Radiopharmaceuticals are an emerging and promising approach for diagnosing and treating various types of Cancer. Radiopharmaceutical therapy (RPT) has demonstrated effectiveness with minimal toxicity compared to other systemic cancer treatments, such as chemotherapy and biologics.

Historically, RPT has been a last-resort treatment option, but recent approvals and promising results have sparked renewed interest, attracting both small and large pharmaceutical companies. However, its development involves a multidisciplinary approach, with expertise in various fields, making it less familiar to pharmaceutical companies and the oncology community.

This article covers the fundamental aspects of radiopharmaceutical therapy and gives examples of radiopharmaceuticals in clinical use. Moreover, it discusses the role of radiopharmaceuticals in immunotherapy and addresses challenges associated with their development and application.

What Are Radiopharmaceuticals?

Radiopharmaceuticals are a group of pharmaceutical drugs that contain radioactive isotopes, also known as radionuclides or radioisotopes. These drugs are designed to deliver potent radiation to specific organs, tissues, or cells in the body, serving various diagnostic and therapeutic purposes.

Recent developments have put radiopharmaceuticals into the spotlight, particularly within the field of oncology. These agents are administered systemically and accumulate on tumors or their microenvironment. Their accumulation can result from several mechanisms, including the involvement of the radionuclide in tumor-related biological processes, conjugation to tumor-targeting delivery vehicles, or passive accumulation through physiological mechanisms.

Delivery vehicles of radiopharmaceuticals include small molecules, radiolabeled peptides, and antibodies. Furthermore, preclinical research explores liposomal and nanoconstruct delivery strategies, while glass and resin microspheres have already established their role in treating liver cancer and metastases.

The choice of delivery vehicle has a significant impact on how radiopharmaceuticals are retained in tumors versus normal tissue. For instance, antibody-mediated delivery generally leads to long retention but can result in increased toxicity in normal organs due to the extended circulation half-life of antibodies. In contrast, small molecules and peptides offer rapid targeting and clearance but typically have shorter tumor retention.

Radiopharmaceuticals are compatible with imaging techniques, which play a crucial role in evaluating their accumulation in tumors, assessing early treatment response, and performing dosimetry calculations.

For RPT, patient-specific, image-based dosimetry is essential. It is like conducting real-time pharmacodynamic studies in treated patients, allowing the quantification of agent distribution in tumors and organs. This helps to optimize radiopharmaceutical administration to increase tumor-absorbed dose while minimizing normal organ toxicity.

A deeper understanding of radionuclides

Radionuclides can emit three types of radiation: photons (X-rays and γ-rays), electrons (such as Auger electrons and β-particles), and α-particles. The choice of radionuclide is critical and depends on factors such as the energy released by emitted particles over a given distance (i.e., linear energy transfer or LET), their tissue penetration range, and their physical half-life.

In general, photons are primarily used for imaging the distribution of radiopharmaceuticals, as positron emissions can be detected by positron emission tomography (PET) cameras. In addition, radionuclides emitting γ-rays can be applied for both imaging and therapy simultaneously.

β-particles, emitted from the nucleus, have low LET and a relatively long tissue range. This results in the irradiation of not only tumor cells but also of the tumor microenvironment, a phenomenon known as the “crossfire effect.” It allows neighboring cells that may not express the molecular target to be irradiated, addressing potential heterogeneity in target expression among cancer cells. Although several β-emitting radionuclides have shown promise, their adoption has been limited due to availability issues, radiochemistry complexity, and regulatory and financial obstacles.

Conversely, α-emitters have a short tissue range and high LET, enabling them to deliver a dense concentration of ionization events locally. Similar to β-emitters, α-particles also irradiate the tumor microenvironment. Due to their high potency and restricted range, α-particles have generated commercial interest in RPT.

Auger electrons have short-range emissions and potential cytotoxicity if the radiopharmaceutical agent localizes within the cell nucleus. While they have demonstrated promise in preclinical investigations, human investigations have had limited clinical success due to difficulties related to drug integration into DNA and unfavorable pharmacokinetics.

The Role of Radiopharmaceuticals in Cancer and Immunotherapy

Radiopharmaceuticals have gained significant attention in cancer diagnosis and therapeutics. In diagnostic imaging, radiopharmaceuticals are administered to patients, and their radioactive emissions are detected by specialized imaging devices like gamma cameras or PET scanners. This allows healthcare providers to visualize and assess tumor characteristics, such as size, location, and metabolic activity.

