Targeted α-Therapy in Cancer Management: Synopsis of Preclinical and Clinical Studies

Abstract

The approval of ²²³Ra dichloride (²²³RaCl₂) in 2013 was a principal event in introducing targeted α-therapy as a form of safe and effective management strategy in cancer. There is an increasing interest in research and development of new targeted α-therapy agents spearheaded by advancements in cancer biology, radiochemistry, and availability of clinically relevant α particles. There are active clinical studies on sequencing or combining ²²³RaCl₂ with other drug regimens in the setting of metastatic prostate cancer and in other cancers such as osteosarcoma and bone-dominant breast cancer. Targeted α-therapy strategy is also being actively explored through many preclinical and few early clinical studies using ²²⁵Ac, ²¹³Bi, ²¹¹At, ²²⁷Th, and ²¹²Pb. Investigations incorporating ²²⁵Ac are more robust and active at this time with promising results. The author provide a brief synopsis of the preclinical and clinical studies in the rapidly evolving field of targeted α-therapy in cancer management.

Introduction

Cancer remains a major public health problem. The scientific community and major research funding agencies have invested heavily in deciphering the complex biology of cancer to improve prevention, diagnosis, and treatment of cancer in the era of precision oncology. Concerted efforts are underway to devise a scientific, regulatory, and policy roadmap with specific priority areas to accelerate translation of bench discoveries to bedside clinical implementation.¹ There are traditional (e.g., surgical resection, radiation therapy, cytotoxic chemotherapy) and now many novel (e.g., targeted therapy, immunotherapy) approaches to cancer treatment. Understanding of the underlying cancer biology has expedited precision or personalized therapies targeted to specific biomarkers, which is further facilitated by systematic integration of diagnostics and therapeutics (i.e., theranostics).

Targeted radionuclide therapy (TRT) has been gaining traction recently as a safe and effective form of cancer treatment.² The classical TRT is more than 75 years old with radioiodine treatment of a patient with thyrotoxicosis by Saul Hertz in 1941 that was soon followed by treatment of patients with thyroid cancer.^3,4 Radioiodine therapy with ¹³¹I (β⁻ and γ emission, half-life = 8.1 d) is based on thyroid biology that traps iodine physiologically. More recently, additional targeted therapies have been approved for patients with neuroendocrine tumors (β particle therapy with ¹⁷⁷Lu-DOTATATE or Lutathera™), recurrent and/or unresectable pheochromocytoma and paraganglioma (β⁻ particle therapy with ¹³¹I-iobenguane or Azedra™), and metastatic castrate-resistant prostate cancer (α particle therapy with ²²³Ra dichloride [²²³RaCl₂] or Xofigo™). While still not approved for clinical use in the United States, there are currently clinical trials on β⁻- and α-particle therapies directed to prostate-specific membrane antigen (PSMA) in patients with metastatic castrate-resistant prostate cancer.⁵

The approval of ²²³RaCl₂ as the first targeted α therapy (TAT) was a key event in furthering the research and development of TAT in patients with cancer.⁶ In this article, the author present a brief synopsis of some of the current preclinical and clinical studies that incorporate TAT as a viable form of cancer management arranged by the parent α-emitting radioisotope.

An α-Particle

An α-particle is a positively charged helium ion (2p, 2n, +2e) that is emitted from the nucleus of an unstable atom as it decays to a different atomic nucleus with reduced atomic mass of 4 and reduced atomic number of 2. Alpha particles are energetic with typical kinetic energy of 5–8 MeV traveling at 5% of speed of light losing large amount of energy (high linear energy transfer of about 80 KeV/μm) in a short distance (50–80 μm) in view their electric charge and relatively large mass.^7
–9 When properly targeted to disease sites, α particles can deposit large amount of energy locally that may lead to cellular apoptosis through catastrophic double-strand DNA breaks in the nucleus. The α-particle cell-killing efficiency is independent of cellular oxygenation. Thus, hypoxic tumor cells, which may be resistant to standard chemoradiation therapy, are vulnerable to targeted α-particle therapy. While the direct damage to cells is at a relatively short range from α-particle deposition, there may be additional damage to neighboring cells through radiation-induced bystander effect. However, the bystander effect is more limited than that with longer range β⁻ particles which typically leads to less collateral damage by the α particles to normal cells adjacent to the tumor microenvironment.¹⁰ Alpha particles may also prompt abscopal effect resulting in damage to remote cells probably through radiation-induced immune response. Alpha particles may be targeted innately in unconjugated form or home to a site for payload delivery based on conjugation to a biologically relevant, specific, and accessible molecule.^11

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²²³Ra

Radium is an alkali earth metal in the same column as calcium, strontium, and barium in the table of elements. Radium was discovered by the Madam Curie and Pierre Curie in 1898, for which they shared the Noble prize in physics with Henri Becquerel in 1903. Despite the discovery of radium and realization of its therapeutic potential at the turn of the 20th century, it was not until recently when ²²³RaCl₂ was approved for treatment of cancer.

