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Journal of Medical Imaging and... Jun 2024Prostate cancer remains one of the leading causes of cancer-related death in the world. There have been significant advances in chemotherapy, hormonal therapy and... (Review)
Review
Prostate cancer remains one of the leading causes of cancer-related death in the world. There have been significant advances in chemotherapy, hormonal therapy and targeted therapy options for patients with castrate-resistant disease. However, these systemic treatments are often associated with unwanted toxicities. Targeted therapy with radiopharmaceuticals has become of key interest to limit systemic toxicity and provides a more precision oncology approach to treatment. Strontium-89, Samarium-153 EDTMP and Radium-223 have been trialled with mixed results. Strontium-89 and Samarium-153 EDTMP have shown benefits in palliating metastatic bone pain but with no impact on survival outcomes. Early therapeutic radiopharmaceuticals targeting PSMA that were developed were beta-emitting agents, but recently alpha-emitting agents are being investigated as potentially superior options. Radium-223 is the first alpha-particle emitter therapeutic agent approved by the FDA, with phase III trial evidence showing benefits in overall survival and delay in symptomatic skeletal events for patients. Recently, 177-Lutetium-PSMA-617 has demonstrated significant survival advantages in pre-treated metastatic castrate-resistant cancer patients in a number of phase II and III studies. Furthermore, 225-Actinium-PSMA-617 also showed promise even in patients pre-treated with 177-Lutetium-PSMA-617. Hence, there has been an explosion of radiopharmaceutical treatment options for patients with prostate cancer. This review explores past and current theranostic capacities in the radiopharmaceutical treatment of metastatic castrate-resistant prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Theranostic Nanomedicine; Bone Neoplasms; Radioisotopes
PubMed: 38632711
DOI: 10.1111/1754-9485.13658 -
Current Radiopharmaceuticals 2024The low range of alpha particles provides an opportunity to better target cancer cells theoretically leading to the introduction of interesting alpha emitter... (Review)
Review
The low range of alpha particles provides an opportunity to better target cancer cells theoretically leading to the introduction of interesting alpha emitter radiopharmaceuticals including Ac, Pb, etc. The combination of high energy and short range of alpha emitters differentiates targeted radiotherapy from other methods and reduces unwanted cytotoxicity of the cells around the tumoral tissue. Among interesting alpha emitters candidates for targeted therapy, At, one of the radioisotopes with the best optimal decay properties, shows great promise for targeted radiotherapy in some animal prostate cancer xenograft studies and bone micro tumors with significant effects compared to other beta and alpha emitters and also demonstrates interesting properties for clinical applications. However, production and application of this alpha emitter in the development of actinium-based radiopharmaceuticals is hampered by many obstacles. This mini-review demonstrates At production methods, chemical separation, radiolabeling procedures, At-radiopharmaceuticals and their clinical trials, transport, logistics, and costs and future trends in the field for ultimate clinical applications. This review showed that there are limited clinical trials on Ac-based radiopharmaceuticals, which is due to the low accessibility of this radioisotope and other limitations. However, the development programs of major industries indicate the development of Ac-based radiopharmaceuticals in the future.
Topics: Radiopharmaceuticals; Humans; Astatine; Alpha Particles; Animals; Neoplasms
PubMed: 37937552
DOI: 10.2174/0118744710262325231025075638 -
Blood Advances Sep 2023Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World...
Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Prognosis; Risk Factors
PubMed: 37142255
DOI: 10.1182/bloodadvances.2023009675 -
PET Clinics Jul 2023Fibroblast activation protein (FAP) was first reported in 1986. However, FAP is not expressed in normal fibroblasts, normal or malignant epithelial cells, or the stroma... (Review)
Review
Fibroblast activation protein (FAP) was first reported in 1986. However, FAP is not expressed in normal fibroblasts, normal or malignant epithelial cells, or the stroma of benign epithelial tumors. FAP is a cell membrane-bound serine peptidase overexpressed on the surface of cancer-associated fibroblasts and, as such, is a novel target for molecular imaging of several tumors. FAP inhibitors (FAPI) are potential theranostic molecular probes for various cancers. A tumor model expressing FAP was used to verify or confirm the usefulness of FAPI experimentally.
Topics: Humans; Membrane Proteins; Precision Medicine; Serine Endopeptidases; Neoplasms; Fibroblasts
PubMed: 36997365
DOI: 10.1016/j.cpet.2023.02.005 -
Clinical Cancer Research : An Official... Jun 2024Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted...
PURPOSE
Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs.
EXPERIMENTAL DESIGN
The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide.
RESULTS
Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models.
CONCLUSIONS
These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306).
Topics: Male; Humans; Animals; Actinium; Mice; Xenograft Model Antitumor Assays; Cell Line, Tumor; Glutamate Carboxypeptidase II; Antigens, Surface; Alpha Particles; Tissue Distribution; Prostatic Neoplasms; Immunoconjugates; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals
PubMed: 38593212
DOI: 10.1158/1078-0432.CCR-23-3746 -
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 -
Cancer Immunology, Immunotherapy : CII Nov 2023Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single...
Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.
