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A Review of 177Lutetium-PSMA and 225Actinium-PSMA as Emerging Theranostic Agents in Prostate Cancer.Cureus Sep 2022The development of prostate-specific membrane antigen (PSMA) ligands labeled with radionuclides is a ground-breaking achievement in the management of prostate cancer.... (Review)
Review
The development of prostate-specific membrane antigen (PSMA) ligands labeled with radionuclides is a ground-breaking achievement in the management of prostate cancer. With the increasing use of Gallium-PSMA and F-DCFPyL (Pylarify) and their approval by the Food and Drug Administration (FDA), other PSMA agents and their unique characteristics are also being studied. Two other PSMA agents, namely Lutetium-PSMA (Lu-PSMA) and Actinium-PSMA (Ac-PSMA), are currently drawing the researcher's attention mainly due to their theranostic importance. Studies focusing on the essential characteristics of these two emerging radiotracers are relatively lacking. Hence, this review article, beginning with a brief introduction, intends to provide insights on the mechanism, efficacy, adverse effects, usefulness, including theranostic implications, and limitations of these two emerging PSMA agents. The Lu-PSMA is commercially accessible, is well tolerated, and has been found to lower prostate-specific antigen (PSA) levels while improving patients' quality of life. It also reduces pain and the requirement for analgesics and is safe for advanced diseases. However, despite its potential advantages, around one-third of patients do not respond satisfactorily to this costly treatment; it is still challenging to personalize this therapy and predict its outcome. Similarly, Ac is compatible with antibody-based targeting vectors, releasing four extremely hazardous high-energy emissions with a longer half-life of 10 days. It has made Ac-PSMA therapy useful for tumors resistant to standard treatments, with a better response than Lu-PSMA. Dosimetry studies show a good biochemical response without toxicity in patients with advanced metastatic castration-resistant prostate cancer (mCRPC). However, it can potentially cause significant damage to healthy tissues if not retained at the tumor site. Encapsulating radionuclides in a nano-carrier, hastening the absorption by tumor cells, and local delivery might all help reduce the harmful consequences. Both have advantages and disadvantages. The choice of PSMA agents may rely on desired qualities, cost, and convenience, among other factors. Further research is warranted in order to better understand their ideal use in clinical settings.
PubMed: 36284803
DOI: 10.7759/cureus.29369 -
European Journal of Nuclear Medicine... Dec 2021This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With... (Review)
Review
PURPOSE
This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With this in-depth discussion on the growing field of PSMA-based alpha therapy (PAT), we aimed to increase the interactions between basic scientists and physician-scientists in order to advance the field.
METHODS
To achieve this, we discuss the potential, current status, and opportunities for alpha therapy and strategies, attempted to date, and important questions that need to be addressed. The paper reviews important concepts, including whom to treat, how to treat, what to expect regarding treatment outcome, and toxicity, and areas requiring further investigations.
RESULTS
There is much excitement about the potential of this field. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other conventional therapies.
CONCLUSION
A better understanding of the strengths and limitations of PAT may help in creating an effective therapy for mCRPC and design a rational combinatorial approach to treatment by targeting different tumor pathways.
Topics: Antigens, Surface; Glutamate Carboxypeptidase II; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 34173838
DOI: 10.1007/s00259-021-05434-9 -
Cancers Dec 2023Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases...
Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting. This study investigated the effects of radiation delivered by Lutetium-177 (Lu) and Actinium-225 (Ac) on the viability and effector function of CAR T cells in vitro to evaluate the feasibility of such therapeutic combinations. After the irradiation of anti-GD2 CAR T cells with various doses of radiation delivered by Lu or Ac, their viability and cytotoxic activity against GD2-expressing human CHLA-20 neuroblastoma and melanoma M21 cells were determined by flow cytometry. The expression of the exhaustion marker PD-1, activation marker CD69 and the activating receptor NKG2D was measured on the irradiated anti-GD2 CAR T cells. Both Lu and Ac displayed a dose-dependent toxicity on anti-GD2 CAR T cells. However, radiation enhanced the cytotoxic activity of these CAR T cells against CHLA-20 and M21 irrespective of the dose tested and the type of radionuclide. No significant changes in the expression of PD-1, CD69 and NKG2D was noted on the CAR T cells following irradiation. Given a lower CAR T cell viability at equal doses and an enhancement of cytotoxic activity irrespective of the radionuclide type, Lu-based TRT may be preferred over Ac-based TRT when evaluating a potential synergism between these therapies in vivo against solid tumors.