²²³Ra is a calcium mimetic and naturally targets the bone hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) matrix. It is produced from uranium mill tailings or in generator form from ²²⁷Ac (half-life of 21.8 years) parent. With a half-life of 11.43 d, ²²³Ra decays to stable ²⁰⁷Pb with an emitted decay energy distribution of 93.5% α particle, <3.6% β⁻ particle, and <1.1% γ radiation.

Preclinical studies

There have been a number of preclinical studies that led to the initial pilot human studies and finally to the landmark Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) clinical trial. In view of brevity and the fact that ²²³RaCl₂ is approved by the U.S. Food and Drug Administration (FDA) for clinical use, they limit their discussion in this section to other preclinical studies with ²²³RaCl₂.

Although ²²³RaCl₂ naturally targets the osteoblastic zone of the bone matrix, it can also be loaded into delivery carriers such as liposomes, which may be coated with ligands for specific biologic targeting and controlled release.¹⁵ Radiation may be associated with abscopal effect. Malams et al. exposed human prostate, breast, and carcinoma cells to sublethal doses of ²²³Ra in vitro. ¹⁶ Sublethal dose of 4–10 Gy of ²²³Ra over 96 h incubation period enhanced CD8⁺ cytotoxic T cell-mediated lysis of each tumor type which was facilitated by protein expression of major histocompatibility complex, MHC-I, and calreticulin (a chaperone protein that helps direct peptide loading into MHC-I) on tumors for augmented antigen presentation. This study suggested that other than direct ²²³Ra-induced cell killing, it may have potential utility in combination with immunotherapy. In keeping with these preclinical results, Kwee et al. reported observations in 2 patients that suggested ²²³RaCl₂ abscopal effect with resultant favorable response in untargeted soft tissue disease.¹⁷ A recent report also supported the notion that cytotoxic bystander effect of ²²³RaCl₂ can delay growth in human breast cancer cells implanted as bone marrow xenografts in female athymic nude mice.¹⁸

Clinical studies

²²³RaCl₂ (Xofigo) is the first in class targeted α-particle therapy that was approved in May 2013 by the U.S. FDA based on the results of the multinational, randomized, double-blind ALSYMPCA clinical trial.¹⁹ ALSYMPCA compared ²²³RaCl₂ (50 kBq/kg intravenously every 4 weeks for six doses plus best standard of care) with placebo (saline intravenously every 4 weeks for six doses plus best standard of care) in men with castration-resistant prostate cancer and symptomatic bone metastases (≥2 lesions) and no visceral metastases (lymph nodes up to 3 cm in short axis were acceptable) and who had adequate bone marrow reserve. This phase III clinical trial incorporated 307 patients in the placebo arm and 614 patients in the treatment arm. The clinical trial demonstrated a 3.6-month overall survival benefit with ²²³RaCl₂ in comparison to that with placebo (median, 14.9 vs. 11.3 months; hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.58–0.83; p < 0.001). The overall survival benefit was present regardless of previous docetaxel treatment (3.1-month survival benefit with previous docetaxel use and 4.6-month survival benefit without previous docetaxel use). There was also longer median time to first symptomatic skeletal-related events (median, 15.6 vs. 9.8 months; HR, 0.66; 95% CI, 0.52–0.83; p < 0.001). Additional post hoc ALSYMPCA data analysis has revealed that ²²³RaCl₂ is associated with reduced hospital days per patient with meaningful quality-of-life improvement and slower decline in quality of life over time in comparison to placebo patients and that the benefit is regardless of baseline opioid use.^20

