Radiopharmaceuticals for Cancer Diagnosis and Therapy:

Abstract

Radiopharmaceutical therapy has emerged as a promising approach for the treatment of various cancers. The exploration of novel targets such as tumor-specific antigens, overexpressed receptors, and intracellular biomolecules using antibodies, peptides, or small molecules has expanded the scope of radiopharmaceutical therapy, enabling precise and effective cancer treatment for an increasing number of tumor types. Alpha emitters, characterized by their high linear energy transfer and short path length, offer unique advantages in targeted therapy due to their potent cytotoxicity against cancer cells while sparing healthy tissues. This manuscript reviews recent advancements in identifying novel targets for radiopharmaceutical therapy and applications in utilizing alpha emitters for targeted treatment.

Introduction

Radiopharmaceutical therapy (RPT) traces its roots back to the discovery of radioactivity by Henri Becquerel in 1896 and the subsequent pioneering work of Marie Skłodowska-Curie and Pierre Curie.¹ The application of radioactive elements in medicine began with the development of diagnostic techniques, but it wasn’t until the mid-20^th century that radiopharmaceutical therapy emerged as a promising avenue in cancer treatment. Broadly, RPT administration results in DNA damage and subsequent cell death due from α or β-mediated radiation administered systemically and then trafficked into cells. In 1941, the first targeted radiotherapy was administered using a mixture of radioactive iodine to treat thyroid disorders.² This empowered researchers to explore the potential of various radioactive isotopes to selectively target and destroy cancer cells while minimizing damage to healthy tissue. The 1950s witnessed significant advancements in radiopharmaceutical research, including the introduction of radiolabeled compounds for imaging and therapeutic purposes. However, cancer-specific targeting continued to remain a challenge and widespread use continued to be relatively limited.

While iodine enjoyed early success and widespread adoption due to the natural availability of the target, the iodide symporter, and the targeting agent, modern agents using simplified production, chelators allowing for testing of different combinations, and rational targeting have dramatically expanded the indications for RPT. Specifically, the relatively recent approvals of ¹⁷⁷Lu-DOTATATE (for neuroendocrine tumors) and ¹⁷⁷Lu-PSMA-617 for metastatic castrate resistant prostate cancer (mCRPC) ushered in new consideration for novel targets and therapeutic agents in routine use, and additional data demonstrating efficacy in even earlier lines of therapy continue to engender excitement around these and other targets.³⁴ There is consensus that the RPT market is a multi-billion-dollar industry with compound annual growth rates up to 20% per year and a total market of $13.07 billion by 2030.⁵⁶

While RPT is now firmly established in the oncology space, there is tremendous opportunity out of the challenges that have been uncovered – the logistical challenges include isotope and drug production and distribution, workforce shortages and regulatory. In addition, biological questions still need to be addressed such as continued off-target toxicity and sub-total cell killing, suboptimal delivery of drug to target, tumor and receptor expression heterogeneity and radiosensitivity.^5,7 The inherent physical properties of the radioligand and the pharmacology of the targeting vector will govern the utility of each specific RPT agent.⁸ Novel targets and vectors, as well as novel α-emitting agents, along with normal tissue safeguarding, can mitigate these issues and further refine RPT, ensuring that this remarkable treatment evolves to match patient and provider needs.

Novel Targets

There are a number of FDA-approved RPT agents in routine clinical use, with attention to ¹³¹I-NaI, ¹⁷⁷Lu-DOTATATE (Lutathera, Novartis AG), ¹⁷⁷Lu-PSMA-617 (Pluvicto, Novartis AG), and ²²³RaCl₂ (Xofigo, Bayer Healthcare). There have also been several agents whose clinical utility was realized but use ultimately waned or was terminated due to replacement by more effective agents or challenges in production, distribution, and use – these include ¹³¹I-MIBG (Azedra, Lantheus), ⁸⁹SrCl₂ (Metastron, GE Healthcare), ¹⁵³Sm lexdronam (Quadramet, Lantheus), ⁹⁰Y-ibritumomab (Zevalin, RIT Oncology), and ¹³¹I-tositumomab (Bexxar, GlaskoSmithKline). While personalized dosimetry and combinatorial therapy may refine application of currently approved agents, novel RPT agents are critically needed for additional tumor types and to mitigate inter-tumoral heterogeneity limiting efficacy of usual agents.⁹ This also presents interesting opportunities for ‘cocktail’ RPT where multiple targets are treated simultaneously with different agents or emitters.