On the other hand, radiopharmaceuticals designed for therapeutic purposes deliver targeted radiation directly to cancer cells, aiming at destroying or damaging these cells while minimizing harm to surrounding healthy tissues.

Radiopharmaceuticals are now emerging as a valuable complement for immunotherapy, a treatment approach generally used to treat advanced cancer. Immunotherapy, which includes checkpoint therapy, adoptive cellular therapy, cancer vaccines, monoclonal antibodies, and cytokine therapy, uses the patient’s immune system to fight cancer.

Unlike chemotherapy which exerts its effects only while the drugs are present in the body, immunotherapy has the potential to offer longer-lasting remissions, due to the immune ‘memory’ created. It is estimated that approximately 15%-20% of patients achieve durable results with immunotherapy.

Enhancing anti-tumor immunity with RPT

RPT has demonstrated several immunogenic effects that can enhance anti-tumor immunity, making it a promising approach for combination therapy with immunotherapies. Current knowledge suggests that:

• RPT induces immunogenic cell death in tumor cells, leading to the expression of damage-associated molecular pattern molecules by tumor cells
• Surviving cells following RPT undergo phenotypic changes, rendering them more susceptible to antigen-specific CD8+ cytotoxic T lymphocyte-mediated killing. Some radiopharmaceuticals, such as 90Y-NM600, activate the stimulator of interferon genes pathway in these surviving cells, leading to the production of interferon-1 and the induction of immune susceptibility markers associated with immune responses
• RPT affects innate immune populations involved in the initial response to radiation therapy and the establishment of an adaptive immune response
• Some clinical studies suggest an increase in immunosuppressive populations, such as myeloid-derived suppressor cells and regulatory T cells in peripheral blood mononuclear cells
• RPT has varying effects on tumor-infiltrating lymphocyte populations. Some studies report an increase in CD8+ T cells following combination therapy with RPT and immunotherapies, while others report varying effects on CD8+ populations

Pursuing combination therapy: radiopharmaceutical therapy and immunotherapy

As a standalone treatment, RPT has demonstrated limited durability in its efficacy against solid tumors. This limitation has fueled investigations into combination therapies involving RPT and immunotherapies to enhance and prolong the anti-tumor immune response.

The combination of RPT with immunotherapy holds significant promise as a strategy to enhance therapeutic response and improve outcomes for metastatic cancer patients. Consequently, several clinical trials have been initiated to evaluate the safety and efficacy of combining RPT with immunotherapy. These trials predominantly focus on patients with metastatic castration-resistant prostate cancer (mCRPC).

For example, in a phase II trial, patients with mCRPC received 153Sm-ethylene diamine tetramethylene phosphonate (153Sm-EDTMP) either alone or in combination with the PSA/TRICOM vaccine (Prostvac®). While there was no significant difference in progression-free survival, the combination therapy resulted in a >30% prostate-specific antigen (PSA) decline in some patients.

Another phase II trial explored the combination of Sipuleucel-T (Provenge®) and 223RaCl2 in mCRPC patients. The combination therapy showed potential benefits in terms of overall and progression-free survival and a >50% PSA decline. However, it was associated with decreased prostatic acid phosphatase-specific peripheral T-cell proliferation compared to Sipuleucel-T alone.

Several ongoing clinical trials are combining RPT with immune checkpoint inhibitors targeting mCRPC (e.g., the combinations of 177Lu-PSMA-617 with pembrolizumab).

There are many other examples of combination therapy under clinical evaluation. Although early findings are promising, the need for randomized controlled trials to further explore the combination of RPT and immunotherapy is evident.

Advantages of Radiopharmaceuticals

Radiopharmaceuticals offer several advantages in cancer diagnosis and treatment:

• Non-invasive imaging: radiopharmaceuticals can contribute to early tumor detection, enabling more effective treatment and potentially improving outcomes. Moreover, radiopharmaceuticals allow for cancer staging, which is essential for treatment planning
• Safety and low toxicity: radiopharmaceuticals are generally well-tolerated by patients, and their toxicity to normal tissues is low. Some radiopharmaceuticals use short half-life isotopes, which means the radiation exposure to patients is limited and decreases rapidly after administration
• Personalized medicine: radiopharmaceuticals can be designed to target specific biomarkers, receptors, or antigens, allowing for precise diagnostic imaging and targeted therapy. This minimizes damage to healthy tissues and reduces side effects
• Abscopal effect: radiation from radiopharmaceuticals can induce an abscopal effect, where radiation therapy at one site leads to the regression of untreated tumors at distant sites. This immune response can enhance cancer treatment outcomes
• Dosimetry-driven treatment planning approach: this distinguishes RPT from treatments like chemotherapy and biologics.

