-
European Journal of Nuclear Medicine... Jun 2024The radionuclide pair cerium-134/lanthanum-134 (Ce/La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (Ac)....
PURPOSE
The radionuclide pair cerium-134/lanthanum-134 (Ce/La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (Ac). The unique properties of Ce offer perspectives for developing innovative in vivo investigations that are not possible with Ac. In this work, Ac- and Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, Ce/La has limitations to the setting of quantitative positron emission tomography imaging.
METHODS
The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG-Tz) were radiolabelled with Ac or Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The Ac and Ce-labelled mcp-PEG-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.
RESULTS
In vitro and in vivo studies with both Ac and Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of Ce's PET-compatible daughter La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing Ac-labelled tracers are not quantitatively represented by Ce PET imaging.
CONCLUSION
When employing slow-internalizing vectors, Ce might not be an ideal match for Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of La. However, this same characteristic makes it possible to estimate the redistribution of Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.
PubMed: 38940841
DOI: 10.1007/s00259-024-06811-w -
Seminars in Nuclear Medicine Jun 2024Radiopharmaceutical approaches for targeting bone metastasis have traditionally focused on palliation of pain. Several agents have been clinically used over the last... (Review)
Review
Radiopharmaceutical approaches for targeting bone metastasis have traditionally focused on palliation of pain. Several agents have been clinically used over the last several decades and have proven value in pain palliation providing pain relief and improving quality of life. The role is well established across several malignancies, most commonly used in osteoblastic prostate cancer patients. These agents have primarily based on targeting and uptake in bone matrix and have mostly included beta emitting isotopes. The advent alpha emitter and FDA approval of 223Ra-dichloride has created a paradigm shift in clinical approach from application for pain palliation to treatment of bone metastasis. The approval of 223Ra-dichloride given the survival benefit in metastatic prostate cancer patients, led to predominant use of this alpha emitter in prostate cancer patients. With rapid development of radiopharmaceutical therapies and approval of other targeted agents such as 177Lu-PSMA the approach to treatment of bone metastasis has further evolved and combination treatments have increasingly been applied. Novel approaches are needed to improve and expand the use of such therapies for treatment of bone metastasis. Combination therapies with different targeting mechanisms, combining chemotherapies and cocktail of alpha and beta emitters need further exploration.
PubMed: 38937221
DOI: 10.1053/j.semnuclmed.2024.05.006 -
Physics in Medicine and Biology Jun 2024.Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy (TAT), however,Ac (t= 9.9 d) lacks direct gamma emissions forimaging.Ac (t= 29.4 h) is a...
.Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy (TAT), however,Ac (t= 9.9 d) lacks direct gamma emissions forimaging.Ac (t= 29.4 h) is a promising element-equivalent matched diagnostic radionuclide for preclinical evaluation ofAc radiopharmaceuticals.Ac has two gamma emissions (158 keV and 230 keV) suitable for SPECT imaging. This work is the first feasibility study forquantitativeAc SPECT imaging and validation of activity estimation..Ac was produced at TRIUMF (Vancouver, Canada) with its Isotope Separator and Accelerator (ISAC) facility. [Ac]Acwas radiolabelled with the bioconjugate crown-TATE developed for therapeutic targeting of neuroendocrine tumours (NET). Mice with AR42J tumour xenografts were injected with either 2 MBq of [Ac]Ac-crown-TATE or 4 MBq of free [Ac]Acactivity and were scanned at 1, 2.5, 5, and 24 h post injection in a preclinical microSPECT/CT. Quantitative SPECT images were reconstructed from the 158 keV and 230 keV photopeaks with attenuation, background, and scatter corrections. Image-basedAc activity measurements were assessed from volumes of interest (VOIs) within tumours and organs of interest. Imaging data was compared withbiodistribution measured via gamma counter.. We present, to the best of our knowledge, the first everquantitative SPECT images ofAc activity distributions. Time-activity curves derived from SPECT images quantify thebiodistribution of [Ac]Ac-crown-TATE and free [Ac]Acactivity. Image-based activity measurements in the tumours and organs of interest corresponded well withbiodistribution measurements.. Here in, we established the feasibility ofAc quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could quantitativepharmacokinetic information essential for estimating toxicities, dosimetry, and therapeutic potency.
PubMed: 38925140
DOI: 10.1088/1361-6560/ad5c37 -
ACS Nano Jun 2024Lanthanide vanadate (LnVO) nanoconstructs have generated considerable interest in radiotherapeutic applications as a medium for nanoscale-targeted drug delivery. For...