While an exhaustive list of novel agents in pre-clinical testing is outside the scope of this review, we discuss a number of promising and late-stage clinically studied targets and corresponding agents. Although the focus is on the targets themselves, there are also a variety of classes of agents such as small molecules, peptides, minibodies, and antibodies each with distinct pharmacologic properties to address each target. A detailed discussion of the differential properties of classes of agents are also beyond the scope of this review.

FAP:

Fibroblast activation protein (FAP) is highly expressed in over 90% of epithelial cancers, as well as sarcomas.¹⁰ It is a transmembrane glycoprotein that is expressed at low or nearly undetectable levels in most normal human cells. The overexpression of FAP in tumors is largely driven by its overexpression on cancer associated fibroblasts (CAFs) even though a minority of cancers demonstrate FAP overexpression on tumor cells themselves. Tumors even just over 1-2 mm in size require a supporting stroma which ultimately may form the majority of the tumor bulk itself.¹¹ In addition, high expression of FAP has been associated with poor prognosis in several solid cancers.¹² Given the wide overexpression of FAP in most solid tumors, there is tremendous excitement over the concept of FAP-targeted agents as a ‘pan-cancer theranostic’ to be applied in cancer care in tumor-agnostic forms. There is considerable attention drawn to FAP as a target for pancreatic carcinoma, soft tissue sarcoma (STS), non-small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC), among others.

FAP-directed imaging, largely with ⁶⁸Ga-radioligands have revealed excitingly very high tumor-to-background ratios. ⁶⁸Ga-FAPI-04 tumor uptake was particularly high in sarcoma, NSCLC, breast cancer, and esophageal cancer, and relatively low in renal cell, differentiated thyroid, and gastric cancer.¹³ However, some non-oncologic conditions such as inflammation or trauma or other pro-fibrotic conditions may increase the expression of FAP, which is a challenge for theranostic pairs but opens up opportunities for non-oncologic imaging or diagnostic differentiation.¹⁴ Soft tissue sarcoma (STS) is particularly attractive, in this context, given the significant tumor diversity of the disease entity and the possibility that RPT could accumulate highly enough to overcome the known relative radioresistance of STS. The DOTA chelator makes these FAP-targets attractive due to ease of pairing ⁶⁸Ga with a therapeutic partner, most commonly ¹⁷⁷Lu, but also ⁹⁰Y and ²²⁵Ac.

Particularly well-studied molecules include the diagnostic FAPI-04 labeled with ⁶⁸Ga (e.g., the Heidelberg compounds, licensed to SOFIE Biosciences) and the theranostic pair FAPI-2286 labeled with ⁶⁸Ga/¹⁷⁷Lu (licensed to Novartis Pharmaceuticals), while others are appearing on the horizon. Results are intriguing but large clinical data are pending and sometimes mixed. FAPI-2286, which has longer tumor retention that FAPI-02 or FAPI-04, was studied by Baum et al in 11 patients with cancer of the pancreas, breast, rectum, or ovary at 5.8 GBq per dose up to 3 cycles with high absorbed doses at mean 3 Gy/GBq without many high-grade adverse events.¹⁵ Two of 11 patients had stable disease at 6-8 weeks post-treatment. This demonstrated sufficient data to proceed forward with future study, the Phase 1/2 LuMIERE study of ¹⁷⁷Lu-FAPI-2286 in advanced solid tumors (Novartis, ClinicalTrials.gov NCT04939610). Another molecule, PNT6555 (Point BioPharma), was studied in the FRONTIER clinical trial (NCT05432193), consisting of a DOTA chelator and a FAP-targeting moiety (Bz-D-Ala-boroPro) connected via an aminomethyl linker. Although in pre-clinical studies there was high tolerability and excellent anti-tumor effect, there was not suitable tumor uptake in the Phase 1 human study to continue onto a Phase II efficacy study.¹⁶ These data demonstrate that although FAP molecules show promise particularly as a pan-cancer diagnostic agents, further molecular bioengineering advancement is required to improve their tumor retention (and hence the tumor absorbed dose) and their therapeutic capability.