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The observed adverse events in ALSYMPCA trial were mild and manageable. In a 3-year safety follow-up study, ²²³RaCl₂ was associated with low incidence of myelosuppression that was similar or slightly higher than those for the placebo group (Grade 3/4 anemia 13% vs. 13%, neutropenia 2% vs. 1%, thrombocytopenia 7% vs. 2%, for ²²³Ra and placebo, respectively).²¹ Baseline predictors for Grade 2–4 hematologic toxicities are extent of disease (6–20 vs. <6 bone metastases) and elevated serum prostate-specific antigen level for anemia, and prior docetaxel chemotherapy, decreased hemoglobin, and decreased platelet levels for thrombocytopenia.²⁵ A recent publication reported on the results of an interim analysis of a global, prospective, noninterventional study (REASSURE) to assess long-term safety of ²²³RaCl₂ in patients with bone metastatic castration-resistant prostate cancer (mCRPC).²⁶ The cohort included 583 patients who were followed for a median duration of 7 months (range 0–20 months). The safety profile of ²²³RaCl₂ was comparable to those reported by other clinical studies and corroborated the observations that drug-related adverse events are more common in patients who have received prior chemotherapy than those patients who had not undergone chemotherapy (63% vs. 48%, respectively). Moreover, patients without prior chemotherapy had a higher proportion of completing the entire prescribed six injections of ²²³RaCl₂ in comparison to patients with prior chemotherapy (63% vs. 45%, respectively). Jadvar et al. reported on their clinical experience in 25 patients 1 year after offering ²²³RaCl₂ at their center.²⁷ About one-quarter of patients completed the entire six-dose treatment. Advancing soft tissue disease was the primary reason for cessation of therapy. A decline in serum alkaline phosphatase was more common than a decline in serum prostate-specific antigen (PSA) level.

Response to ²²³RaCl₂ may be predicted by ¹⁸F-NaF PET imaging.^28,29 Despite interpatient and intrapatient heterogeneity of absorbed dose estimates to bone metastases, the baseline uptake of ¹⁸F-NaF appears to be correlated significantly with the ²²³RaCl₂ localization to the lesion. Further analysis of the ALSYMPCA trial data has also revealed significant total alkaline phosphatase decline by 87% in the ²²³RaCl₂ group vs. 23% in the placebo group by week 12 (p < 0.001). Similar observations were made with lactate dehydrogenase. The decline in serum PSA level was not statistically significant (27% in ²²³RaCl₂ group vs. 14% in the placebo group, p = 0.160). Therefore, both total alkaline phosphatase and lactate dehydrogenase levels are useful for monitoring response to ²²³RaCl₂ therapy, although neither alkaline phosphatase nor lactate dehydrogenase can act as surrogates for overall survival.³⁰ However, another investigation showed that overall survival was correlated with alkaline phosphatase level.³¹

There have been a number of studies that have focused on sequencing or combining ²²³RaCl₂ with other available therapies (e.g., sipuleucel-T, abiraterone acetate, enzalutamide, pembrolizumab, atezolizumab, niraparib, olaparib, and paclitaxel) in the clinical setting of men with mCRPC.³² Studies have shown that ²²³RaCl₂ is effective regardless of prior docetaxel and that additional chemotherapy following ²²³RaCl₂ is feasible and well-tolerated.^33,34 Morris et al. performed a phase I dose escalation and a randomized phase IIa trial combining ²²³RaCl₂ with docetaxel in patients with castration-resistant prostate cancer and bone metastases.³⁵ The end points were safety, efficacy, and treatment-related changes in serum and imaging biomarkers. The dose escalation study included 20 patients for the purpose of defining the recommended phase II dose (RP2D). The RP2D was determined to be ²²³RaCl₂ at 55 kBq/kg every 6 weeks × 5 doses plus docetaxel 60 mg/m² every 3 weeks × 10 doses with febrile neutropenia as the dose limiting factor. The 2:1 randomized phase IIa portion of the investigation compared the combination arm at RP2D with docetaxel at a dose of 75 mg/m² every 3 weeks. The combination arm had longer median time to PSA progression than the monochemotherapy arm (6.6 vs. 4.8 months, respectively). Similar observations were made with median time to alkaline phosphatase progression and osteoblastic bone findings on imaging. Similar encouraging results have been reported with ²²³RaCl₂ in combination with paclitaxel.³⁶