PubMed: 38201618
DOI: 10.3390/cancers16010191 -
Blood Advances Sep 2023This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of... (Randomized Controlled Trial)
Randomized Controlled Trial
This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. Half of the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). The coprimary end points were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = .48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio, 0.97; 95% confidence interval, 0.83-1.14; stratified log-rank P = .73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine and 36% and 14% for TC, respectively. A large proportion of patients (42%) received <4 cycles of treatment in both the arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; log-rank P = .02]). There was no significant difference in the proportion of patients with grade ≥3 adverse events (AEs) between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs of febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, no significant difference was observed in the efficacy of guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.
Topics: Humans; Treatment Outcome; Azacitidine; Cytarabine; Leukemia, Myeloid, Acute
PubMed: 37276510
DOI: 10.1182/bloodadvances.2023010179 -
Translational Andrology and Urology Jun 2018Radium (Ra) is the first alpha-emitting therapy proven effective in human cancer. Prospective randomized trials indicate that Ra, which concentrates after intravenous... (Review)
Review
Radium (Ra) is the first alpha-emitting therapy proven effective in human cancer. Prospective randomized trials indicate that Ra, which concentrates after intravenous injection in areas of osteoblastic metastatic disease, can prolong survival in bone-dominant castrate resistant prostate cancer patients. Though radium isotopic therapy is conceptually critical to demonstrate that alpha emitters can be safe and effective, Ra has inherent limitations given its restriction to bone metastatic disease. To overcome this limitation, targeted alpha therapy (TAT) is now being actively evaluated in prostate cancer, and other neoplasms. Key to TAT in prostate tumors in current studies is the overexpression of prostate specific membrane antigen (PSMA), a folate hydrolase expressed on the cell surface of malignant adenocarcinomas of the prostate. Using PSMA targeting (small molecules or antibodies), alpha emitting agents such as Actinium (Ac) or Bismuth (Bi) can be delivered to PSMA expressing tumors regardless of their metastatic location. Initial results from TAT in prostate cancer are highly promising and rapid development of these agents is anticipated in the years ahead assuming adequacy of isotope availability and appropriate clinical trial design. TAT may be develop as an independent approach, or synergize with a variety of other approaches including external beam radiation, hormonal therapies, chemotherapies, various radiation sensitizers, DNA repair inhibitors, and/or immune modulators. Clinical investigation opportunities in this field will rapidly increase in the years ahead.
PubMed: 30050802
DOI: 10.21037/tau.2018.02.07 -
Seminars in Nuclear Medicine Mar 2020Within the last decades, there has been no major improvement in treatment of patients with glioma, especially with glioblastoma multiforme (GBM) which is related to... (Review)
Review
Within the last decades, there has been no major improvement in treatment of patients with glioma, especially with glioblastoma multiforme (GBM) which is related to specific features of this tumor type, such as heterogeneity at the macroscopic, microscopic and genetic level, the infiltrative nature of tumors and the obstacle of the brain-blood barrier which limits the accessability of most drugs. The current standard of care is surgical resection, followed by radio- and chemotherapy. After first-line treatment of the primary lesion, tumor recurrence is diagnosed in virtually all GBM patients. Treatment of tumor recurrence represents a challenging clinical task. Surgical resection to relief symptoms of mass effect and/or salvage chemotherapy are often considered as last therapeutic option. A new treatment option is urgently needed. Targeted alpha therapy with an intratumoral injection of Bi-DOTA-Substance P (SP) or Ac-DOTAGA-Substance P has been introduced into the therapeutic armamentarium of recurrent GBM. There are many advantages of using SP such as very high prevalence of increased NK-1 expression in GBM cells, regardless of the degree of malignancy, and expression of the NK-1 receptor system not only on the membrane of cancer cells but also strong expression of NK1 receptors within the tumor neovasculature suggesting concomitant targeting of vascular and neoplastic structures. Radioisotopes with different physical properties, mainly beta-emitting metallic radionuclides, were implemented for brain tumor treatment. Based on their radiophysical properties, however, alpha emitters exhibit more promising properties. In investigator-initiated phase I and II studies, targeted alpha therapy using Bi-213/Ac-225 radiolabeled Substance P for malignant gliomas compare favorably with standard therapy, with the limitation that no large controlled series have so far been generated. Further development should focus on the improvement of the biological and chemical properties of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within growth and infiltrative zone of these glial neoplasms.