GRPr:

Gastrin-releasing peptide (GRP) is a bombesin analogue that acts on the Gastrin-releasing peptide receptor (GRPr) expressed in the central nervous and gastrointestinal system.¹⁷ GRPr is a cell surface receptor that is overexpressed on many human cancers, including those of the prostate and breast, and may have implications in carcinogenesis and tumor mobility. GRPr has relatively low expression in mammalian normal tissue except for lymphoid tissue and some enteric tissues specifically the pancreas. Antagonist GRPr-ligands show superior tolerability compared to GRPr-agonists and have been chosen for further development largely as peptides. Given the relatively high expression in cancer, low expression in normal organs, and ability to target with a peptide (GRP-antagonists), there is high interest in pursuing GRPr-targeting theranostics especially given that a DOTA-chelated theranostic pairs are available. These peptides as a class are attractive given rapid uptake and clearance, limited immunogenicity, and relatively simple production and labeling.

Since there is heterogeneity of human cancers, for example approximately 15-20% of men with mCRPC will not have PSMA expression, alternative or complementary targets to PSMA present attractive opportunities such as GRPr-ligands. Several imaging studies have demonstrated high diagnostic ability of GRPr-compounds particularly in prostate cancer. Touijer et al reported on a prospective cohort of men imaged with intact prostate cancer treated with radical prostatectomy. ⁶⁸Ga-RM2 PET/MRI demonstrated nearly 89% accucaracy compared to ground truth pathology specimens.¹⁸ In breast cancer, there is strong association of GRPr expression with hormone receptor positive (HR+) breast cancer, in some studies showing 93-100% positivity of GRPr in these patients.^19,20

A number of theranostic trials, both tumor-specific and basket, aim to exploit the high expression of GRPr in these cancers.²¹ The NeoRay study, a multi-center open-label Phase I/II study, is examining the safety and anti-tumor efficacy of every six week infusion of GRPr analogue ¹⁷⁷Lu-NeoB (Advanced Accelerator Applications and Novartis) in patients with advanced solid cancers expressing GRPr (ClinicalTrials.gov, NCT03872778). There was primarily renal excretion and lower-than-expected toxicity in at-risk organs such as the pancreas and red bone marrow, without safety concerns at doses of 150-250 MBq per administration. The total kidney dose is estimated 7.8Gy per highest investigated dose of 11.1 GBq over 6 cycles, and 56.3 Gy cumulative to the tumor. Specific to breast cancer, ¹⁷⁷Lu-NeoB will be escalated from 100-250 mCi per cycle in combination with ribociclib, a CDK4/6 antagonist and the anti-estrogen agent fulvestrant in a Phase Ib multi-center study (NCT05870579). Specific to men with mCRPC ineligible to receive ¹⁷⁷Lu-PSMA-617, the COMBAT Phase I/IIa study will examine the theranostic pair ⁶⁴Cu-SAR-BBN/⁶⁷Cu-SAR-BBN (Clarity Pharmaceuticals, ClinicalTrials.gov NCT05633160). While ¹⁷⁷Lu represents an available and familiar β-emitting therapeutic, α-emitting molecules are also under study. A Phase 1 study is underway to characterize ²¹²Pb-DOTAM-GRPR1 in advanced and recurrent solid tumors that express GRPr, specifically mCRPC, hormone receptor positive breast cancer, colorectal cancer, cervical cancer, cutaneous melanoma, and NSCLC. In the dose-escalation phase, 5.5mCi will be administered per cycle with up to 24mCi in 4 cycles (Orano Med LLC, ClinicalTrials.gov NCT05283330). Clinical results for these GRPr molecules are pending, but these GRPr targeting agents represent an exciting frontier for patients whose tumors express these molecules and may not be candidates for already approved or more tumor-specific agents. Of note, GRPr targeting ligands do not have significant accumulation in the salivary glands, thus making these drugs excellent alternatives for α-labeled PSMA radioligands, for which xerostomia is one of the main dose limiting toxicities.

