Review Article With CME

Clinical Evidence of Combining Radiopharmaceutical Therapy With Immune Checkpoint Inhibitors

Malick Bio Idrissou PhD; Muralidhar Anusha † PhD; Hernandez Reinier † PhD; Quaovi H. Sodji MD
Published Date: March 1, 2025

Affiliations

  1. 1 Department of Medical Physics, University of Wisconsin-Madison, Madison WI
  2. 2 Department of Cancer Biology, University of Wisconsin-Madison, Madison WI
  3. 3 Department of Radiology, University of Wisconsin-Madison, Madison WI
  4. 4 Carbone Cancer Center, University of Wisconsin-Madison, Madison WI
  5. 5 Department of Human Oncology, University of Wisconsin-Madison, Madison WI
  6. 6 William S. Middleton Memorial Veterans Hospital, Madison WI

CME credits available here.

Radiopharmaceutical therapy (RPT) and immune checkpoint inhibitors (ICIs) represent transformative approaches in treating metastatic cancers. RPT uniquely delivers targeted radiation to primary and metastatic tumors, modulating the tumor microenvironment (TME) to enhance antitumor immunity. The therapeutic advantages of combining RPT with ICI have been shown preclinically. Clinical trials are now emerging, offering insights into the potential therapeutic synergy between RPT and ICI. This review highlights clinical trials of RPT combined with ICI, emphasizing their ability to improve metastatic cancer outcomes while addressing challenges such as toxicity, immunosuppressive TME, and logistical barriers, and underscores their promise to redefine cancer care.

Introduction

Metastatic disease accounts for approximately 90% of cancer-related deaths.1 - 6 Unfortunately, effective therapeutic strategies remain limited despite tremendous advances in cancer research.7 Radiopharmaceutical therapy (RPT) represents a groundbreaking approach to treating metastatic disease by delivering targeted radiation to tumors throughout the body.8, 9 Leveraging pharmaceuticals that selectively bind to cancer cells or accumulate through physiological mechanisms, RPT provides a precise and effective treatment modality. Remarkably, RPT has demonstrated significant therapeutic efficacy with minimal toxicity in several cancer types.8 As the role of RPT in metastatic disease management is on the rise, its combination with immune checkpoint inhibitors (ICIs) holds the potential to enhance clinical responses beyond that achievable by either monotherapy alone.

For over a century, radiation therapy, including external beam radiation therapy (EBRT) and RPT, has shown dual benefits: tumor eradication and immune activation.10 Radiation triggers cancer cells to release damage-associated molecular patterns (DAMPs), activating the cGAS-STING pathway, which induces type I interferons and the release of cytokines that recruit immune cells.11, 12 The growing promise of RPT in treating metastatic cancer, coupled with emerging insights into the immunogenic effects of radiation, has spurred preclinical and clinical studies exploring the combination of RPT and immunotherapy, such as ICIs. This review explores clinical trials investigating the combination of RPT with ICI, highlighting key clinical findings, potential challenges, and future directions in this emerging field.

ADVERTISEMENT

Radiopharmaceutical Therapy

RPT has emerged as a promising systemic therapy, enabling radiation delivery to both local and metastatic lesions while sparing healthy tissues ( Figure 1A ).8, 13 Unlike EBRT, which delivers radiation to all tissues in the radiation field, including malignant and adjacent normal tissues, RPT uses tumor-targeting biomolecules (eg, antibodies, peptides, or small molecules) linked to a radionuclide to form a “radiopharmaceutical” that preferentially targets cancer cells ( Figure 1 ). The radiopharmaceutical binds selectively to receptors overexpressed on tumor cells, thus delivering radiation to the tumor while minimizing damage to surrounding tissues.14 This molecularly targeted approach makes RPT particularly effective for treating metastatic and microscopic tumors,8, 15 - 17 where EBRT’s utility is often limited. The efficacy of RPT depends on the targeting molecule’s properties, the radionuclide’s physical characteristics, and tumor characteristics such as receptor expression, size, and tumor type. Additional factors, such as the administrated activity, tumor uptake, and pharmacokinetics, also impact the treatment outcome.18 Therefore, carefully considering these factors is crucial for RPT’s clinical efficacy and safety. The approvals of several radiopharmaceuticals, such as [223 Ra]Ra-dichloride (Xofigo) and [177 Lu]Lu-PSMA-167 (Pluvicto) for metastatic castration-resistant prostate cancer (mCRPC) and [177 Lu]Lu-DOTATATE (Lutathera) for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), have sparked a new excitement in the field.19 - 21 RPT faces challenges like suboptimal targeting, radioresistance, and limited immune stimulation, hindering tumor eradication.22 - 24 Combining RPT with systemic therapies like ICIs may overcome these limitations and improve outcomes.

Figure 1.
ADVERTISEMENT

Radiopharmaceutical therapy delivers systemic radiation to tumor. (A) A radiolabeled, tumor-specific compound known as a “radiopharmaceutical” is administered intravenously, resulting in selective accumulation of radionuclide in the tumor microenvironment. (B) Pharmacophoric model of radiopharmaceutical agent. A targeting molecule is conjugated to a therapeutic radionuclide via a linker and chelator, forming a radiopharmaceutical that ensures precise delivery of radiation to tumor cells.

