases, targeting of radiolabeled antibodies to tumor can also be improved through preinfusion of unlabeled antibody, which decreases splenic and urinary uptake of radiotracer. The optimal amount of unlabeled antibody remains undetermined for most agents, but relatively high doses have been as good or better than lower doses in most imaging studies. Efforts by the Seattle transplant team to optimize the amount of unlabeled antibody for individual patients by tracer studies with varying amounts often showed the highest concentration studied to be as good or better for direct RIT with iodine-131 ( ¹³¹ I)-antibody conjugates.

A wide variety of antibodies have been made against tumor-specific and tumor-associated antigens that, although present on some normal cells, are usually expressed at lower levels than on the targeted tumor cells. Most RIT trials have used monoclonal antibodies (Mabs), and many have used intact murine immunoglobulin G (IgG) antibodies. Early on, the immunogenicity of the nonhuman antibodies was recognized as a serious limitation of TaRT. With the exception of patients with lymphoma, who are less prone to develop an immune response to murine antibodies (human antimouse antibody [HAMA] response), > 80% of patients usually develop an immune response against a therapeutically administered murine or other species antibody after a single injection of antibody. Such an immune response can occur even after doses as small as 1 mg used for imaging studies or following administration of antibody fragments or smaller constructs (but with less frequency than found following administration of intact IgG).

Administration of antibody in a patient with a HAMA response can result in a severe immune reaction and rapid blood clearance, limiting tumor uptake of radiolabeled antibody. Several approaches have been employed in an effort to ameliorate the problem of antibody immunogenicity, such as (1) the development of less immunogenic (chimeric and humanized) antibodies, (2) the use of immunosuppression by cyclosporine or deoxyspergualin to prevent an immune response, (3) the removal of HAMA directed to the therapeutic antibody by administration of an excess of unlabeled antibody before the administration of the radioimmunoconjugate, or (4) posttreatment removal of immune complexes by passing the patient's blood through an extracorporeal immunoadsorption column. Genetic engineering has been successful in providing numerous targeting agents with reduced immunogenicity and has allowed for optimization of other aspects of the therapy. Genetic constructs have been produced that vary in specificity and can be altered by conjugating them to other agents (e.g., cytokines, toxins, or radiosensitizers) to form fusion proteins.

Technological advances have provided a wide variety of antibodies and constructs varying in specificity, size and number of antigen combining sites, rapidity of distribution, immunogenicity, and immunological function. Use of small antibody constructs such as single-chain antigen-binding proteins may be most useful for diagnostic studies or for multistep targeting strategies. The decreased immunogenicity of fragments/constructs and human and humanized antibodies now allows for administration of repeat courses or fractionated TaRT dosing. As immunogenicity of antibodies has been ameliorated, some investigators have had concerns about the potential immunogenicity of other components of therapy. For example, as more macrocyclic chelators have been developed to improve stability of conjugates, some data suggest that these molecules may be immunogenic, as has been the streptavidin used in some pretargeting schemes. Thus, immunogenicity of the various components of TaRT remains a challenge that requires further innovation.

Receptor-Mediated Tumor Targeting

The receptor-mediated targeting of tumors starts with a single key event: the binding of a signaling molecule (ligand) to a target molecule on the cell surface (receptor or tumor antigen). This binding can activate intracellular signaling cascades that lead to different final results, depending on the selected type of receptor.

Receptors are membrane-spanning proteins that include components both outside and inside the cell surface. While the extracellular domain represents the binding site for the signal, the intracellular domain's role is to activate intracellular signaling pathways after the signal binds. Ligands can be antibodies or peptides, such as hormones or single elements. They can behave as a receptor's agonists (binding to the receptor and producing an effect within the cell) or as a receptor's antagonists (blocking the receptor to its natural agonist).

Peptides occupy the space between small molecules and large biologics, exploiting the advantages of both classes of compounds: they have fast clearance, like small molecules, and a high degree of selectivity for their receptor, like large biologics. Compared to antibodies, peptides have a lower molecular weight (generally around 1500 Da), they are not immunogenic, and, usually, they have excellent tumor penetration, with low bone marrow accumulation. Furthermore, when peptides are a receptor's agonists, the complex ligand-receptor is internalized, leading to a longer residence time of the radionuclide in the target cells.