Of the ongoing clinical trials on combination therapies, the trial on ²²³RaCl₂ plus abiraterone acetate has produced interesting results suggesting that while combination therapies may be effective, they may not always be safe. Smith et al. reported on an international, multicenter, randomized, double-blind, placebo-controlled, phase III trial on 806 patients who received either ²²³RaCl₂ (401 patients) or placebo (405 patients) in addition to abiraterone acetate (abi) plus prednisone or prednisolone.³⁷ Eligible patients had progressive chemotherapy-naive asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The primary endpoint was symptomatic skeletal event-free survival. The study was unblinded early when an interim analysis showed more fractures and deaths in the combined ²²³RaCl₂ and abiraterone acetate group in comparison to the combined placebo and abiraterone acetate group. Median symptomatic skeletal event-free survival was 22.3 months in radium+abi group and 26.0 months in the placebo+abi group. Fractures occurred in 29% and 11% of the radium+abi and placebo+abi groups, respectively. This trial concluded that combined radium+abi did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases. Van der Doelen et al. summarized the data on the updated interim analysis noting that majority of extra fractures in the radium+abi group were at sites with no bone metastases (i.e., not pathologic fracture).³⁸ Fractures occurred more frequently in patients with osteoporosis, those who did not receive concurrent bone health agents (e.g., bisphosphonates, denosumab), or had lower number of bone metastases at baseline (<6 vs. ≥6). In view of these observations, the European Medicines Agency (EMA) announced the following restriction in September 2018: “Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone. In addition, Xofigo should not be started in the first 5 d following the last dose of abiraterone and prednisone/prednisolone. Subsequent systemic cancer treatment should not be initiated for at least 30 d after the last administration of Xofigo.” The U.S. FDA has not changed the original package insert information. Interestingly, a more recent prospective phase II trial (eRADicAte) in 31 patients with metastatic castration-resistant prostate cancer treated with combined ²²³RaCl₂ and abiraterone acetate plus prednisone reported improvement in quality life and pain measures without unexpected adverse events.³⁹ The differing conclusions of the currently available data on the utility and limitations of combination use of ²²³RaCl₂ with abiraterone acetate suggest the need for additional investigations in this clinical setting.

The PEACE-3 (NCT02194842) clinical trial is a randomized phase III open label trial to assess if upfront combination of enzalutamide (160 mg daily) and ²²³RaCl₂ (50 kBq/kg standard dose monthly for 6 months) improves radiological progression-free survival (defined by the Prostate-Cancer clinical trials Working Group 2) compared to enzalutamide alone (160 mg daily) in asymptomatic or mildly symptomatic castration-resistant prostate cancer bone metastases. The trial is currently recruiting patients and is anticipated to be completed in April 2021.

Sartor et al. reported on a prospective phase I/II study of 44 patients who were retreated with ²²³RaCl₂ after completing the initial six cycles of ²²³RaCl₂ therapy without on-treatment progression of osseous metastatic disease.⁴⁰ In this cohort, approximately two-thirds of the patients completed all six retreatment administrations with no major adverse events, suggesting that in a subset of patients with stable bone metastases, retreatment with ²²³RaCl₂ may be a viable therapeutic option.

There has also been an interest in exploring the use of ²²³RaCl₂ earlier in the continuum of metastatic prostate cancer (i.e., metastatic castration-sensitive prostate cancer). Osvaldo et al. reported on their initial experience with the feasibility, safety, and efficacy (decline in bone pain) of combining ²²³RaCl₂ and androgen deprivation therapy in 7 men with mCSPC.⁴¹ Another small-scale study of 10 patients with mCSPC after radical prostatectomy demonstrated similar findings of reduced bone pain based on self-reporting Brief Pain Inventory questionnaire with median decrease of 36% after three cycles and 40% after end of all six therapy cycles.⁴² Potential efficacy of ²²³RaCl₂ combined with androgen deprivation therapy and stereotactic body radiation therapy of patients with oligometastatic disease (<4 metastases on conventional imaging) is also being explored.⁴³

Although ²²³RaCl₂ has been approved since 2013 for treatment of patients with castration-resistant prostate cancer and bone metastases, there have been other active investigations on the potential use of ²²³RaCl₂ in cancers other than prostate cancer (e.g., osteosarcoma, bone-dominant breast cancer).^44,45 Dizdarevic et al. provides an excellent recent review of ²²³RaCl₂ mono- or combination trials in prostate cancer and other tumors.⁴⁶

²²⁵Ac

Actinium-225 is another potentially useful α-emailer in TRT. It has a half-life of 9.9 d and decays to ²⁰⁹Bi (half-life of 1.9 × 10¹⁹ years) through net production of four α particles with energies in the range of 5.8–8.4 MeV at tissue travel distance of 47–85 μm, two β⁻ particles, and γ emissions at 218 and 440 KeV. ²²⁵Ac may be sourced from ²²⁹Th with current worldwide production of ∼68 GBq per year which is anticipated to grow.^47
–49 The National Isotope Development Centers provide alerts when new batches of the accelerator-produced ²²⁵Ac are available through the U.S. Department of Energy Isotope Program.