Examples of Radiopharmaceuticals in Action

Historically, radiopharmaceuticals have had a significant impact on treating thyroid malignancies, and it remains a prominent application. Hematological malignancies have been studied since the early 1990s and continue to be an area of interest. In addition, radiopharmaceutical therapy for liver malignancies and prostate cancer (PCa) has seen substantial growth, particularly due to the development of new radiopharmaceuticals.

Currently, there are several radiopharmaceuticals available in the market, along with many more in various stages of development. These agents include both β-particle and α-particle emitters.

Unconjugated or chelated radionuclide radiopharmaceuticals

Examples of unconjugated or chelated radionuclide radiopharmaceuticals used in cancer include:

• [131I]NaI (radioiodine): radioiodine therapy is used to treat hyperthyroidism and thyroid carcinomas, especially differentiated thyroid cancer. Patients with thyroid cancers that do not concentrate iodine are not responsive to this therapy. Iodine-131 (β-particle emitter) concentrates in thyroid cells through a sodium-iodide symporter
• 223Ra (radium-223): it is the first FDA-approved α-emitting radiopharmaceutical agent. Radium-223 is used to treat metastatic castration-resistant PCa by emitting energetic α-particles that damage osteoblasts and osteoclasts in bone metastases, affecting cancer cell growth indirectly
• 153Sm (samarium-153): this β-emitting radionuclide is used for palliative treatment in patients with osteoblastic and mixed bone metastases in various cancers. When it is chelated with phosphate ligands, it forms a complex that accumulates in hydroxyapatite. The attraction of phosphonate for calcium found in rapidly growing bone contributes to the accumulation of 153Sm in metastatic lesions. Quadramet®, an FDA-approved radiopharmaceutical, combines 153Sm with the EDTMP chelator

Small molecule radiopharmaceuticals

Small-molecule radiopharmaceuticals targeting receptors like prostate-specific membrane antigen (PSMA) and folate receptors have gained popularity in recent years. They have been used in PCa and other cancers, delivering therapeutic radionuclides to tumor neovasculature expressing these receptors. Examples include:

• [131I]mIBG (meta-iodobenzylguanidine): iodide-131 has been incorporated into targeting vectors for treating neuroblastomas and other cancers. The U.S. Food and Drug Administration (FDA) granted approval for the treatment of unresectable metastatic phaeochromocytoma or paraganglioma
• 177Lu-labelled PSMA-617: currently undergoing a phase III randomized trial (VISION) in multiple centers. A phase II trial showed favorable responses in patients with metastatic castration-resistant PCa, particularly those expressing high levels of PSMA as detected by PET imaging. The use of imaging-based screening criteria allows for patient selection based on the distribution of the therapeutic target
• 177Lu-labelled PSMA-R2: this PSMA-targeting ligand is in a phase I/II multicenter dose-escalation study. Patients with a positive PSMA PET scan are eligible for this trial
• 177Lu-labelled CTT-1403: this PSMA inhibitor, which includes an albumin-binding motif, is in a first-in-human phase I dose-escalation trial. A companion diagnostic, CTT-1057, is a 18F-labelled PET agent
• Folate receptor-targeted radiotherapeutics: folate receptor is overexpressed in various cancers but has limited expression in normal tissue. Radiopharmaceuticals based on folate derivatives for imaging and therapy have been developed, but clinical translation is pending.
• Phospholipid ether analogues, which target the altered membrane composition of neoplastic cells, have shown rapid and persistent tumor accumulation. They are under clinical trial investigation for a wide range of hematological malignancies and solid tumors, making them potential pan-cancer radiopharmaceuticals.

Peptide radiopharmaceuticals

Peptide receptor radionuclide therapy (PRRT) uses radiolabeled somatostatin analogue peptides for the treatment of neuroendocrine tumors. Initially, diagnostic radionuclide indium-111 was used, but over the past two decades, beta-emitters like yttrium-90 and lutetium-177 have become more common due to their longer-range emissions.