Targeting Molecules

In RPT, antibodies, peptides, or small molecules are designed to bind selectively to tumor-specific receptors or antigens, ensuring precise delivery of radiation to cancer cells while sparing healthy tissues.25

Antibodies

Their high specificity and potentially strong binding affinity make antibodies ideal for targeting tumor-associated antigens and delivering radiation to cancer cells.26, 27 Effective antibodies target antigens that are highly expressed on tumors but minimally expressed or absent in healthy tissue. However, antibody size can limit tumor microenvironment (TME) penetration28 and prolong circulation,29 increasing off-target toxicities. Smaller monoclonal antibody (mAb) fragments like single-chain variable fragments partially retain target binding capacity while improving TME penetration. The US Food and Drug Administration/European Medical Agency (FDA/EMA)-approved examples of antibody-based radiopharmaceuticals include Zevalin ([90 Y]Y-ibritumomab tiuxetan)30 and Bexxar ([131 I]I-tositumomab),31 which target the CD20 protein on the surface of B-cells expressed by non-Hodgkin lymphoma.

Peptides

Peptides are versatile for RPT owing to rapid TME penetration, high uptake, and quick clearance from nontarget tissues, offering optimized pharmacokinetics. Their relatively higher stability enables chemical modifications and radiolabeling, making them versatile agents in nuclear medicine. A notable example of a peptide-based FDA/EMA-approved radiopharmaceutical is Lutathera ([177 Lu]Lu-DOTA-TATE), indicated for the treatment of somatostatin receptor 2-positive gastroenteropancreatic neuroendocrine tumors.32, 33

Small Molecules

Small molecule-based radioligands offer advantages as radiopharmaceuticals due to their efficient TME penetration and rapid clearance from systemic circulation, reducing off-target effects and toxicity. Although less specific than antibodies or peptides, small molecules effectively target cancer-associated antigens, such as the prostate-specific membrane antigen (PSMA) in prostate cancer. A notable example is the FDA-approved [177 Lu]Lu-PSMA-167 (Pluvicto) for mCRPC,34 showcasing radioligand therapy’s potential in precision oncology.

Each targeting molecule in RPT offers a unique balance of strengths and limitations, with selection guided by tumor traits, precision, clearance, and off-target risks. This enables personalized and effective cancer therapy.

Radionuclides

A wide range of radionuclides is available for RPT, and selecting the appropriate one is crucial, as it directly influences treatment safety and efficacy. This choice is guided by factors such as physical half-life, availability, cost, radiochemical methods, and radiation properties, including energy level, type (α, β, or Auger electrons), linear energy transfer (LET), and penetration range ( Figure 2 and Table 1 ).

Figure 2.

Characteristics of various radionuclides used for radiopharmaceutical therapy.

Table 1.

Radionuclides Used in Radiopharmaceutical Therapy and Their Physical Properties

Particle Emitted Energy Range in Tissue LET (keV/µm) Key DNA Damage Characteristics Example of Radionuclides
β-particles 0-2.3 MeV μm to1.2 cm 0.1-1.0 Most single-strand breaks and some double-strand breaks but is easily repairable. (lower lethal damage efficiency) 131 I,90 Y,177 Lu
α-particles 5-9 MeV 50-100 µm 50-230 Mostly clustered double-strand breaks, making them complex and difficult to repair. (higher lethal damage efficiency) 225 Ac,211 At,223 Ra
Auger and conversion electrons <1 keV <1 µm 4-26 Mix of clustered double-strand breaks and single-strand breaks (lethality dependent on nuclear DNA proximity) 123 I,125 I,195m Pt,111 In

Abbreviation : LET, linear energy transfer.

Physical Half-Life

The time needed for half of an RPT’s radioactive atoms to decay is critical. The half-life must be amenable to the radiolabelling process, the distribution logistics of the agent, and the targeting molecule’s pharmacokinetics. While radionuclides with a short half-life, measured in hours, are preferred for imaging application, RPTs featuring short T 1/2 radionuclides may lead to a significant decay before the radiopharmaceutical reaches the TME, thus reducing treatment efficacy. Conversely, a long half-life can increase radiation exposure to healthy tissue, thus increasing treatment-related side effects. Ideally, RPT radionuclides should have a half-life of 1 to 7 days for optimal balance.35

Linear Energy Transfer

The linear energy deposited by ionizing radiation per unit distance in tissue (keV/µm) significantly influences its biological effect. High LET of radiation (eg, α-particles, 50-230 keV/µm) induces dense clusters of double-strand DNA breaks (DSBs), causing irreparable DNA damage and high cytotoxicity. Intermediate LET radiation (eg, Auger electrons, 4-26 keV/µm) generates localized single-strand DNA breaks (SSBs) and DSBs, with cytotoxicity dependent on nuclear proximity due to limited penetration. Low LET radiation (eg, β-particles, 0.2 keV/µm) primarily induces SSBs and indirect damage via free radicals, which are often repairable, though clustered SSBs may result in DSBs.36, 37 Radionuclides used in RPT are classified into 3 main categories based on their radiation type: β-particle emitters, α-particle emitters, and Auger/conversion electrons emitters.

  • β-particle emitters such as lutetium-177 (177 Lu), yttrium-90 (90 Y), and iodine-131 (131 I), with a low LET (~0.2 keV/µm) and tissue penetration up to 12 mm, have been widely used in RPT. Owing to their deeper penetration range (several millimeters), low-LET β⁻-emitters can effectively treat heterogeneous (target expression) tumors,38, 39 resulting in more effective tumor coverage,40, 41 but may have lower lethal damage efficiency per unit dose.