Topics: Humans; Mice; Female; Animals; Carcinoma, Ovarian Epithelial; Receptors, Chimeric Antigen; Ovarian Neoplasms; Antigens, Neoplasm; T-Lymphocytes; WT1 Proteins
PubMed: 37635172
DOI: 10.1007/s00262-023-03529-w -
Blood Advances Oct 2023Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of...
Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged between <1 month and 88 years treated on Children's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): pediatric (0-17, 1744), adolescent/young adult (18-39, 444), intermediate-age (40-59, 640), older (≥60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (n = 288; IDH1 [n = 123, 42.7%]; IDH2 [n = 165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P < .001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P = .368; overall survival [OS]: 50.3% vs 55.4%, P = .196). IDH mutations frequently occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-internal tandem duplication (ITD) (22.4%) mutations. Patients with IDHmut AML with NPM1 mutation (IDHmut/NPM1mut) had significantly improved survival compared with the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P < .001; OS: 66.5% vs 35.2%, P < .001). DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Age group analysis demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients aged <60 years; older patients had poor outcomes regardless of NPM1 status. These trials were registered at www.clinicaltrials.gov as #NCT00070174, #NCT00372593, #NCT01371981, #NCT00049517, and #NCT00085709.
Topics: Adolescent; Young Adult; Humans; Child; Infant; Child, Preschool; Prognosis; Isocitrate Dehydrogenase; Nucleophosmin; Retrospective Studies; Leukemia, Myeloid, Acute; Mutation
PubMed: 37267439
DOI: 10.1182/bloodadvances.2022008282 -
Leukemia Research Nov 2023Numerous recent advances have been made in therapeutic approaches toward acute myeloid leukemia (AML). Since 2017, we have seen eleven novel Food & Drug Administration... (Review)
Review
Numerous recent advances have been made in therapeutic approaches toward acute myeloid leukemia (AML). Since 2017, we have seen eleven novel Food & Drug Administration (FDA)-approved medications for AML, all of which extend beyond the classical cytarabine-based cytostatic chemotherapy. In the recent two decades, the role of immune surveillance in AML has been intensively investigated. The power of one's own innate and adaptive immunity has been harnessed pharmacologically toward the goal of clearance of AML cells. Specifically, pre-clinical studies have shown great promise for antibodies that disinhibit T cells and macrophages by blocking checkpoint receptors within the immunologic synapse, thereby resulting in the elimination of AML cells. Anti-CD33 CAR-T therapies and anti-CD3/CD123 bispecific antibodies have also exhibited encouraging results in pre-clinical and early clinical studies. However, despite these translational efforts, we currently have no immune-based therapies for AML on the market, with the exception of gemtuzumab ozogamicin. In this focused review, we discuss molecular target validation and the most relevant clinical updates for immune-based experimental therapeutics including anti-CD47 monoclonal antibodies, CAR-T therapies, and bispecific T cell engagers. We highlight barriers to the clinical translation of these therapies in AML, and we propose solutions to optimize the manufacturing and delivery of the most novel immune-based therapies in the pipeline.
Topics: Humans; Receptors, Chimeric Antigen; Antibodies, Monoclonal; Gemtuzumab; Antibodies, Bispecific; Leukemia, Myeloid, Acute
PubMed: 37729719
DOI: 10.1016/j.leukres.2023.107388 -
Nuclear Medicine and Biology 2024Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human...
Initial insights into the interaction of antibodies radiolabeled with Lutetium-177 and Actinium-225 with tumor microenvironment in experimental human and canine osteosarcoma.
BACKGROUND
Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human monoclonal antibody IF3 to an insulin-like growth factor 2 receptor (IGF2R) radiolabeled with either alpha-emitting Actinium-225 (Ac) or beta-emitting Lutetium-177 (Lu) radionuclides with the OS cells and tumor microenvironment (TME) in experimental human and canine OS.
BASIC PROCEDURES
SCID mice bearing canine Gracie or human OS-33 OS tumors were treated with Lu- or Ac-labeled IF3 antibody, sacrificed at 24, 72 or 168 h post-treatment and their tumors were analyzed by immunohistochemistry (IHC) for the presence of OS cells, various elements of TME as well as for the double DNA strand breaks with γH2AX and caspase 3 assays.
MAIN FINDINGS
IHC revealed a reduction in IGF2R-positive OS cells and OS stem cell populations post therapy with Ac- and Lu-labeled IF3 antibody. Notably, radiolabeled IF3 antibody effectively diminished pro-tumorigenic M2 macrophages, highlighting its therapeutic promise. The study also unveiled varied responses of natural killer (NK) cells and M1 macrophages, shedding light on the intricate TME interplay. Time-dependent increase in γ-H2AX staining in canine Gracie and human OS-33 tumors treated with [Lu]Lu-IF3 and [Ac]Ac-IF3 was observed at 24 and 72 h post-RIT.
PRINCIPAL CONCLUSIONS
These findings suggest that radiolabeled antibodies offer a hopeful avenue for personalized OS treatment, emphasizing the importance of understanding their impact on the TME and potential synergies with immunotherapy.
Topics: Lutetium; Tumor Microenvironment; Animals; Dogs; Humans; Osteosarcoma; Radioisotopes; Mice; Cell Line, Tumor; Actinium; Antibodies, Monoclonal; Isotope Labeling; Bone Neoplasms
PubMed: 38718557
DOI: 10.1016/j.nucmedbio.2024.108917