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European Journal of Nuclear Medicine... Sep 2022Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate...
PURPOSE
Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the β-emitting lutetium-177 with the α-emitting actinium-225. Actinium-225 is thought to have a higher therapeutic efficacy due to the high linear energy transfer (LET) of the emitted α-particles, which can increase the amount and complexity of the therapy induced DNA double strand breaks (DSBs). Here we evaluated the relative biological effectiveness of [Ac]Ac-PSMA-I&T and [Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficacy.
METHODS AND RESULTS
The PSMA-expressing PCa cell line PC3-PIP was used for all in vitro assays. First, binding and displacement assays were performed, which revealed similar binding characteristics between [Ac]Ac-PSMA-I&T and [Lu]Lu-PSMA-I&T. Next, the assessment of the number of 53BP1 foci, a marker for the number of DNA double strand breaks (DSBs), showed that cells treated with [Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [Ac]Ac-PSMA-I&T and [Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [Lu]Lu-PSMA-I&T.
CONCLUSION
We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [Ac]Ac-PSMA-I&T compared to [Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [Ac]Ac-PSMA-I&T compared to [Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.
Topics: Actinium; Cell Line, Tumor; DNA; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radioisotopes
PubMed: 35556158
DOI: 10.1007/s00259-022-05821-w -
JAMA Oncology Jun 2019In retrospective studies, 68Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with... (Clinical Trial)
Clinical Trial
IMPORTANCE
In retrospective studies, 68Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with conventional imaging.
OBJECTIVE
To assess 68Ga-PSMA-11 PET accuracy in a prospective multicenter trial.
DESIGN, SETTING, AND PARTICIPANTS
In this single-arm prospective trial conducted at University of California, San Francisco and University of California, Los Angeles, 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%) underwent 68Ga-PSMA-11 PET. Presence of prostate cancer was recorded by 3 blinded readers on a per-patient and per-region base. Lesions were validated by histopathologic analysis and a composite reference standard.
MAIN OUTCOMES AND MEASURES
Endpoints were positive predictive value (PPV), detection rate, interreader reproducibility, and safety.
RESULTS
A total of 635 men were enrolled with a median age of 69 years (range, 44-95 years). On a per-patient basis, PPV was 0.84 (95% CI, 0.75-0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI, 0.88-0.95) by the composite reference standard (n = 217). 68Ga-PSMA-11 PET localized recurrent prostate cancer in 475 of 635 (75%) patients; detection rates significantly increased with prostate-specific antigen (PSA): 38% for <0.5 ng/mL (n = 136), 57% for 0.5 to <1.0 ng/mL (n = 79), 84% for 1.0 to <2.0 ng/mL (n = 89), 86% for 2.0 to <5.0 ng/mL (n = 158), and 97% for ≥5.0 ng/mL (n = 173, P < .001). Interreader reproducibility was substantial (Fleiss κ, 0.65-0.78). There were no serious adverse events associated with 68Ga-PSMA-11 administration. PET-directed focal therapy alone led to a PSA drop of 50% or more in 31 of 39 (80%) patients.
CONCLUSIONS AND RELEVANCE
Using blinded reads and independent lesion validation, we establish high PPV for 68Ga-PSMA-11 PET, detection rate and interreader agreement for localization of recurrent prostate cancer.
TRIAL REGISTRATION
ClinicalTrials.gov identifiers: NCT02940262 and NCT03353740.
Topics: Adult; Aged; Aged, 80 and over; Edetic Acid; Gallium Isotopes; Gallium Radioisotopes; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Oligopeptides; Positron-Emission Tomography; Predictive Value of Tests; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 30920593
DOI: 10.1001/jamaoncol.2019.0096 -
Medical Principles and Practice :... 2023Actinium-225 (Ac-225) labelled PSMA RLT has been tested recently in metastatic castration-resistant prostate cancer (mCRPC), with encouraging results. Ac-225, being an... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Actinium-225 (Ac-225) labelled PSMA RLT has been tested recently in metastatic castration-resistant prostate cancer (mCRPC), with encouraging results. Ac-225, being an alpha emitter, is expected to have higher efficacy and fewer side effects compared to the beta-emitters such as Lutetium-177. We have performed a meta-analysis to assess the therapeutic responses, survival effects, and significant side effects of Ac-225 PSMA RLT in patients with mCRPC.
METHODOLOGY
Systematic literature search was carried out from five electronic databases PubMed/MEDLINE, SCOPUS, EMBASE, Web of Science, and Cochrane Library until March 2021. Eight studies were found to be eligible for this metanalysis.
RESULTS
Eight studies with 226 patients were analyzed in this metanalysis. 81% (95% CI 73-89) patients had a decline in PSA levels. 60% of the patients showed more than 50% PSA decline. Two studies assessed survival effects of radioligand naïve patients compared to patients who had received Lu-PSMA therapy previously and the pooled HR for radioligand naïve patients is 0.22. The most common toxicity reported was xerostomia in 167 patients out of 226 patients (73.9%, 95% CI 67.6-79.5%); however, most of them were confined to grade I and II levels. Other reported side effects include hematologic toxicity and nephrotoxicity.