  • α-particle emitters such as radium-223 (223 Ra) and actinium-225 (225 Ac) deliver potent therapy with high LET (50-230 keV/µm) and a short tissue range (50-100 µm); thus, they are ideal for treating micrometastases.39, 40, 42 Their high LET causes dense clusters of DSBs, which are difficult to repair,39 making them highly cytotoxic.43

  • Auger/conversion electron emitters such as iodine-123 (123 I), iodine-125 (125 I), and indium-111 (111 In) have a very short tissue range (< 1 µm), making them effective near critical cell structures like nuclear DNA, and a medium-to-high LET (4-26 keV/µm) inducing a mix of SSBs and DSBs.16, 39, 42

Many β-particle and Auger emitters also emit γ rays, enabling their dual use for therapy and imaging.44 For example, γ emissions from177 Lu allow real-time visualization of radiopharmaceutical distribution, ensuring accurate targeting and dose optimization.45, 46

Overall, radionuclide selection for RPT depends on properties like half-life, LET, radiation type, and tissue penetration. β-emitters appear to be better suited for larger tumors, while α-emitters target micrometastases with high cytotoxicity, and Auger emitters provide precise, localized radiation (< 1 µm) near critical structures like nuclear DNA.

ADVERTISEMENT

Immunomodulatory Effects of RPT and Rationale for Combining RPT With ICI

The efficacy of RPT extends beyond direct cytotoxicity as it induces significant pro-inflammatory immune responses.47, 48 Ionizing radiation enhances tumor immunogenicity, modulates the TME, and promotes innate and adaptive immunity.47, 48 Irradiated tumor cells release DAMPs49 and express immunomodulatory molecules, recruiting antigen-presenting cells to activate T cells and drive systemic antitumor immunity.50 Potluri et al showed that [90 Y]Y-NM600 modified the TME by increasing CD8+ T cell infiltration and PD-L1 expression on myeloid cells.51 In a murine study, Hernandez et al observed a reduction in immunosuppressive regulatory T cells and a notable increase in activated CD8+ T cells in EL4 murine tumors treated with [90 Y]Y-NM600 compared with controls.52 Furthermore, upon rechallenging [90 Y]Y-NM600-treated complete responders with EL4 cells, none developed tumors,52 suggesting the induction of a tumor-specific memory in RPT-treated mice. Emerging preclinical data suggest that targeted α-particle therapy (TAT) can also induce immunostimulatory effect.53 Lejeune et al further demonstrated that TAT triggers transcriptional and molecular signatures consistent with immunogenic cell death in preclinical syngeneic tumor models.54 Despite the reported immunomodulatory effects of RPT, its efficacy as a monotherapy often lacks durability, underscoring the compelling rationale for combining RPT with immunotherapy.55 Foundational studies have shown the synergism between RPT and immunotherapy, such as improved survival with [90 Y]-anti-CEA (carcinoembryonic antigen) antibodies in combination with a CEA/TRICOM (TRICOM: 3 T-cell costimulatory molecules B7-1, ICAM-1, and LFA-3) vaccine in colon cancer models.56 This combination represents a promising strategy for achieving durable tumor control; thus, it may pave the way for enhancing patient outcomes through synergistic treatment strategies.

ADVERTISEMENT

Clinical Trials Combining RPT With ICI

Building on preclinical evidence, several clinical trials have been initiated to evaluate the safety and efficacy of RPT-ICI combinations across cancers. Key outcomes are discussed here, underscoring the potential of these combination therapies to advance clinical treatment paradigms. Table 2 concisely summarizes these clinical trials, categorized by disease type for clarity.

Table 2.
ADVERTISEMENT

Selected Clinical Trials Evaluating Radiopharmaceutical Therapy Combined With Immune Checkpoint Blockade in Cancer

Disease Trial Phase Disease Status Target RPT ICI Combination Sequence Trial Status/Result Reference
Prostate cancer NCT02814669 Ib mCRPC Bone metastases [223 Ra]Ra: 55 kBq/kg (IV) every 28 days, 6 administrations Atezolizumab: 840 mg (IV) every 14 days Concurrent or staggered Combination: greater toxicity 57
NCT03093428 II mCRPC Bone metastases [223 Ra]Ra: every 4 weeks at a predetermined dose (IV) Pembrolizumab: every 3 weeks at a predetermined dose (IV) Concurrent No improved efficacy 58
NCT03658447 ( PRINCE ) I mCRPC PSMA [177 Lu]Lu-PSMA-617: 8.5 GBq (IV), every 6 weeks, up to 6 cycles Pembrolizumab: 200 mg every 3 weeks (IV) Concurrent PSA-RR: 76%

No safety concerns

rPFS: 11.2 months

PSA-PFS: 8.2 months

OS: 17.8 months		 59
Lung cancer NCT03325816 I/II Extensive stage SCLC SSTR [177 Lu]Lu -DOTA0-Tyr3-Octreotate: 3.7 or 7.4 GBq (IV), every 8 weeks, 4 cycles Nivolumab: 240 mg every 2 weeks (IV) Concurrent Combination well tolerated