Preclinical studies

There is a fair range of preclinical studies in various cancers that have demonstrated the potential utility of ²²⁵Ac for targeted therapy.⁵⁰ Kelly et al. showed that a single dose of 148 kBq ²²⁵Ac conjugated to albumin-binding PSMA-targeting RPS-074 (²²⁵Ac-RPS-074) in LNCaP xenograft mouse model of human prostate cancer induced a complete response in six of seven tumors without major toxic effects.⁵¹ Lower doses produced transient partial responses. More recently, researchers reported on a useful mouse model of human metastatic prostate cancer by injecting C4–2 cells into the left ventricle of immunodeficient male NSG mice, which was then used to evaluate the effectiveness of ²²⁵Ac-PSMA-617 at various disease stages.⁵² This preclinical study suggested that early ²²⁵Ac-PSMA-617 intervention is more efficacious in the setting of widespread metastatic prostate cancer. Delivery to tumor may also be accomplished by loading ²²⁵Ac into PEGylated liposomes targeted to mouse antihuman PSMA J591 antibody or A10 PSMA aptamer.⁵³ Liposomes when loaded with ²²⁵Ac or other α-emitters are attractive delivery systems since they can be modified in various ways selectively to improve therapeutic efficacy.⁵⁴

Encouraging results have been reported with in vitro experiments utilizing an antihuman epidermal growth factor type 2 (HER-2) nanobody (²²⁵Ac-DOTA-Nb) in tumor cells overexpressing HER-2.⁵⁵ Mouse models of human ductal carcinoma in situ tumor treated with ²²⁵Ac-trastuzumab targeting HER2/neu also demonstrated utility as a worthwhile treatment modality without renal toxicity.^56,57

In diseases that are challenging to eradicate such as peritoneal carcinomatosis, TAT may provide a useful therapeutic option. German investigators showed that in mice bearing intraperitoneal MDA-MB-435 xenograft tumors, both vascular tumor-homing peptide F3 targeted with ²²⁵Ac-DOTA-F3 and ²¹³Bi-DTPA-F3 and administrated intraperitoneally prolonged median survival in treated mice with mild renal toxicity in comparison to control untreated mice.⁵⁸

Melanocortin 1 receptor (MC1R) may be used as a relevant biological target for treatment of melanoma. In a recent report, Tafreshi et al. evaluated ²²⁵Ac-DOTA-MC1R radioligand in BALB/c mice bearing MC1R-positive and -negative tumors demonstrating the efficacy of the TAT as a potential novel therapy for metastatic uveal melanoma.⁵⁹

Clinical studies

There have been a number of small clinical studies using TRT with ²²⁵Ac as the conjugated α-emitter in a variety of cancers with generally encouraging efficacy and acceptable and/or manageable safety profile. Jurcic reported on a phase I study of 18 patients with relapsed or refractory acute myeloid leukemia who underwent anti-CD33 humanized monoclonal antibody treatment with ²²⁵Ac-lintuzumab for doses up to 111 kBq/kg demonstrating up to 28% objective responses.⁶⁰

There has been much interest in potential efficacy of ²²⁵Ac-labeleled PSMA-targeted in treatment of patients with mCRPC. Some of these early experiences, mostly as case reports or small case series, have been encouraging with remarkable favorable responses in individual patients although at some cost with xerostomia.⁶¹ Kratochwil et al. from Germany reported on dosimetry estimates and empiric dose finding for targeted therapy of mCRPC with ²²⁵Ac-PSMA-617.⁶² The author found that a treatment activity of 100 kBq/kg of ²²⁵Ac-PSMA-617 per cycle every 8 weeks was an apparent optimal trade-off between toxicity and biochemical efficacy.