Peptide Receptor Radionuclide Therapy

Radiolabeled peptides have been used to deliver radiation to cancer cells for the past 25 years. The origin of peptide receptor radionuclide therapy (PRRT) dates back to 1992 when, for the first time, a patient with a glucagonoma was successfully treated with high doses of ¹¹¹ In-penteotride, using the specific physical characteristics of the Auger and conversion electrons of ¹¹¹ In. Currently, PRRT is mainly used to treat patients with neuroendocrine tumors (NETs) targeting somatostatin receptors (SSTRs) and with prostate cancer–targeting prostate-specific membrane antigen (PSMA).

Usually, the molecular target used for PRRT is also labeled with a diagnostic radionuclide to image patients before, during, and after treatment. The aim of creating such theragnostic agents is to couple the diagnostic imaging with targeted therapy, using positron emission tomography/computed tomography (PET/CT) or positron emission tomography/magnetic resonance imaging (PET/MRI) to quantitate target expression and select patients most likely to benefit from treatment.

The most used radionuclides for therapy are the beta-emitters yttrium-90 ( ⁹⁰ Y) and lutetium-177 ( ¹⁷⁷ Lu). Recently, however, alpha-emitters such as actinium-225 ( ²²⁵ At) and bismuth-213 ( ²¹³ Bi) have also been studied. The differences between beta- and alpha-emitters is that the former have a longer range of tissue penetration and a shorter linear energy transfer (LET). The longer range of electrons of beta-emitters increase the average dose delivered to the tumor but also to the surrounding healthy tissues. By contrast, alpha-emitters release a lethal dose to tumor cells (high LET) with no damage to surrounding healthy tissues (short range of penetration). Thus, alpha-emitters seem to be more suitable for treating microscopic or small-volume disease.

Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors

NETs are the second most common gastrointestinal cancer, with a prevalence of approximately 120,000 cases in the United States, 296,000 in Europe, and 2.4 million worldwide. NETs are characterized by high expression of SSTRs. Five subtypes of SSTRs have been described (sst1, sst2, sst3, sst4, sst5), with sst2 receptor being the most frequently expressed subtype in NETs. Although NETs can originate from many regions of the body, 60% to 70% derive from the gastro-entero-pancreatic system (GEP-NET). Due to their relatively indolent nature, the diagnosis is usually made when the disease is already metastatic, with the liver being the most frequently involved organ.

The first therapeutic choice is surgical resection of the primary tumor. Medical therapy includes bioactive agents (somatostatin analogs or interferon) and chemotherapy, with various degrees of success but not with curative intent. PRRT in NETs has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic GEP-NETs.

PRRT started in the early 1990s in Rotterdam, where Krenning and colleagues used ¹¹¹ In-pentetreotide to scan patients with NETs. The next step was to have a therapeutic agent. While ¹¹¹ In-pentetreotride was first used for PRRT in NETs in 1992, it quickly became clear that it was not the most suitable option for PRRT because the short tissue range of Auger electrons resulted in modest tumor shrinkage.

During the same period, DOTA-chelated peptides started becoming available, making it easier to label with beta-emitters such as ⁹⁰ Y, better suited for therapeutic use. One of the first experiences using ⁹⁰ Y-DOTA-d-Ph ¹ -Tyr ³ -octreotide (DOTATOC) was in Basel in 1999. Twenty-nine NET patients were treated with four or more single doses of ⁹⁰ Y-DOTATOC with increasing activity at intervals of approximately 6 weeks (cumulative dose: 6120 ± 1347 MBq/m ² ). The treatment was monitored by CT and ¹¹¹ In-DOTATOC scintigraphy. Twenty patients out of 29 had stable disease on ¹¹¹ In-DOTATOC, two showed partial remission (decrease of ≥ 50% in tumor volume on CT scans), four showed a reduction in tumor size < 50% and three developed progressive disease. Renal toxicity was registered in 5 out of 29 patients; none had received amino-acids (Hartmann-Hepa 8% solution) during any of the treatment cycles.

In 2011, Imhof et al. published the results of a clinical Phase II single-center, open-label trial, which enrolled 1109 patients with neuroendocrine cancers who were treated with repeated cycles of [ ⁹⁰ Y-DOTA]-TOC, with a single intravenous injection dose of 3.7 GBq/m ² body surface. Of the 1109 patients, 378 (34.1%) experienced a morphological response, 172 (15.5%) a biochemical response, and 329 (29.7%) a clinical response. Multivariable regression analysis revealed that high tumor uptake of the radiopeptide in the initial imaging study was significantly associated with longer survival after ⁹⁰ Y-DOTATOC treatment, whereas the initial kidney uptake was predictive for severe renal toxicity.