PR: 1 out 7 patients		 60
NCT03996473 I Metastatic NSCLC Bone metastases [223 Ra]Ra: 55 kBq/kg (IV), every 6 weeks, up to 6 cycles Pembrolizumab: 200 mg every 3 weeks (IV) up to 35 doses Concurrent Study closed
Renal cancer (ccRCC) NCT05663710 Ib/II Advanced ccRCC CAIX [177 Lu]Lu-girentuximab: 1.48 GBq/m2 (IV), every 12 weeks, up to 3 cycles Nivolumab (dose not available) Cabozantinib: given orally Concurrent Ongoing 61
NCT05239533 (STARLITE 2) II Advanced ccRCC CAIX [177 Lu]Lu-girentuximab: 1.8 or 2.4 GBq/m2 (IV), every 12-14 weeks, up to 3 cycles Nivolumab: 200 mg every 2 weeks Concurrent Ongoing 62
Merkel cell cancer NCT05583708 II Metastatic SSTR [177 Lu]Lu-DOTATATE: 7.4 GBq (IV), every 2 months, up to 4 doses Pembrolizumab: 400 mg every 6 weeks (IV) Concurrent Temporarily suspended
NCT04261855 (GoTHAM) Ib/II Metastatic SSTR [177 Lu]Lu -DOTATATE: 2 administrations separated by 8-10 weeks Avelumab: 10 mg/kg every 2 weeks for 24 months (IV) Concurrent Ongoing
Thyroid cancer NCT03215095 I Recurrent/metastatic rhTSH [131 I]I : 100 mCi Durvalumab: 1500 mg IV every 4 weeks Concurrent Active, not recruiting
Refractory neuroblastoma NCT02914405 (MiNivAN) I Relapsed or refractory High risk Norepinephrine transporter [131 I]I-meta-iodobenzylguanidine Nivolumab: 3 mg/kg Dinutuximab (anti-GD2 monoclonal antibody): 50 or 100 mg/m2 Concurrent Recruiting
NETs with liver metastases NCT03457948 II Metastatic SSTR [177 Lu]Lu-DOTA0-Tyr3-Octreotate Pembrolizumab Concurrent Recruiting

Abbreviations : CAIX, carbonic anhydrase IX; ccRCC, clear cell renal cell carcinoma; ICI, immune checkpoint inhibitor; IV, intravenous injection; mCRPC, metastatic castration-resistant prostate cancer; NET, neuroendocrine tumor; NSCLC, non-small cell lung cancer; OS, overall survival; PR, partial response; PSA-PFS, prostate-specific antigen progression-free survival; PSA-RR, PSA response rate (≥50% decrease in PSA level); PSMA: prostate-specific membrane antigen; rhTSH, recombinant human thyroid stimulating hormone; rPFS, radiographic progression-free survival; RPT, radiopharmaceutical therapy; SCLC, small cell lung cancer; SSTR, somatostatin receptor.

Prostate Cancer

A phase Ib study ( NCT02814669 ) investigated the combination of [223 Ra]RaCl ₂ with atezolizumab in mCRPC patients with bone, lymph node, or visceral metastases. This combination resulted in greater toxicity than either agent alone and failed to show clinical benefit.57 Among the grade 3/4 adverse events, 34.1% were attributed to atezolizumab, while 27.3% were associated with [223 Ra]RaCl ₂.

A randomized phase II study ( NCT03093428 ) evaluated [223 Ra]RaCl ₂ with pembrolizumab in patients with mCRPC. A recent report showed a median progression-free survival (PFS) of 6.1 months for [223 Ra]RaCl ₂ + pembrolizumab versus 5.7 months for [223 Ra]RaCl ₂ alone and a median overall survival (OS) of 16.9 months versus 16.0 months, respectively.58 While the combination was well tolerated with no unexpected toxicity, it did not demonstrate improved efficacy.

PRINCE ( NCT03658447 ), a phase I clinical trial, evaluated the safety and efficacy of [177 Lu]Lu-PSMA-617 in combination with pembrolizumab in patients with mCRPC. The prostate-specific antigen response rate (PSA-RR) was 76% compared with 46% with [177 Lu]Lu-PSMA-617 alone. The median radiographic PFS, PSA-PFS, and OS were 11.2 months, 8.2 months, and 17.8 months, respectively.59 No additional safety concerns were identified with the addition of pembrolizumab, confirming the favorable safety profile of this combination.

Lung Cancer

Advanced lung cancer has also been the focus of clinical trials exploring the combination of RPT with immunotherapy. A phase I/II trial ( NCT03325816 ) investigating nivolumab with Lutathera in patients with extensive-stage small cell lung cancer (SCLC) demonstrated a tolerable toxicity profile. Lutathera, a β-emitting [177 Lu]Lu-labeled somatostatin analog approved for GEP-NETs,63 targets somatostatin receptor-expressing cells. The combination therapy was well tolerated. Furthermore, 1 out of 7 patients achieved a partial response (PR), while 2 with pulmonary atypical carcinoid maintained stable disease (SD) for 6 months. Notably, the patient with PR exhibited the highest tumor uptake of ⁶⁸Ga-DOTATATE on PET/CT, underscoring the potential of this approach.60

A phase I study ( NCT03996473 ) sought to evaluate the safety and efficacy of combining [223 Ra]RaCl 2 with pembrolizumab in metastatic non-SCLC. The trial included patients who were either treatment-naïve for advanced disease or had progressed after prior PD-1/PD-L1 checkpoint blockade. The primary objectives were assessing tumor shrinkage, duration, and treatment safety. However, the study was closed early due to insufficient accrual.