²¹³Bi

Bismuth-213 is an α-emitter that has received attention for potential clinical use. ²¹³Bi emits both α (∼92.7%) and β (∼7.3%) particles with a relatively short half-life of 46 min. The 8.375 MeV α particle that is emitted by ²¹³Po along the decay path of ²¹³Bi comprises more than 98% of the α-particle energy from ²¹³Bi disintegration.⁶³ The decay cascade also includes 26.1% probability of 440 KeV γ-ray emission that allows imaging the ²¹³Bi biodistribution.

Preclinical studies

There has been an increasing interest in the use of TAT in the setting of metastatic prostate cancer spearheaded by the approval of ²²³RaCl₂.⁶⁴An in-vitro and LNCaP xenograft animal model study of two PSMA targeted α-radioligands (²¹³Bi-PSMA I&T and ²¹³Bi-JVZ-008) confirmed α-particle induced double-strand DNA damage.⁶⁵ An investigation using a prostate cancer animal model compared ²¹³Bi-DOTA-PESIN (DOTA-PEG(4)-bombesin) and ²¹³Bi-AMBA (DO3A-CH(2)CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH(2)) with ¹⁷⁷Lu-DOTA-PESIN reported that α particle therapy with either of 2 agents tested was more efficacious than the counterpart β particle agent therapy.⁶⁶ McDevitt and colleague used ²¹³Bi-J591 targeted to PSMA directed against androgen-sensitive LNCaP spheroids resulting in significantly improved median tumor-free survival.⁶⁷ Radionuclide therapy with ²¹³Bi-labeled plasminogen activator inhibitor type 2 targeting cell surface urokinase plasminogen activator receptor (uPAR) in prostate cancer nude mouse xenograft model has also demonstrated efficacy without major toxicity.⁶⁸

Another preclinical study with myeloma xenografts treated with ²¹³Bi-anti-CD38-Mab showed evidence for tumor DNA damage and apoptosis that was associated with significantly prolonged animal survival in comparison to untreated control animals.⁶⁹ Similar results for myeloma have been reported with ²¹³Bi-anti-mCD138 radioimmunotherapy as an alternative to Melphalan.^70
–72 Therapeutic efficacy with no acute or chronic toxicity has also been shown in a mouse model of gastric cancer with ²¹³Bi-d9 monoclonal antibody targeting d9-E-cadherin.⁷³ Similar good results have been reported in preclinical models of pancreatic neuroendocrine tumors with ²¹³Bi-[DOTA0, Tyr3]octreotide peptide receptor and in pancreatic adenocarcinoma targeting tumor-associated antigen MUC-1 with ²¹³Bi-CHX-A”-C595 leading to regression of tumor cells in vitro and delay and inhibition of tumor growth in vivo. ^74,75 In breast cancer models, ²¹³Bi-labeled-plasminogen activator inhibitor type 2, ²¹³Bi-Herceptin (targeting HER2/neu), and ²¹³Bi-labeled humanized anti-Lewis Y monoclonal antibody hu3S193 have shown therapeutic efficacy.^76

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In setting of experimental model of lymphoma, ²¹³Bi-labeled anti-CD74 showed suppression of tumor growth and in some cases cures.⁸¹ Therapeutic efficacy with ²¹³Bi-anti-CD45 antibodies has been shown in leukemic cells overcoming DNA repair mechanisms and chemoradioresistance.⁸² Kennel et al. showed that ²¹³Bi-mAb 201B targeted to lung blood vessels can effectively control tumors growing in the lung.⁸³ Swedish investigators showed the potential efficacy of ²¹³Bi-labeled monoclonal antibody MX35 in intraperitoneally inoculated human ovarian cancer cells in female BALB/c (nu/nu) mice.⁸⁴ Similar efficacy has been shown with ²¹³Bi-DTPA-F3 targeting vascular tumor-homing peptide F3 in combination with paclitaxel in treating intraperitoneal OVCAR-3 tumor xenografts.⁸⁵

Delivery of ²¹³Bi via immunoliposomal vehicles has also been demonstrated in a rat/neu transgenic mouse model of metastatic breast cancer targeting HER-2/neu expressing tumors.⁸⁶ An in vitro study assessed the effect of hypoxia on cellular killing efficacy of ²¹³Bi-anti-epidermal growth factor receptor (EGFR).⁸⁷ Cell death was shown to be independent of cellular oxygenation, which suggests sensitivity of hypoxic cells to α therapy in competitive advantage over chemoradiotherapy.