CA-IX:

Carbonic anhydrase IX (CA-IX) is a cell surface glycoprotein that can be overexpressed in hypoxic states, and inhibition of which can reduce tumor growth and metastatic potential via suppression of cancer stem cells.²² CA-IX is strongly upregulated by hypoxia (e.g., HIF-1α) and subsequently modulates pH in the microenvironment. CA-IX primarily is restricted in normal organ expression to the small intestine but is overexpressed in a variety of malignancies including cancers of the kidney, breast, colon, lung, cervix, and head and neck. Clear cell renal cell carcinoma (RCC) is somewhat unique in that CA-IX expression is somewhat independent from the hypoxia cascade, and largely governed by impaired function of the von Hippel-Lindau tumor suppressor that would negatively regulate HIF-1α. Given this inherent nature of clear cell RCC, CA-IX targeting is particularly attractive as a theranostic pair. However, outside of CA-IX expression in the hypoxic niche generally there is enhanced efficacy of anti-CA-IX agents when combined with other therapies e.g., cytotoxic chemotherapy.

The most investigated ligand for CA-IX is girentuximab (cG250), a monoclonal antibody, characterized early with a ¹²⁴I-cG250 diagnostic study quantifying uptake in kidney tumors.²³ An early Phase II study by Muselaers et al analyzed patients with advanced clear cell RCC who received 2405MBq/m2 of ¹⁷⁷Lu-girentuximab and a second dose at 75% of first dose for those without progressive disease or toxicity.²⁴ Disease was stabilized in 9 of 14 patients with progressive metastatic ccRCC, but most patients experienced Grade 3-4 myelotoxicity. Clinical trials are currently underway in CA-IX expressing RCC for ¹⁷⁷Lu-girentuximab in combination with cabozantinib and nivolumab (STARLITE-1, NCT05663710) or nivolumab alone (STARLITE-2, NCT05239533). The phase 1b STARSTRUCK trial (NCT05868174) is studying the combination of ¹⁷⁷Lu-girentuximab with peposertib, a DNA-Protein Kinase (DNA-PK) inhibitor in CA-IX expressing tumors. Antibodies are not, however, the sole approach. The Phase 1b/2 GaLuCi clinical trial seeks to establish the safety of CA-IX targeting with a peptidomimetic-based theranostic pair ¹⁷⁷Lu/⁶⁸Ga-DPI-4452. In earlier study and reporting of the imaging portion, administration of the diagnostic agent demonstrated in patients with clear cell RCC mean SUVmax of 64.6 with 17/36 ‘ground truth’ lesions not detected on prior contrast-enhanced CT imaging (NCT05706129). These very high tumor-to-background ratios demonstrate high potential for theranostic translation.

Additional targets and relevant clinical trials are demonstrated in Table 1. These include CXCR4, FGFR, cMET, and integrins.

Table 1:

Clinical trials of select novel targets for radiopharmaceutical therapies

Target	Therapeutic	Phase	Clinical Trial Title	Disease	Trial Identifier
CXCR4	177Lu-Pentixather	I/II	COLPRIT trial	Neuroendocrine tumors	Eudra-CT 2015-001817-28
	212Pb-Pentitaxather	I	A Safety Study of 212Pb-Pentixather Radioligand Therapy	Atypical lung carcinoid, neuroendocrine tumors	NCT05557708
	90Y-Pentitaxather	I/II	[90Y]Y-PTT Endoradiotherapy in CNS Lymphoma Patients	Lymphoma	NCT06132737
IGF-IR	225Ac-FPI-1434	I/II	A Phase 1/2 Study of [225Ac]-FPI-1434 Injection	Multiple: breast cancer, cervical cancer, uterine cancer, head and neck	NCT03746431
EGFR-cMET	225Ac-FPI-2068	I	A Phase 1, Dose-escalation Study of [225Ac]-FPI-2068 in Adult Patients With Advanced Solid Tumours	Multiple: head and neck squamous cell carcinoma, non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma	NCT06147037
FGFR	225Ac-FPI-1966	I/II	A Study of [225Ac]-FPI-1966 in Participants With Advanced Solid Tumours	Multiple: bladder, ovarian and head and neck cancers	NCT05363605
Integrin αvβ6	177Lu DOTA-ABM-5G	I	First-in-human Study of the Theranostic Pair [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G in Pancreatic Cancer	Pancreatic cancer	NCT04665947