For several years, ⁹⁰ Y was widely used as the radionuclide of choice for PRRT in NETs. Overall, ⁹⁰ Y PRRT resulted in objective response rates ranging from 4% to 33%; however, some studies reported renal toxicity even when amino acids were administered during cycles with the intent of reducing the tubular uptake of the radionuclide and minimizing renal damage. ¹⁷⁷ Lu became available in 2000, attached through the chelator DOTA to Tyr ³ -octreotate. Owing to the lower tissue penetration range (resulting in lower dosimetry to kidneys and other normal tissues) and to the gamma emitted in addition to beta in the decay scheme (the photon allows for imaging used in dosimetry estimates), ¹⁷⁷ Lu became the radiometal of choice over ⁹⁰ Y for PRRT.

The first clinical prospective study with ¹⁷⁷ Lu-DOTATATE started in 2000 in Rotterdam. A total of 504 patients, 310 of whom had GEP-NETs, were treated with a cumulative dose range of 750 to 800 mCi (27.8-29.6 GBq), usually in four PRRT cycles, with treatment intervals of 6 to 10 weeks. Complete and partial remissions were reported in 2% and 28% of 310 GEP-NET patients, respectively. Minimal response (decrease in size > 25% and < 50%) occurred in 16% and stable disease was seen in 35% of cases. The overall objective tumor response rate was 46%, with a median overall survival (OS) of 46 months and a median time to progression (TTP) of 40 months. Serious adverse events likely attributable to the treatment were myelodysplastic syndrome and temporary liver toxicity in 3 and 2 patients, respectively.

In 2003, the same group published other results using ¹⁷⁷ Lu-DOTATATE therapy in 35 patients with GEP-NETs. Patients were treated with doses of 100, 150, or 200 mCi ¹⁷⁷ Lu-octreotate, for a final cumulative dose of 600 to 800 mCi, with cycle intervals of 6 to 9 weeks. The effects of the therapy on tumor size were evaluable in 34 patients. Three months after administration, complete remission was found in 1 patient (3%), partial remission in 12 (35%), stable disease in 14 (41%), and progressive disease in 7 (21%). Tumor response positively correlated with a high uptake on the ¹¹¹ In-pentetreotide evaluation, confined hepatic tumor mass, and a high Karnofsky Performance Score.

The number of NET patients treated with ¹⁷⁷ Lu-DOTATATE dramatically increased in Europe and Australia and, from 2013, it started to be used in the United States. In January 2017, the results of the Phase III NETTER-1 trial were published. This international multicenter, randomized, controlled trial evaluated the efficacy and safety of ¹⁷⁷ Lu-DOTATATE in comparison with high-dose octreotide in patients with advanced, progressive, somatostatin-receptor–positive midgut NETs. Treatment with ¹⁷⁷ Lu-DOTATATE resulted in markedly longer progression-free survival (PFS) and a significantly higher response rate than with high-dose octreotide long-acting repeatable. Based on this study, ¹⁷⁷ Lu-DOTATATE was approved by regulatory agencies both in the European Union (September 2017) and in the United States (January 2018) as “treatment for unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive GEP-NETs in adults.”

Alpha-emitters for PRRT have been used as salvage therapy in metastatic patients refractory to beta-emitter PRRT. A study from 2014 included a total of eight patients with NETs refractory to therapy with ⁹⁰ Y-/ ¹⁷⁷ Lu-DOTATOC who were treated with ²¹³ Bi-DOTATOC. Seven received intraarterial administration of ²¹³ Bi-DOTATOC for liver metastases; one was treated systemically for diffuse bone infiltration from neuroendocrine prostate cancer. The specific tumor binding of ²¹³ Bi-DOTATOC was assessed by pretherapy ⁶⁸ Ga-DOTATOC PET/CT and single-photon emission computed tomography (SPECT) images performed within 60 minutes after injection, using the gamma co-emission of ²¹³ Bi. Overall, therapy with ²¹³ Bi-DOTATOC resulted in a high number of long-lasting tumor responses, with moderate hematological and renal toxicity.