Renal Cancer

Clear cell renal cell carcinoma (ccRCC) is characterized by carbonic anhydrase IX expression resulting from von Hippel-Lindau loss, representing a compelling target for RPT-based therapies. The integration of RPT with immunotherapy in advanced ccRCC is gaining momentum, with 2 phase II clinical trials currently underway ( NCT05239533 ; NCT05663710 ). These trials aim to evaluate the safety and efficacy of combining [177 Lu]Lu-girentuximab with nivolumab as a novel treatment strategy for advanced ccRCC.61, 62

Merkel Cell Carcinoma

Two case reports underscore the significant therapeutic potential of combining RPT with ICI in metastatic Merkel cell carcinoma (MCC). These cases involved patients who had progressed on first-line avelumab or second-line therapies combining ipilimumab, nivolumab, and EBRT.64, 65 While up to half of patients with MCC either may not respond to or may develop resistance to ICIs,65 the frequent expression of somatostatin receptors in MCC makes it a suitable target for [177 Lu]Lu-DOTATATE. In one case, a patient with extensive MCC metastases treated with [177 Lu]Lu-DOTATATE and anti-PD-L1 therapy demonstrated a rapid response, achieving a near-complete response within 1 month.64 Another patient receiving [177 Lu]Lu-DOTATOC, along with ipilimumab and nivolumab, achieved and sustained a PR for 5 months.65 Clinical trials ( NCT05583708 ; NCT04261855 ) have been initiated to evaluate [177 Lu]Lu-DOTATATE combined with nivolumab or pembrolizumab in patients with metastatic MCC.

Other ongoing clinical trials are exploring RPT with ICI, including radioiodine (131 I) with durvalumab ( NCT03215095 ) for thyroid cancer,131 I-MIBG with nivolumab and dinutuximab (anti-GD2 monoclonal antibody) for refractory neuroblastoma ( NCT02914405 ), and177 Lu-DOTA0-Tyr3-Octreotate with pembrolizumab ( NCT03457948 ) for NETs with liver metastases.

ADVERTISEMENT

Challenges and Future Perspectives

Combining RPT with immunotherapy is a promising therapeutic option for metastatic cancers. With its targeted radiation delivery and ability to modulate the TME, RPT can complement the systemic antitumor effects of immunotherapy. Preclinical studies highlight the potential of RPT and ICI combination,47 - 54 but robust clinical evidence remains limited. Nevertheless, few studies have shown promising results, including case reports with [177 Lu]Lu-DOTATATE or [177 Lu]Lu-DOTATOC plus ICI in MCC metastases,64, 65 and the phase I PRINCE trial with [177 Lu]Lu-PSMA-617 in combination with ICI in mCRPC.59 Beyond these studies, we are awaiting results from ongoing clinical trials ( Table 2 ). Nevertheless, challenges persist, including increased toxicities57 with immune-related events and radiation-induced toxicities. The immunosuppressive TME, influenced by regulatory T cells and immune checkpoint expression, may further dampen treatment efficacy. Variability in patient responses, driven by tumor heterogeneity, highlights the need for predictive biomarkers for optimal patient selection. Economic and logistical barriers also hinder implementation.66 - 70 The production and administration of RPT require specialized infrastructure and expertise, while its high costs necessitate cost-benefit analyses for integration into clinical practice. Future research should optimize trial designs for sequencing, dosing, and timing of RPT-ICI combinations. Advances in imaging, dosimetry, and collaboration among specialists, along with efforts to reduce costs and improve access, are key to transforming metastatic cancer treatment. Moreover, most trials do not clearly differentiate whether observed toxicities stem from immune-related effects or radiation exposure. Gaining a deeper understanding of the predominant mechanism, whether immune-mediated or radiation-induced, is essential for optimizing toxicity management and improving the safety profile of these combinations.

ADVERTISEMENT

Conclusion

The combination of RPT and immunotherapy offers a transformative approach to metastatic cancer, overcoming current treatment limitations. As shown in Figure 3 , RPT synergizes with immunotherapy, including ICIs, by reducing tumor burden, releasing neo-antigens, enhancing MHC-I expression, and modifying the TME, while immunotherapy amplifies and sustains these effects, countering immune evasion and optimizing tumor control, especially in “cold” tumors. Despite challenges such as toxicity and logistical barriers, advances in radiopharmaceutical design, immune modulation, and personalized biomarkers driven by interdisciplinary collaboration could redefine cancer care for advanced, treatment-resistant, and metastatic malignancies.

Figure 3.
ADVERTISEMENT

Potential synergistic interactions between radiopharmaceutical therapy and immune checkpoint inhibitors (ICIs).