Alpha Therapies

While most approved RPT are β-emitters, interest in use of α emitters has substantially increased. Αlpha emitters are attractive due to very high linear energy transfer (LET) for cell kill and very limited range in tissue limiting off-target toxicity.^25,26 Beta-particles have relatively low LET at 0.2 keV/μm, yield potentially repairable DNA lesions (single-strand breaks), and have a relatively long path length at 1000-10000μm; however, α-particles have higher linear energy transfer (50–230 keV/μm), causing clusters of DNA damage that are likely lethal (double-strand breaks), and have shorter path lengths of 50-100 μm. Alpha emitters may also have enhanced bystander and immunologic effects and due to the high LET and may be less sensitive to hypoxic environments as DNA damage is less dependent on generation of reactive oxygen species. Finally, α emitter administration may release additional α particles during decay, serving as ‘in vivo α generators’ of sorts.²⁷ Daughter radionuclides may also yield therapeutic effect which can beneficial; however, limiting unwanted daughter release can also limit radiometal toxicity and off-target toxicity. For example, ²²⁵Ac emits 4 α particles when decaying down to stable ²⁰⁹Pb. Conversely, the crossfire effect, that is the ability to deliver therapeutic ionizing radiation to cancer cells that do not express the putative target of a radioconjugate, is attributed to β-emitters because they can travel much farther than α emitters and is thought to contribute to the therapeutic effect of β particle emitting conjugates. One analysis of the global market for α emitters indicates projected growth to $5.2 billion by 2027 from estimated $672.3 million in 2020.⁶

Alpha emitters in the clinic:

The first clinical α particle emitting radioconjugate developed was the CD33 targeted, ²¹³Bi-labeled monoclonal antibody HuM195 (later lintuzimab) developed in the 1990s for the treatment of myeloid leukemias.²⁸ A principal challenge of this conjugate was the short physical half-life of ²¹³Bi (t_1/2 = 45.6 min), which complicates its production workflow given that the labeling and quality assurance processes require at least two half-lives. Unsurprisingly, the ²¹³Bi generator, ²²⁵Ac (t_1/2 = 10.1 d) which has a more favorable physical half-life, later supplanted the ²¹³Bi α conjugates and was later tested in clinical trials.²⁷ In these intervening years, several α particle-emitting radioconjugates have been evaluated clinically (Table 2). That said, only ²²³RaCl₂ is currently FDA approved for use in bone-limited symptomatic metastatic castration resistant prostate cancer.²⁹ While ²²³RaCl₂ accumulates in sites of bone turnover, including bone metastases, directing ²²³Ra to soft tissue via chelation remains a challenge, though some progress has been made to that end (Abou Chemical Science 2021). It is also worth noting that ²²³RaCl₂ may be used off-label to treat bone metastases in people with breast cancer, although it is not FDA-approved for this scope.^{30 211}At has been used clinically in recurrent brain tumor or as a part of a novel conditioning regimen for bone marrow transplant, although widespread use remains limited.^31,32

Table 2:

Common alpha emitters, half-life, normal organ accumulation

Isotope	Half life	Decay Mode	% α Decay	Radiochemistry	Free isotope accumulation
211At	7.2 hours	α	42	tin precursor	lung, spleen, stomach, thyroid
225Ac	9.9 days	α	100	DOTA chelators	bone, liver
212Pb	10.6 hours	β		TCMC	blood, kidneys, liver bones
212Bi	60.6 minutes	α, β	36	DOTA, DTPA, NETA	kidneys
227Th	18.7 days	α	100	DOTA	bone
223Ra	11.4 days	α	100		bone