PRRT has been successful in treating inoperable or metastatic gastroenteropancreatic and bronchopulmonary neuroendocrine tumors, phaeochromocytomas, and paragangliomas. The most frequently used radiopeptides, 90Y-octreotide and 177Lu-octreotate, achieve disease control rates of 68%-94%. In addition, studies showed that PRRT is well-tolerated with low to moderate toxicity.

Ongoing research aims to enhance PRRT outcomes. This includes exploring somatostatin receptor antagonists, such as 177Lu-DOTA-JR11, which demonstrated promising results with fewer treatment cycles. Moreover, α-emitters like lead-212 and actinium-225 are being investigated for patients resistant to conventional PRRT.

In addition to PRRT, other receptor-targeted radionuclide therapies are being explored, such as bombesin analogue peptides for cancers like prostate and breast cancer.

Antibody radiopharmaceuticals

Antibodies of the IgG class, known for their long half-life and precise antigen recognition, have been extensively employed in radiopharmaceutical therapy. These monoclonal antibodies are used to target specific antigens on cancer cells, especially in hematological and lymphoid malignancies.

For instance, iodine-131-labeled antibodies have been used to replace total body irradiation in bone marrow transplantation preparation and to target lineages with uncontrolled proliferation, such as acute myelogenous leukemia.

Humanized antibodies and the availability of alpha-particle-emitting radionuclides like bismuth-213 and actinium-225 expanded the arsenal against CD33-positive cancers, showing potent antileukemic responses with minimal off-target effects.

Similar strategies have been applied to lymphoma treatment using the CD20 antigen as a target. Antibodies like ibritumomab tiuxetan (Zevalin®) and tositumomab (Bexxar®), conjugated to yttrium-90 and iodine-131, respectively, were developed. In clinical trials, these agents exhibited higher response rates compared to unlabelled antibodies, offering a targeted radiation therapy option with manageable toxicity.

Challenges and Ongoing Developments in Radiopharmaceutical-Based Immunotherapy

Recent advances in RPT, especially in the use of α-emitters and tumor-targeting agents, such as antibody-based RPT, confirm its potential as a valuable therapeutic option for cancer treatment, particularly for difficult-to-treat cancers.

While RPT theoretically holds promise for application in a broad range of cancers that meet the radionuclide delivery criteria, its implementation has been limited to specific cancer types. Factors like the availability of suitable targets, RPT agents, expert knowledge, and clinical investigators at academic institutions have limited its adoption. For example, although solid cancers like colorectal and breast cancer remain of interest, they have not witnessed the same level of development that has driven RPT advances in liver malignancies and PCa.

In the case of solid tumors, radiolabeled antibodies have faced challenges, including the need for higher absorbed doses to achieve therapeutic efficacy, limited tumor penetration, and high bone marrow radiation. To overcome these limitations, strategies like pretargeting have been explored, temporally separating radiolabel delivery from tumor targeting to enhance the specificity and effectiveness of antibody-based RPT in solid cancers.

Furthermore, progress in isotope production are expanding the possibilities for creating new radiopharmaceuticals, whereas technological progress, like mini cyclotrons and automated quality control testing, is increasing access to radiopharmaceuticals, especially in developing countries. Innovations like total-body PET scanners could potentially change the traditional distribution model for radiopharmaceuticals, allowing for wider availability of established and shorter-lived radionuclides.

Conclusion

Over the past five decades, the field of radiopharmaceutical sciences and nuclear medicine has experienced remarkable growth and transformation. Exciting developments are on the horizon, including the approval of new diagnostic and therapeutic radiopharmaceuticals by the FDA, marking the era of theranostics.

The ability to deliver precision treatment by targeting cancer cells with short-ranged potent radiation, combined with the capacity to image and quantitatively characterize the biological outcomes of the treatment, offer several advantages in cancer diagnosis and treatment.

As we look to the future, the quest for even more specific tumor-associated targets will be a driving force, as will advances in radiochemistry and the increased availability of radionuclides, particularly those emitting α-particles. The exploration of combination therapies will continue to expand the horizon of cancer treatment.

However, significant challenges await resolution. Early-stage clinical trials that incorporate imaging and dosimetry will be determinant for the rigorous evaluation and comparison of RPT with existing therapeutic approaches.

Vial

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