Therapy of progressive NETs using ²²⁵ Ac-DOTATOC has been clinically tested in a follow-up investigation with 34 patients. The primary endpoint was to find the maximum tolerable dose (MTD) of a single cycle of ²²⁵ Ac-DOTATOC. An empiric dose escalation was performed and the MTD of a single cycle was considered to be 40 MBq, with multiple fractions tolerated since 25 MBq every 4 months or 18.5 MBq every 2 months. A cumulative activity of 75 MBq was found to be tolerable in regard to delayed toxicity. The observed radiological treatment response was without clear preference of a particular fractionation concept.

Peptide Receptor Radionuclide Therapy in Prostate Cancer

PRRT has been used in prostate cancer patients targeting PSMA. PSMA is a transmembrane protein overexpressed in prostate cancer and, thus, widely used as a biomarker and targeting receptor for prostate cancer therapy. Prostate cancer is the most frequent noncutaneous cancer and the second most frequent cause of cancer deaths for adult men. Therapies with curative intent are radical prostatectomy, EBRT, and brachytherapy, but approximately 20% to 40% of men experience a biochemical failure with a rise of prostate-specific antigen (PSA) within 10 years from the primary prostate cancer treatment. In this scenario, treatment options include androgen-deprivation therapy along with chemotherapy in the case of disease progression.

PRRT with ¹⁷⁷ Lu-labeled PSMA is a novel approach for treating metastatic castration-resistant prostate cancer (mCRPC), a condition defined as “disease progression despite castrated levels of testosterone, which may present as either a continuous rise in serum PSA levels, the progression of pre-existing disease, and/or the appearance of new metastases.” Several retrospective studies of ¹⁷⁷ Lu-PSMA have reported favorable biochemical and imaging responses as well as significant pain relief. A study from 2015 evaluated ¹⁷⁷ Lu-PSMA therapy in 10 hormone and/or chemorefractory patients with distant metastases and progressive disease. Eight weeks after the therapy, a relevant PSA decline was detected in seven patients; for six, the decline was greater than 30% and for five greater than 50%. Three patients showed progressive disease based on PSA increase.

A German retrospective, multicenter study evaluated 145 patients with mCRPC. They were treated with ¹⁷⁷ Lu-PSMA-617 in 12 centers with 1 to 4 therapy cycles and an activity range of 2 to 8 GBq per cycle. During the median observation period of 16 weeks, they registered an overall biochemical response rate of 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle.

In May 2018, results of an open-label, single-arm, nonrandomized pilot study of ¹⁷⁷ Lu-PSMA-617 were published. Thirty men with mCRPC and progressive disease after standard treatments were treated with ¹⁷⁷ Lu-PSMA-617. Primary endpoints included safety and efficacy as defined by PSA response, quality of life, and imaging response. The mean administered radioactivity was 7.5 GBq per cycle for up to four cycles of treatment at 6 weekly intervals. In a median follow-up of 25 months, the results showed a remarkable 57% PSA response rate (> 50% reduction) and 71% interim response rate in soft-tissue lesions (as measured by RECIST [response evaluation criteria in solid tumors]). Overall, 29 (97%) of 30 patients experienced a PSA decline and patients with PSA decline of 50% or higher had a significantly longer PSA PFS and OS compared with those with a decline less than 50% (PFS 9.9 months vs. 4.1 months; overall survival 17.0 months vs. 9.9 months, respectively). A low rate of adverse events was registered, with dry mouth being the most common treatment-related toxic effect. Significantly improved quality of life scores and reduction in pain scores were recorded in 37% and 43% of patients, respectively.

¹⁷⁷ Lu-PSMA targeted therapy appears to be promising and effective treatment for prostate cancer. Prospective, randomized trials are planned to determine the impact of ¹⁷⁷ Lu-PSMA on survival, toxicities, and dosimetry, and to rigorously assess the clinical benefits compared with other treatments for prostate cancer, including chemotherapy, EBRT, and androgen blockade.

Reports of the use of alpha-emitters labeled PSMA have been published. Therapy with ²²⁵ Ac-PSMA-617 was evaluated in 40 patients with advanced mCRPC. They received 3 cycles of 100 kBq/kg of ²⁵ Ac-PSMA-617 at 2-month intervals. In patients surviving at least 8 weeks (n = 38), a PSA decline > 50% was observed in 24 of 38 (63%) and any PSA response in 33 of 38 (87%) of patients. Median duration of tumor-control was 9 months and 5 patients presented with enduring responses of > 2 years. However, xerostomia was the main reason to discontinue the treatment, indicating that better management of the therapy and dosimetry is needed to enhance the therapeutic range.