The β particle-emitting somatostatin receptor (SSTR)- and prostate-specific membrane antigen (PSMA)-specific radioconjugates ¹⁷⁷Lu-DOTATATE and ¹⁷⁷Lu-PSMA-617 are approved in patients with SSTR+ gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and metastatic castration resistance prostate cancer, respectively.^3,4 While most patients exhibit improved progression free survival and quality of life improvement with these agents, the responses are relatively short-lived, some patients are either resistant or refractory to treatment ab inicio, or inevitably develop progression (i.e. resistance) following initial response. In such patients, there is emerging evidence that using the α particle emitting radioconjugate to the same target can confer a therapeutic benefit.^33-35 A prospective randomized multicenter clinical phase 3 trial of ²²⁵Ac-DOTATATE vs. best standard of care in subjects with neuroendocrine tumors relapsed after initial response to ¹⁷⁷Lu-labeled octreotide derivatives (ACTION-1 trial; clinicaltrials.gov NCT05477576) is currently ongoing. On the mCRPC front, a recent critical evaluation by Sathekge et al demonstrated exciting activity of ²²⁵Ac-PSMA RPT in the WARMTH act cohort (Sathekge et al Lancet Oncology 2024). 488 men with mCRPC received at least one cycle of at least 8 MBq (median 2 cycles) of ²²⁵Ac-PSMA radioligand therapies (RLT) across multiple centers. 32% and 4% received prior ¹⁷⁷Lu-PSMA-RLT and ²²³RaCl₂, respectively. Median overall survival was 15.5 months and progression-free survival 7.9 months. 73% of patients had any PSA decline with 57% having a greater than 50% decline in PSA. These observations are encouraging and offer a potential salvage therapy based on known targets to patients with otherwise limited treatment options.

Toxicities of alpha emitter therapy:

Importantly, while there may be benefit in pursuing an α emitting radioconjugate that targets the same tumor associated antigen as the β emitting counterpart, toxicity differences need to be considered. Because PSMA is naturally expressed in the salivary glands, a common toxicity for PSMA-targeted peptidomimetics (e.g., PSMA-617, PSMA-I&T) is xerostomia and xerophtalmia. For α conjugates, the toxicities are more profound, longer lasting, and can significantly affect patient quality of life. One small (n=26) study by Feuerecker et al. that enrolled patients with progression of disease following ¹⁷⁷Lu-PSMA-617 to receive ²²⁵Ac-PSMA-617 therapy showed grade 1 or 2 xerostomia is all patients.³⁴ Despite apparently low-grade toxicity, 23% of patients requested stopping treatment due to severe xerostomia. In the above WARMTH act study, 68% of patients reported xerostomia after the first cycle of ²²⁵Ac-PSMA with nearly certain xerostomia after additional cycles given.³⁶ Permanent Grade 3 or 4 hematological toxicity was seen in one-third of patients.³⁴ Others have reported late nephrotoxicity following treatment with ²²⁵Ac-PSMA-617.³⁷ While toxicities may vary depending on the number and type of therapies patients previously received, effective mitigation strategies are needed. Furthermore, as these agents are being explored in earlier lines of treatment, including chemotherapy naïve patients, attention to these late toxicities will be critical since these patients may have longer actuarial survival.³⁸

The toxicity profile of radioconjugates is partially dictated by the pharmacokinetic biodistribution of the agents in question. Unsurprisingly, salivary, kidney and marrow accumulation of the PSMA-targeted peptidomimetics predicts for toxicities in these end organs as previously described. Because full-length antibodies exhibit different biodistribution and no appreciable salivary gland accumulation, ²²⁵Ac-J591, a PSMA-specific monoclonal antibody, is being explored alone and in combination with ¹⁷⁷Lu-PSMA-I&T in attempt to limit salivary gland toxicities while preserving antitumor activity.³⁹ Full reports of safety and efficacy are still pending at the time of this writing. In the neuroendocrine space, toxicities of ²²⁵Ac-DOTATATE may involve bone marrow, although reports suggest these may be reversible.⁴⁰ A related SSTR-targeting ligand ²¹²Pb-DOTAMTATE was evaluated in a small (n=20) prospective study of patients with NETs without prior treatment with radioligand therapy and showed high radiographic responses 80% and no serious treatment-emergent adverse events, which were limited to nausea, fatigue, and alopecia.⁴¹