CONCLUSION
Ac-PSMA RLT is a safe and potentially effective treatment option for patients with mCRPC.
Topics: Male; Humans; Actinium; Prostatic Neoplasms, Castration-Resistant; Prostate-Specific Antigen; Prostate; Dipeptides; Treatment Outcome; Retrospective Studies
PubMed: 37247612
DOI: 10.1159/000531246 -
Pharmaceutics Jun 2023The actinium-225 (Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the Ac radionuclide presents multiple... (Review)
Review
The actinium-225 (Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on Ac is discussed. Quality control measures in the preparation of Ac-conjugates are also highlighted.
PubMed: 37376167
DOI: 10.3390/pharmaceutics15061719 -
Journal of Clinical Oncology : Official... Feb 2022Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies.
PURPOSE
Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD).
METHODS
This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS).
RESULTS
Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; = .02), 76.2% (HR, 1.02; 0.60 to 1.72; = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; = .037).
CONCLUSION
CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.
Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Cyclophosphamide; Disease-Free Survival; Drug Therapy, Combination; Female; Germany; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Myeloablative Agonists; Recurrence; Tacrolimus; Time Factors; Transplantation Conditioning; United States; Young Adult
PubMed: 34855460
DOI: 10.1200/JCO.21.02293 -
Journal of Hematology & Oncology May 2023Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the... (Clinical Trial)
Clinical Trial
BACKGROUND
Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting.
METHODS
Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses.
RESULTS
Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT.
CONCLUSION
Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.
Topics: Adult; Humans; Antibodies, Bispecific; Cardiovascular Diseases; Inotuzumab Ozogamicin; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Salvage Therapy
PubMed: 37131217
DOI: 10.1186/s13045-023-01444-2 -
Frontiers in Medicine 2022According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the... (Review)
Review
According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the worst prognosis. Due to its infiltrating characteristic, molecular heterogeneity, and only partly preserved function of the blood-brain barrier, the median overall survival time is short (9-15 months), regardless of comprehensive treatment including surgery, radiotherapy, and chemotherapy. Several novel treatment strategies are under investigation. Unfortunately, none of them produced successful results; 90% of patients have a recurrence of the disease within 6 months. Local administration of the drug could be a promising approach to delivering treatment with minimized side effects, due to the recurrence of 95% glioblastomas in a margin of 2 cm at the primary site. Several ligand-receptor systems have been evaluated, such as targeting tenascin, the extracellular matrix protein, or radiolabeled somatostatin analogs, as it is overexpressed with the SSTR-2 receptor system in around 80% of gliomas. Moreover, this study revealed that the NK-1 receptor is overexpressed in GB, suggesting that substance P (SP) may serve as a ligand. A variety of radioisotopes, beta- (I, Y, or Lu) and alpha emitters (Bi, Ac, or At), with different physical properties were tested for treatment. Alpha particles have many advantages over beta radiation such as short range with higher linear energy transfer. According to that characteristic, it is extremely dose delivered to the targeted cells, while reducing harm to nearby healthy tissue. Additionally, the biological effect of alpha radiation is independent of the cell cycle phase, cell oxygenation and O-6-methylguanine-DNA methyltransferase () gene promoter methylation status. In this article, we summarize the experience with local treatment of primary and secondary GBs with locally used radioisotopes such as [Bi]Bi-DOTA-SP or [Ac]Ac-DOTA-SP.
PubMed: 36590948
DOI: 10.3389/fmed.2022.1085245 -
Seminars in Radiation Oncology Jan 2021In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed... (Review)
Review
In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed therapy and norepinephrine transporter targeted I-MIBG therapies by the FDA and the rapid progress of highly promising beta and alpha emitter tagged PSMA directed therapy of prostate cancer have stimulated clinically impactful changes in practice. Many novel strategies are being explored and novel radiopharmaceutical therapeutic agents including peptide based ligands as well as antibodies or antibody fragments are being developed preclinically or are in early phase clinical trials. While beta particle emitters have most commonly been used for targeted radiotherapy and radioimmunotargeting, there is an emerging interest in alpha emitters that cause greater density of ionization events leading to increased double-strand DNA damage and cluster breaks because of the high-energy particles within a shorter tissue range of penetration and thereby lower toxicity to adjacent normal tissues.
Topics: Humans; Male; Precision Medicine; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 33246639
DOI: 10.1016/j.semradonc.2020.07.010 -
Blood Advances May 2023Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological...
Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.
Topics: Humans; Middle Aged; Aged; Aged, 80 and over; Leukemia, Lymphocytic, Chronic, B-Cell; Nivolumab; Programmed Cell Death 1 Receptor; B-Lymphocytes; Lymphoma, Large B-Cell, Diffuse
PubMed: 36287248
DOI: 10.1182/bloodadvances.2022008790 -
Pharmaceuticals (Basel, Switzerland) Jan 2024The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation... (Review)
Review
The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.
PubMed: 38256909
DOI: 10.3390/ph17010076