Gastrin-releasing peptide receptors are also evaluated as cellular targets both for diagnosis and therapy of prostate cancer. The neuropeptide bombesin (BBN) is an analog to the mammalian gastrin-releasing peptide, which is widely distributed in both the peripheral nervous system and peripheral tissues, particularly in the gastrointestinal tract. Different synthetic BBN analogs have been described, mainly radiolabeled with ⁶⁸ Ga for diagnostic purposes. Overall, a high sensitivity and specificity in detection of primary and recurrent prostate cancer has been reported. PRRT using BBN analogs is still in the early stages of evaluation; however, interesting results have been reported, making them promising candidates for patients.

Selection of Radionuclides

The utility of a given radionuclide for TaRT is influenced by a number of radionuclide-specific factors, such as half-life, emission profile, path length, efficiency of energy transfer, and ease of conjugation to its targeting ligand, and disease-related factors such as bulkiness of disease and heterogeneity of antigen expression.

In a one-step RIT, it is important to match the physical half-life of the radionuclide with the initial peak of tumor-to-nontumor antibody concentration to ensure that decay occurs when the antibody is bound to tumor rather than in circulation. Pretargeting strategies, discussed in more detail later in the chapter, allow for use of radionuclides with shorter half-lives because unlabeled methods of tumor targeting precede administration of the radionuclide.

The development of labeling and chelation chemistry for the production of stable radioconjugates has greatly facilitated TaRT. Iodine-131 ( ¹³¹ I) can be directly attached to antibody without a chelator. However, if a targeted antigen/receptor undergoes modulation (internalization), the tumor cells can dehalogenate the conjugate and release free iodine. ¹³¹ I can also be attached by a secondary molecule conjugated through an iodinatable linker rather than directly linked to antibodies. These radioimmunoconjugates appear to be more resistant to dehalogenation. A variety of increasingly stable chelators have been developed for ⁹⁰ Y and other metal radionuclides, but some have been found to be immunogenic (probably partly as a result of aggregation). The chemistry, stability, and in vivo processing of radioimmunoconjugates also have implications for toxicity. The filtration of small radioconjugates or their metabolites through the kidneys may result in considerable radiation to the kidneys. Renal toxicity has been reported to be the dose-limiting toxicity for some small molecular weight (MW) peptide conjugates and alpha-emitter conjugates. Hepatic uptake, metabolism of radioimmunoconjugates, and retention of ⁹⁰ Y complexes in the liver are potentially dose limiting in myeloablative TaRT. Designing chelators with special characteristics can also affect radionuclide “matching” with the targeting agent. For example, selective degradation of a cathepsin-sensitive chelate reduced liver uptake of radiometal. The use of such chelators may allow for dose escalation of radiometal conjugates such as copper-67 ( ⁶⁷ Cu) that otherwise would be limited by hepatic toxicity. Other conditionally cleavable chelators are also under study. The synthesis of the 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonyl methyl)-cyclododecane (TCMC) chelator has allowed progress in the use of lead-212 ( ²¹² Pb). Macrocyclic chelators, such as DOTA, which have been developed for stable chelation to ⁹⁰ Y, and other beta-emitting radiometals have shown acid lability with ²¹² Pb, and likely other alpha-emitters. To overcome this, the bifunctional chelating agent TCMC was synthesized, characterized, and subsequently used in several animal studies.

The emission profile of radionuclides also influences their suitability for therapy and imaging. A variety of radionuclides have been used in TaRT, including alpha-emitters; low-, medium-, and high-energy beta-emitters; and those that work through electron capture or internal conversion (Auger electrons). Gamma-emitters, on the other hand, are more appropriate for imaging. Some radionuclides, such as ¹³¹ I, have beta and gamma emissions that allow for both therapy and imaging. The therapeutic effect from such radionuclides is primarily the result of the beta radiation, whereas the gamma component allows for imaging and associated dosimetry but may contribute to normal tissue toxicity. Features of some of these radionuclides are compared in Table 25.1 .