There are challenges to the use of α-emitting therapies and routine use, aside from established use of ²²³RaCl₂, is limited to trial therapies.²⁵ Dosimetric calculations are likely more challenging for α emitting therapies as daughter products need also to be considered, which have different pharmacokinetic properties. The first-of-its-kind dosimetry of ²²⁵Ac-DOTATATE of the ACTION-1 dosimetry substudy was presented at the SNMMI MidWinter Meeting. Dosimetry calculations were obtained by imaging the gamma photons of ²²¹Fr and ²¹³Bi in the ²²⁵Ac cascade.⁴²

Instability of alpha emitters and daughter radioisotopes may cloud the exact purity of the administered doses, so control of progeny become paramount. Concomitantly, radiobiological knowledge is imperfect for α-emitting therapies which may further complicate dosimetric evaluation. A foundational challenge is production, distribution, and viable cost of manufacturing α-emitting molecules. For example, in 2018, the total capacity of ²²⁵Ac generation was 75 GBq which is wholly inadequate to meet patient needs.¹ For each approved ²²⁵Ac RPT, there is an estimated need of 200-400GBq per year of patient need.⁶ This has necessitated both public (e.g. IAEA) and private cooperation and agreement to increase stock and explore novel methods of production, including creation of entities such as PRISMAP consortium to centralize coordination and communication regarding radionuclide production. This has also engendered interest in multiple clinically useful α emitters, for example, ²²⁷Th/²²³Ra, ²²⁵Ac, ²¹¹At, and ²¹²Pb/²¹²Bi, to diversify production and implementation options.⁴³ Although there are hundreds of α-emitting particles available, limited half-life of most and challenges in production in many will fuel development of likely several specific high-value α emitters.

Conclusions and Looking Forward

There are several exciting new targets and emitting particles to optimize the therapeutic ratio in RPT. While there is an urgent need to establish efficacy of these novel molecules, there are still large opportunities to further enhance the efficacy of established therapies. The most recently approved agents (e.g. ¹⁷⁷Lu-DOTATATE, ¹⁷⁷Lu-PSMA-617) are administered as flat activities, independent of the patient tumor burden, individual lesion absorbed dose and radiosensitivity. Such an approach, while easy to execute, ignores the readily available information gained from theranostics, specifically tumor burden and uptake/dose as imaged by the diagnostic radiopharmaceutical, as well as the intrinsic radiosensitivity of the treated disease. Earlier administration of theranostic molecules may allow for improved efficacy before tumor de-differentiation or increased tumor heterogeneity. Combination theranostics with DNA-damaging agents (e.g., PARP-inhibitors), immunotherapy, cytotoxic chemotherapy, external beam radiation, or agents to increase target expression may enhance cell killing, by either modulating the target expression or altering tissue radiosensitivity. While there is some degree of overlap with external beam radiobiology, RPT has distinct features that differ substantially compared to external beam therapy (e.g. pharmacokinetics, biological half-lives of ligands), and must be studied as its own unique entity. For instance, preclinical studies suggest that low dose radiopharmaceutical therapy may sufficiently activate host immunity to turn immunologically inert tumors to ones that robustly respond to immunotherapy.⁴⁴ Personalized dosimetry may allow for unique opportunities for both dose escalation or dose reduction, but there is much work to be done to establish efficacy of this approach and then facilitate widespread adoption. Ultimately, the entirety of advancement of both novel targets and novel α emitting therapy will hinge on strong fundamental foundations for treatment efficacy (by calibrating the administered activity on tumor dose and evaluation of radiosensitivity), RPT production and distribution, equitable access, optimal patient selection, multidisciplinary collaboration, and training.