References

1. Seyfried TN Huysentruyt LC . On the origin of cancer metastasis. Crit Rev Oncog. 2013; 18 ( 1-2 ): 43 - 73. 10.1615/critrevoncog.v18.i1-2.40
2. Spano D Heck C De Antonellis P Christofori G Zollo M . Molecular networks that regulate cancer metastasis. Semin Cancer Biol. 2012; 22 ( 3 ): 234 - 249. 10.1016/j.semcancer.2012.03.006
3. Ganesh K Massagué J . Targeting metastatic cancer. Nat Med. 2021; 27 ( 1 ): 34 - 44. 10.1038/s41591-020-01195-4
4. Coleman RE . Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006; 12 ( 20 pt 2 ): 6243s - 6249s. 10.1158/1078-0432.CCR-06-0931
5. van Roij J Brom L Youssef-El Soud M van de Poll-Franse L Raijmakers NJH . Social consequences of advanced cancer in patients and their informal caregivers: a qualitative study. Support Care Cancer. 2019; 27 ( 4 ): 1187 - 1195. 10.1007/s00520-018-4437-1
6. Costa L Badia X Chow E Lipton A Wardley A . Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer. 2008; 16 ( 8 ): 879 - 889. 10.1007/s00520-008-0418-0
7. Lambert AW Pattabiraman DR Weinberg RA . Emerging biological principles of metastasis. Cell. 2017; 168 ( 4 ): 670 - 691. 10.1016/j.cell.2016.11.037
8. Sgouros G Bodei L McDevitt MR Nedrow JR . Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020; 19 ( 9 ): 589 - 608. 10.1038/s41573-020-0073-9
9. Salih S Alkatheeri A Alomaim W Elliyanti A . Radiopharmaceutical treatments for cancer therapy, radionuclides characteristics, applications, and challenges. Molecules. 2022; 27 ( 16 ): 5231. 10.3390/molecules27165231
10. Murphy JB Hussey RG Nakahara W Sturm E . Studies on X-ray effects: Vi. Effect of the cellular reaction induced by X-rays on cancer grafts. J Exp Med. 1921; 33 ( 3 ): 299 - 313. 10.1084/jem.33.3.299
11. Storozynsky Q Hitt MM . The impact of radiation-induced DNA damage on cgas-STING-mediated immune responses to cancer. Int J Mol Sci. 2020; 21 ( 22 ): 8877. 10.3390/ijms21228877
12. Constanzo J Faget J Ursino C Badie C Pouget JP . Radiation-induced immunity and toxicities: the versatility of the cgas-STING pathway. Front Immunol. 2021; 12: 680503. 10.3389/fimmu.2021.680503
13. Dumortier J Decullier E Hilleret M-N . Adjuvant intraarterial lipiodol or131 I-lipiodol after curative treatment of hepatocellular carcinoma: a prospective randomized trial. J Nucl Med. 2014; 55 ( 6 ): 877 - 883. 10.2967/jnumed.113.131367
14. Shea AG Idrissou MB Torres AI et al. Immunological effects of radiopharmaceutical therapy. Front Nucl Med. 2024; 4: 1331364. 10.3389/fnume.2024.1331364
15. Brady D O’Sullivan JM Prise KM . What is the role of the bystander response in radionuclide therapies? Front Oncol. 2013; 3: 215. 10.3389/fonc.2013.00215
16. Idrissou MB Pichard A Tee B et al. Targeted radionuclide therapy using auger electron emitters: the quest for the right vector and the right radionuclide. Pharmaceutics. 2021; 13 ( 7 ): 980. 10.3390/pharmaceutics13070980
17. Gudkov SV Shilyagina NY Vodeneev VA Zvyagin AV . Targeted radionuclide therapy of human tumors. Int J Mol Sci. 2015; 17 ( 1 ): 33. 10.3390/ijms17010033
18. Capello A Krenning E Bernard B et al. 111 In-labelled somatostatin analogues in a rat tumour model: somatostatin receptor status and effects of peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2005; 32 ( 11 ): 1288 - 1295. 10.1007/s00259-005-1877-x
19. Poeppel TD Handkiewicz-Junak D Andreeff M et al. EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2018; 45 ( 5 ): 824 - 845. 10.1007/s00259-017-3900-4
20. Hennrich U Eder M . [177 Lu]LU-PSMA-617 (pluvictotmTM ): the first FDA-approved radiotherapeutical for treatment of prostate cancer. Pharmaceuticals. 2022; 15 ( 10 ): 1292. 10.3390/ph15101292
21. Hennrich U Kopka K . Lutathera® : the first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals. 2019; 12 ( 3 ): 114. 10.3390/ph12030114
22. Wu Y Song Y Wang R Wang T . Molecular mechanisms of tumor resistance to radiotherapy. Mol Cancer. 2023; 22 ( 1 ): 96. 10.1186/s12943-023-01801-2
23. Gao Z Zhao Q Xu Y Wang L . Improving the efficacy of combined radiotherapy and immunotherapy: focusing on the effects of radiosensitivity. Radiat Oncol. 2023; 18 ( 1 ): 89. 10.1186/s13014-023-02278-5
24. Bellavia MC Patel RB Anderson CJ . Combined targeted radiopharmaceutical therapy and immune checkpoint blockade: from preclinical advances to the clinic. J Nucl Med. 2022; 63 ( 11 ): 1636 - 1641. 10.2967/jnumed.122.264373
25. Zhang T Lei H Chen X et al. Carrier systems of radiopharmaceuticals and the application in cancer therapy. Cell Death Discov. 2024; 10 ( 1 ): 16. 10.1038/s41420-023-01778-3
26. Zhao Z Ukidve A Kim J Mitragotri S . Targeting strategies for tissue-specific drug delivery. Cell. 2020; 181 ( 1 ): 151 - 167. 10.1016/j.cell.2020.02.001