Topics: Actinium; Bismuth; Glioma; Humans; Radioisotopes; Substance P
PubMed: 32172799
DOI: 10.1053/j.semnuclmed.2019.11.004 -
PloS One 2022Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are...
Hepatocellular carcinoma is the most common primary liver cancer and the fifth most frequently diagnosed cancer worldwide. Most patients with advanced disease are offered non-surgical palliative treatment options. This work explores the first alpha-particle emitting radioembolization for the treatment and monitoring of hepatic tumors. Furthermore, this works demonstrates the first in vivo simultaneous multiple-radionuclide SPECT-images of the complex decay chain of an [225Ac]Ac-labeled agent using a clinical SPECT system to monitor the temporal distribution. A DOTA chelator was modified with a lipophilic moiety and radiolabeled with the α-particle emitter Actinium-225. The resulting agent, [225Ac]Ac-DOTA-TDA, was emulsified in ethiodized oil and evaluated in vivo in mouse model and the VX2 rabbit technical model of liver cancer. SPECT imaging was performed to monitor distribution of the TAT agent and the free daughters. The [225Ac]Ac-DOTA-TDA emulsion was shown to retain within the HEP2G tumors and VX2 tumor, with minimal uptake within normal tissue. In the mouse model, significant improvements in overall survival were observed. SPECT-imaging was able to distinguish between the Actinium-225 agent (Francium-221) and the loss of the longer lived daughter, Bismuth-213. An α-particle emitting TARE agent is capable of targeting liver tumors with minimal accumulation in normal tissue, providing a potential therapeutic agent for the treatment of hepatocellular carcinoma as well as a variety of hepatic tumors. In addition, SPECT-imaging presented here supports the further development of imaging methodology and protocols that can be incorporated into the clinic to monitor Actinium-225-labeled agents.
Topics: Alpha Particles; Animals; Bismuth; Carcinoma, Hepatocellular; Embolization, Therapeutic; Hep G2 Cells; Humans; Liver Neoplasms, Experimental; Male; Mice; Rabbits; Radioisotopes; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Xenograft Model Antitumor Assays
PubMed: 35061763
DOI: 10.1371/journal.pone.0261982 -
Frontiers in Medicine 2022Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue... (Review)
Review
Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.
PubMed: 36619636
DOI: 10.3389/fmed.2022.1020188 -
World Journal of Nuclear Medicine 2021Neuroendocrine neoplasms (NENs) are a very diverse group of tumors with a worldwide rise in incidence. Systemic therapy remains the mainstay treatment for unresectable... (Review)
Review
Neuroendocrine neoplasms (NENs) are a very diverse group of tumors with a worldwide rise in incidence. Systemic therapy remains the mainstay treatment for unresectable and/or metastatic NENs. Lu-DOTATATE, a radiopharmaceutical which emits beta particles, has emerged as a promising therapy for metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, limited treatment options are available particularly after the failure of Lu-DOTATATE therapy. This review aims to identify and summarize the available evidence for, and potential adverse events of, targeted alpha-particle therapy (TAT) in the treatment of metastatic NENs, specifically GEP-NENs. The MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases were searched. Two articles which met the inclusion criteria were identified and included in the review. Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include Actinium (Ac)-DOTATATE and Bismuth (Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, Ac-DOTATATE, in the treatment of metastatic NENs.
PubMed: 35018146
DOI: 10.4103/wjnm.wjnm_160_20 -
The Lancet. Haematology Dec 2021Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2... (Review)
Review
Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia.
Topics: Antineoplastic Agents; Gemtuzumab; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute
PubMed: 34687602
DOI: 10.1016/S2352-3026(21)00270-2