Clinical studies

Krolicki et al. used ²¹³Bi-substance P (²¹³Bi-DOTA-SP) radioligand therapy, targeted to neurokinin type 1 receptor, to treat 50 patients with recurrent glioblastoma multiforme by injecting the radioligand (1–6 doses of 0.9–2.3 GBq in 2 months intervals) into the tumor cavity.⁸⁸ Proper localization of the therapy radioligand was confirmed with coinjection of ⁶⁸Ga-DOTA-SP. The median progression-free survival and overall survival were 5.8 and 16.4 months, respectively, with transient headache as the main side effect. In another recent study from the same group of investigators, one to seven therapy doses of activity up to 11.2 GBq at 2-month intervals in 20 patients with recurrent glioblastoma multiforme was noted to be safe and well-tolerated with overall survival benefit compared to historical outcome data with conventional therapies.⁸⁹ Others have reported similar findings in the clinical settings of functional critically located gliomas and low-grade gliomas.^90,91 Although these are encouraging results for tumor control in this challenging disease, prospective studies with proper controls are needed to assess the incremental outcome benefit with this form of TRT.

Preclinical and follow-up clinical studies have investigated the intravesical administration of ²¹³Bi-immunoconjugate targeting EGFR in treating 12 patients with biopsy-proven carcinoma-in-situ of the urinary bladder refractory to bacillus Calmette-Guerin therapy.^92,93 These author showed well-tolerated efficacy in this limited number of patients and suggested a phase I clinical trial to be followed. In patients with metastatic melanoma, efficacy of local metastasis-directed therapy with intralesional injection of ²¹³Bi immunoconjugate targeting vector 9.2.27 has been shown to be efficacious.⁹⁴ Such approach may be workable in the setting of metastatic-directed therapy in oligometastatic disease, which is of much current interest as a form of interim management approach in lieu of systematic therapy.

As previously discussed, α particle therapy targeted to the PSMA is efficacious and a topic of major interest in research. Sathekge et al. from South Africa presented a case report of a patient with mCRPC who demonstrated exceptional response to ²¹³Bi-PSMA-617 therapy.⁹⁵

²¹¹At

Preclinical and clinical studies

Astatine-211 is an α-emitter radiohalogen with half-life of 7.2 h with mean energy of 6.9 MeV with a currently limited availability.⁹⁶ Vaidyanathan and Zalutsky provide an excellent review of potential applications of ²¹¹At.⁹⁷ Kennel et al. showed efficacy against lung tumor colonies of EMT-6 cells using lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[²¹¹At-[astatophenethyl) succinamate linker.⁹⁸ Other preclinical studies have been reported in settings of leukemia (²¹¹At-anti-CD25 monoclonal antibody 7G7/B6), metastatic melanoma (²¹¹At-methylene blue), and peritoneal carcinomatosis (²¹¹At-microsphere colloids), and ¹³¹I-refractory metastatic thyroid cancer.^99

–102 In the clinical arena, 12 patients with relapsed epithelial ovarian cancer were treated with intraperitoneal administration of 215 MBq/L of ²¹¹At-MX25 F(ab′)2.¹⁰³ No signs of radiation-induced toxicity were noted and dosimetric calculations suggested that further dose optimization can be performed to increase efficacy.

²²⁷Th

Preclinical studies

Thorium-227 is another α-emitting radioisotope that is gaining traction in TRT of cancer. It has a half-life of 19 d decaying first to ²²³Ra and then follows the decay of ²²³Ra.

A preclinical study reported on mesothelin (MSLN)-targeted conjugate of ²²⁷Th, comprising fully human IgG1 antibody BAY 86–1903, covalently conjugated to a 3,2-HOPO chelator enabling stable complexation of ^227Th.¹⁰⁴ MSLN is 40 kDa membrane-anchored glycoprotein expressed in mesothelial cells lining of pleura, pericardium, and peritoneum, which is thought to be involved in cell adhesion and is overexpressed in many cancers. Hagemann et al. showed the potential value of ²²⁷Th-MSLN conjugate in vitro and in vivo in cell line and patient-derived xenograft (PDX) models of breast, colorectal, lung, ovarian, and pancreatic cancers.¹⁰⁴ Wickstroem et al. evaluated the efficacy of ²²⁷Th-MSLN conjugate in combination with the DNA damage response inhibitor, olaparib, in the OVCAR-3 xenograft model.¹⁰⁵ The encouraging results have prompted a first human study of such construct in patients with MSLN expressing tumors (NCT03507452). In the preclinical setting of athymic nude mouse model of intraperitoneal human ovarian carcinoma (SKOV3-luc-D3 cells), targeted therapy with ²²⁷Th-trastuzumab has been found to be more efficacious than unlabeled trastuzumab anti-HER2 therapy.¹⁰⁶