27. Almagro JC Kodangattil S . Novel approaches in discovery and design of antibody-based therapeutics. Novel Approaches and Strategies for Biologics, Vaccines and Cancer Therapies. Elsevier ; 2015: 147 - 170. 10.1016/B978-0-12-416603-5.00007-9
28. Cruz E Kayser V . Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy. Biologics. 2019; 13: 33 - 51. 10.2147/BTT.S166310
29. Beckman RA Weiner LM Davis HM . Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer. 2007; 109 ( 2 ): 170 - 179. 10.1002/cncr.22402
30. Grillo-López AJ . Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma. Expert Rev Anticancer Ther. 2002; 2 ( 5 ): 485 - 493. 10.1586/14737140.2.5.485
31. Friedberg JW Fisher RI . Iodine-131 tositumomab (Bexxar®): radioimmunoconjugate therapy for indolent and transformed B-cell non-hodgkin’s lymphoma. Expert Rev Anticancer Ther. 2004; 4 ( 1 ): 18 - 26. 10.1586/14737140.4.1.18
32. Research C for DE. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. FDA. 2024. Accessed 30 October 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-treatment-gep-nets
33. Lutathera. European Medicines Agency (EMA). 2018. Accessed 30 October 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/lutathera
34. Fallah J Agrawal S Gittleman H et al. FDA approval summary: lutetium lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2023; 29 ( 9 ): 1651 - 1657. 10.1158/1078-0432.CCR-22-2875
35. Qaim SM . Therapeutic radionuclides and nuclear data. Radiochim Acta. 2001; 89 ( 4-5 ): 297 - 304. 10.1524/ract.2001.89.4-5.297
36. Howell RW Rao DV Hou DY Narra VR Sastry KSR . The question of relative biological effectiveness and quality factor for auger emitters incorporated into proliferating mammalian cells. Radiat Res. 1991; 128 ( 3 ): 282 - 292: 282. 10.2307/3578051
37. Rao D Howell R Narra V Govelitz G Sastry K . IN-vivo radiotoxicity of DNA-incorporated 125I compared with that of densely ionising alpha-particles. Lancet. 1989; 334 ( 8664 ): 650 - 653. 10.1016/S0140-6736(89)90896-9
38. Marcu L Bezak E Allen BJ . Global comparison of targeted alpha vs targeted beta therapy for cancer: in vitro, in vivo and clinical trials. Crit Rev Oncol Hematol. 2018; 123: 7 - 20. 10.1016/j.critrevonc.2018.01.001
39. Pouget J-P Navarro-Teulon I Bardiès M et al. Clinical radioimmunotherapy—the role of radiobiology. Nat Rev Clin Oncol. 2011; 8 ( 12 ): 720 - 734. 10.1038/nrclinonc.2011.160
40. Dekempeneer Y Keyaerts M Krasniqi A et al. Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle. Expert Opin Biol Ther. 2016; 16 ( 8 ): 1035 - 1047. 10.1080/14712598.2016.1185412
41. Czerwińska M Bilewicz A Kruszewski M Wegierek-Ciuk A Lankoff A . Targeted radionuclide therapy of prostate cancer-from basic research to clinical perspectives. Molecules. 2020; 25 ( 7 ): 1743. 10.3390/molecules25071743
42. Poty S Francesconi LC McDevitt MR Morris MJ Lewis JS . α-emitters for radiotherapy: from basic radiochemistry to clinical studies-part 1. J Nucl Med. 2018; 59 ( 6 ): 878 - 884. 10.2967/jnumed.116.186338
43. Sgouros G Roeske JC McDevitt MR et al. MIRD pamphlet no. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010; 51 ( 2 ): 311 - 328. 10.2967/jnumed.108.058651
44. Stokke C Kvassheim M Blakkisrud J . Radionuclides for targeted therapy: physical properties. Molecules. 2022; 27 ( 17 ): 5429. 10.3390/molecules27175429
45. Othman MFB Mitry NR Lewington VJ Blower PJ Terry SYA . Re-assessing gallium-67 as a therapeutic radionuclide. Nucl Med Biol. 2017; 46: 12 - 18. 10.1016/j.nucmedbio.2016.10.008
46. Pirovano G Jannetti SA Carter LM et al. Targeted brain tumor radiotherapy using an auger emitter. Clin Cancer Res. 2020; 26 ( 12 ): 2871 - 2881. 10.1158/1078-0432.CCR-19-2440
47. Gaipl US Multhoff G Scheithauer H et al. Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy. Immunotherapy. 2014; 6 ( 5 ): 597 - 610. 10.2217/imt.14.38
48. Filatenkov A Baker J Mueller AMS et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res. 2015; 21 ( 16 ): 3727 - 3739. 10.1158/1078-0432.CCR-14-2824
49. Bianchi ME . DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007; 81 ( 1 ): 1 - 5. 10.1189/jlb.0306164
50. Takeshima T Chamoto K Wakita D et al. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with th1 cell therapy. Cancer Res. 2010; 70 ( 7 ): 2697 - 2706. 10.1158/0008-5472.CAN-09-2982
51. Potluri HK Ferreira CA Grudzinski J et al. Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors. J Immunother Cancer. 2022; 10 ( 8 ): e005060. 10.1136/jitc-2022-005060
52. Hernandez R Walker KL Grudzinski JJ et al. 90Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell non-hodgkin’s lymphoma. Commun Biol. 2019; 2 ( 1 ): 79. 10.1038/s42003-019-0327-4