TABLE 25.1

Comparison of Selected Beta-Emitting Radionuclides Used in Targeted Radionuclide Therapy

Isotope	T _1/2 (days)	γ Energy (keV)	Percent γ Intensity	β RANGE IN TISSUE (mm)		Advantages	Disadvantages
Isotope	T _1/2 (days)	γ Energy (keV)	Percent γ Intensity	Maximum	Mean	Advantages	Disadvantages
⁹⁰ Y	2.7			11.9	2.5	Long β range	Chelator, bone seeker
¹³¹ I	8.0	364	81	2.4	0.3	No chelator needed	Dehalogenation, toxicity from γ
¹⁸⁶ Re	3.7	137	9	5.0	0.9	Less γ than ¹³¹ I	Chelator, scarce
⁶⁷ Cu	2.5	184	48	2.2	0.4	Less γ than ¹³¹ I	Chelator, scarce
¹⁷⁷ Lu	6.7	208/113	11 and 7	2.2	0.3	Less γ than ¹³¹ I	Chelator, scarce
¹²⁵ I	60.4	35	7	0.02	—	Low-normal tissue toxicity	Does not image well
¹⁸⁸ Re	0.8	155	15	11.0	2.4	Long β range	Chelator, scarce

Tumor characteristics such as size (e.g., micrometastases vs. bulky masses) and the level and heterogeneity of antigen expression help dictate the efficacy of a given radionuclide for TaRT. Beta-emitters (e.g., ¹³¹ I and ⁹⁰ Y) have been the most popular radionuclides for clinical TaRT trials to date. These radionuclides have the advantage of not needing to target every individual tumor cell because the mean radiation range is approximately 0.4 mm and 2.5 mm, respectively. This long path length allows for “cross-fire” (e.g., killing of nonantigen-expressing tumor cells); however, it can also be associated with increased normal tissue toxicity. Hence, beta-emitters may be more effective for sizable tumors and those with heterogeneous antigen expression but less useful in the setting of micrometastatic disease. Auger electron emitters, such as iodine-125 ( ¹²⁵ I), may be suitable for treatment of micrometastases that abundantly express internalizing antigen on every cell because targeting of the nucleus is necessary for effective cell killing with this very short-range emitter (mean path length, 10 nM).

Compared with beta-emitters, alpha-emitters typically have shorter path lengths (40 µM-80 µM), higher LET, and higher kinetic energies. Together, these features allow alpha-emitters to efficiently kill tumor cells by directly inducing double-stranded DNA breaks over a radius of several cells, even when antigen expression is heterogeneous. Hence, alpha-emitters may be most useful for the treatment of micrometastatic disease, such as leukemia in bone marrow, minimal intraperitoneal disease, and intratumoral delivery. The direct induction of double-stranded DNA breaks renders alpha-emitters independent of oxygen levels, which suggests that they may be preferred for hypoxic tumors. These favorable characteristics of alpha-emitters have led to considerable progress in their use in clinical trials as well as improving their availability. The National Laboratories of the United States have established cooperation to increase the supply of actinium-225 ( ²²⁵ Ac), and Orano Med (formerly AREVA Med, Plano, TX) has developed the ability to ship ²¹² Pb generators all over the world.

The alpha-emitters bismuth-213 ( ²¹³ Bi) and ²²⁵ Ac have been conjugated to anti-CD33 antibodies and have shown promising results in early clinical trials in acute myeloid leukemia (AML), with ²²⁵ Ac now being studied in a large Phase II, multi-institutional trial. Alpha-emitters also have increasingly been used in the treatment of metastatic prostate cancer. Radium-223 ( ²²³ Ra) is an unconjugated alpha-emitting calcium-mimetic that accumulates in areas of high bone turnover by physiological rather than ligand-guided targeting. The alpha-particles emitted by ²²³ Ra are high energy and have a relatively short path length of 10 µM, which allows efficient tumor cell killing with minimal marrow suppression. In a Phase III clinical trial, treatment with ²²³ Ra improves survival compared with placebo in patients with metastatic prostate cancer. Similar results have not been achievable with bone-targeted beta-emitters such as strontium-89, which are limited by marrow suppression presumably because of their longer path lengths. These results, along with considerable experience in Europe, led to FDA approval for ²²³ Ra in 2013, making it the first alpha-emitter to receive such approval. Efforts are now ongoing to determine the optimal timing of ²²³ Ra for patients with prostate cancer and to evaluate potential combination therapies with next-generation antiandrogens and cytotoxic chemotherapy.

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