As declared above, PSMA has been identified as a clinically valuable biomarker for theranostics in prostate cancer. In addition to reports on ²²⁵Ac- and ²¹³Bi-labeled PSMA-based agents described previously, Hammer et al. described the preclinical efficacy of ²²⁷Th-PSMA conjugates in PDX models of prostate cancer, which prompted an ongoing phase I trial in patients with mCRPC (NCT03724747).¹⁰⁷ Synergistic efficacy has also been demonstrated with HER2 targeted ²²⁷Th conjugates in combination with DNA repair inhibitor drug, olaparib (poly ADP ribose polymerase inhibitor) in BRCA2 deficient xenograft tumor models.¹⁰⁸ The same group of investigators have also reported on the potential utility of ²²⁷Th conjugates targeting the fibroblast growth factor receptor 2 (FGFR2), which is overexpressed in many cancers, and in acute myeloid leukemia targeting CD33.^109,110

²¹²Pb

Preclinical and clinical studies

Pb-212 is a β⁻-emitter (half-life 10.64 h) and serves as an in vivo nanogenerator of ²¹²Bi (half-life 1.01 h), which decays to stable ²⁰⁸Pb via α-particle emission. Yong and Brechbiel provide a comprehensive review of ²¹²Pb in targeted α-particle therapy of cancer.^111,112

Recently, the group of investigators from Johns Hopkins University reported on a proof-of-concept therapy study of dose-dependent inhibition of human prostate tumor growth in PSMA⁺ tumors in animal hosts.¹¹³ The tumor evolution could be monitored with scintigraphy using the surrogate radionuclide, ²⁰³Pb (half-life 51.9 h, γ = 279 KeV) using single-photon computed tomography, supporting the notion of ²⁰³Pb/²¹²Pb as a relevant and useful theranostic radionuclide pair.¹¹⁴

Preclinical efficacy of ²¹²Pb-labeled antivascular cell adhesion molecule-1 (VCAM-1) in treatment of brain metastases of human breast cancer cells injected into the left ventricle of nude mice has been demonstrated.¹¹⁵ Similar encouraging results have been noted in animal models of ²¹²Pb-DOTAMTATE in treatment of somatostatin receptor overexpressing neuroendocrine tumors.¹¹⁶ Kasten et al. evaluated the potential therapeutic utility of ²¹²Pb-labled antibody 225.28 targeted to chondroitin sulfate proteoglycan 4 in triple negative breast cancer.¹¹⁷ These author found that ²¹²Pb-225.28 was effective in eliminating triple negative breast cancer tumors in xenograft and orthotopic animal models. Same investigators reported similar results with therapeutic efficacy of ²¹²Pb-labeled B7–H3 targeting human pancreatic ductal adenocarcinoma and ovarian cancer xenografts in immunodeficient mice.^118,119 Milenic et al. performed preclinical studies of ²¹²Pb-cetuximab targeted to HER1-positive disseminated peritoneal carcinomatosis showing such TRT may be potentially useful clinically.¹²⁰

First-in-human studies of ²¹²Pb-TCMC-trastuzumab therapy of HER2-positive intraperitoneal ovarian cancer metastases have been shown to be safe, although efficacy needs further investigations to be established.^121,122

Summary

The author summarized some of the preclinical and clinical studies in the setting of targeted α-therapy. ²²³RaCl₂ is an established first-in-class targeted α-therapy in metastatic castration-resistant prostate cancer with bone metastases. Many preclinical and early clinical studies are also being pursued with ²²⁵Ac, ²¹³Bi, ²¹¹At, ²²⁷Th, and ²¹²Pb of which those with ²²⁵Ac are more robust and probably closer to translation into the clinic. Targeted α-particle therapy is destined to become an important strategy within the armamentarium of cancer management in the near future.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

Supported, in part, by grants R21-EB017568 and P30-CA014089 from the National Institutes of Health.

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