53. Perrin J Capitao M Allard M et al. Targeted alpha particle therapy remodels the tumor microenvironment and improves efficacy of immunotherapy. Int J Radiat Oncol. 2022; 112 ( 3 ): 790 - 801. 10.1016/j.ijrobp.2021.10.013
54. Lejeune P Cruciani V Berg-Larsen A et al. Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy. J Immunother Cancer. 2021; 9 ( 10 ): e002387. 10.1136/jitc-2021-002387
55. Zukotynski K Jadvar H Capala J Fahey F . Targeted radionuclide therapy: practical applications and future prospects: supplementary issue: biomarkers and their essential role in the development of personalised therapies. Biomark Cancer. 2016; 8s2: S31804. 10.4137/BIC.S31804
56. Chakraborty M Gelbard A Carrasquillo JA et al. Use of radiolabeled monoclonal antibody to enhance vaccine-mediated antitumor effects. Cancer Immunol Immunother. 2008; 57 ( 8 ): 1173 - 1183. 10.1007/s00262-008-0449-x
57. Fong L Morris MJ Sartor O et al. A phase Ib study of atezolizumab with radium-223 dichloride in men with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2021; 27 ( 17 ): 4746 - 4756. 10.1158/1078-0432.CCR-21-0063
58. Choudhury AD Kwak L Cheung A et al. Randomized phase II study evaluating the addition of pembrolizumab to radium-223 in metastatic castration-resistant prostate cancer. Cancer Immunol Res. 2024; 12 ( 6 ): 704 - 718. 10.1158/2326-6066.CIR-22-0306
59. Sandhu S Joshua AM Emmett L et al. PRINCE: phase I trial of177 lu-PSMA-617 in combination with pembrolizumab in patients with Metastatic Castration-Resistant Prostate Cancer (mcrpc). JCO. 2022; 40 ( 16_suppl ): 5017 - 5017. 10.1200/JCO.2022.40.16_suppl.5017
60. Kim C Liu SV Subramaniam DS et al. Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung. J Immunother Cancer. 2020; 8 ( 2 ): e000980. 10.1136/jitc-2020-000980
61. Feldman DR Motzer RJ Knezevic A et al. STARLITE 2: phase 2 study of nivolumab plus177 lutetium-labeled anti-carbonic anhydrase IX (CAIX) monoclonal antibody girentuximab (177 lu-girentuximab) in patients (pts) with advanced clear cell renal cell carcinoma (ccrcc). JCO. 2022; 40 ( 16_suppl ): TPS4603. 10.1200/JCO.2022.40.16_suppl.TPS4603
62. Jonasch E Hasanov E Flynt L et al. Phase 1b/2 study of combination177 lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC. JCO. 2024; 42 ( 16_suppl ): TPS4610. 10.1200/JCO.2024.42.16_suppl.TPS4610
63. Strosberg JR Wolin EM Chasen B et al. NETTER-1 phase III: progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-LU-dotatate. JCO. 2016; 34 ( 4_suppl ): 194 - 194. 10.1200/jco.2016.34.4_suppl.194
64. Kasi PM Sharma A Jain MK . Expanding the indication for novel theranostic 177Lu-dotatate peptide receptor radionuclide therapy: proof-of-concept of PRRT in merkel cell cancer. Case Rep Oncol. 2019; 12 ( 1 ): 98 - 103. 10.1159/000496335
65. Ferdinandus J Fendler WP Lueckerath K et al. Response to combined peptide receptor radionuclide therapy and checkpoint immunotherapy with ipilimumab plus nivolumab in metastatic merkel cell carcinoma. J Nucl Med. 2022; 63 ( 3 ): 396 - 398. 10.2967/jnumed.121.262344
66. Decroisette C Monnet I Berard H et al. Epidemiology and treatment costs of bone metastases from lung cancer: A french prospective, observational, multicenter study (GFPC 0601). J Thorac Oncol. 2011; 6 ( 3 ): 576 - 582. 10.1097/JTO.0b013e318206a1e3
67. Félix J Andreozzi V Soares M et al. Hospital resource utilization and treatment cost of skeletal-related events in patients with metastatic breast or prostate cancer: estimation for the portuguese national health system. Value Health. 2011; 14 ( 4 ): 499 - 505. 10.1016/j.jval.2010.11.014
68. Hoefeler H Duran I Hechmati G et al. Health resource utilization associated with skeletal-related events in patients with bone metastases: results from a multinational retrospective - prospective observational study - a cohort from 4 european countries. J Bone Oncol. 2014; 3 ( 2 ): 40 - 48. 10.1016/j.jbo.2014.04.001
69. Lüftner D Lorusso V Duran I et al. Health resource utilization associated with skeletal-related events in patients with advanced breast cancer: results from a prospective, multinational observational study. Springerplus. 2014; 3 ( 1 ): 328. 10.1186/2193-1801-3-328
70. Pockett RD Castellano D McEwan P et al. The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in spain. Eur J Cancer Care. 2010; 19 ( 6 ): 755 - 760. 10.1111/j.1365-2354.2009.01135.x

Citation

Idrissou MB, Muralidha A, Hernandez R, Sodji QH. Clinical Evidence of Combining Radiopharmaceutical Therapy With Immune Checkpoint Inhibitors. Appl Radiat Oncol. 2025;(1):6-16.
doi:10.37549/ARO-D-24-00039

March 1, 2025

5 not found