Lanthanide vanadate (LnVO) nanoconstructs have generated considerable interest in radiotherapeutic applications as a medium for nanoscale-targeted drug delivery. For cancer treatment, LnVO nanoconstructs have shown promise in encapsulating and retaining radionuclides that emit alpha-particles. In this work, we examined the structure formation of LnVO nanoconstructs doped with actinium (Ac) and radium (Ra), both experimentally and using large-scale atomistic molecular dynamics simulations. LnVO nanoconstructs were synthesized via a precipitation method in aqueous media. The reaction conditions and elemental compositions were varied to control the structure, fluorescence properties, and size distribution of the LnVO nanoconstructs. LnVO nanoconstructs were characterized by X-ray diffraction, Raman spectroscopy, and fluorescence spectroscopy. Molecular dynamics simulations were performed to obtain a fundamental understanding of the structure-property relationship between radionuclides and LnVO nanoconstructs at the atomic length scale. Molecular dynamics simulations with well-established force field (FF) parameters show that Ra atoms tend to distribute across the nanoconstructs' surface in a broader coordination shell, while the Ac atoms are arranged inside a smaller coordination shell within the nanocluster. The Ba atoms prefer to self-assemble around the surface. These theoretical/simulation predictions of the atomistic structures and an understanding of the relationship between radionuclides and LnVO nanoconstructs at the atomic scale are important because they provide design principles for the future development of nanoconstructs for targeted radionuclide delivery.
PubMed: 38885179
DOI: 10.1021/acsnano.3c13213 -
Research Square Jun 2024Lenalidomide maintenance is associated with a significantly improved progression-free in patients with newly diagnosed multiple myeloma. Maintenance with lenalidomide is...
Lenalidomide maintenance is associated with a significantly improved progression-free in patients with newly diagnosed multiple myeloma. Maintenance with lenalidomide is generally well tolerated; however, lenalidomide associated diarrhea is a common side effect and bile acid malabsorption has been suggested as an underlying mechanism. We conducted a single arm phase 2 trial of colesevelam, a bile acid binder, for lenalidomide-associated diarrhea in multiple myeloma. Patients were treated with colesevelam daily starting at 1250 mg (2 tablets 625 mg) for 12 weeks. The trial included 25 patients, 1 patient with grade 3 diarrhea, 14 with grade 2, and 10 with grade 1 diarrhea. All patients were on treatment with single agent lenalidomide maintenance and no patient progressed during the trial. Colesevelam treatment was highly effective for treatment of lenalidomide-associated diarrhea; 22 (88%) of the 25 patients responded where 17 patients (68%) had complete resolution of diarrhea, and 5 patients (20%) had improvement by 1 grade of diarrhea. The responses to colesevelam were seen within the first two weeks of treatment. These findings support the conclusion that lenalidomide-associated diarrhea is driven by bile acid malabsorption. Five patients reported mild gastrointestinal side effects including constipation. Importantly, the pharmacokinetics of lenalidomide were not affected by concomitant colesevelam treatment. The stool microbiome composition was not significantly different before and after colesevelam treatment. Patients reported improved diarrhea, fewer gastrointestinal symptoms, and less interference with their daily life after starting colesevelam. In summary, colesevelam was safe and highly effective for treatment of lenalidomide-associated diarrhea in multiple myeloma and does not reduce the clinical effect of lenalidomide.
PubMed: 38883739
DOI: 10.21203/rs.3.rs-4406606/v1 -
Journal of Nanobiotechnology Jun 2024Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous...
Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([Ac]Ac). Encapsulation of [Ac]Ac within PLGA nanoparticles (Z = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [Ac]Ac. Chelation of [Ac]Ac to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [Ac]AcBLPhen significantly increased the delivery of [Ac]Ac to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [Ac]Ac in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles.
Topics: Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Actinium; Humans; Cell Line, Tumor; Animals; Alpha Particles; Mice; Female; Biocompatible Materials; Breast Neoplasms; Radioimmunotherapy
PubMed: 38825717
DOI: 10.1186/s12951-024-02520-6 -
Blood Cancer Journal May 2024B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective,... (Comparative Study)
Comparative Study
B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Male; Female; Middle Aged; Aged; Retrospective Studies; Immunotherapy, Adoptive; Adult; Infections; Antibodies, Bispecific; Aged, 80 and over; Incidence; Immunoconjugates
PubMed: 38821925
DOI: 10.1038/s41408-024-01043-5 -
Blood Cancer Journal May 2024The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the...
Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy.
The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.
Topics: Humans; Multiple Myeloma; Male; Female; Middle Aged; Aged; Immunotherapy, Adoptive; Retrospective Studies; Receptors, Chimeric Antigen; Adult; Treatment Outcome; Standard of Care; Neoplasm Recurrence, Local
PubMed: 38821914
DOI: 10.1038/s41408-024-01068-w -
Blood Cancer Journal May 2024Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data...
Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.
Topics: Humans; Multiple Myeloma; Male; Female; Middle Aged; Antibodies, Monoclonal, Humanized; Aged; Immunotherapy, Adoptive; Retrospective Studies; Prognosis; Adrenal Cortex Hormones; Adult; Receptors, Chimeric Antigen; Aged, 80 and over
PubMed: 38802346
DOI: 10.1038/s41408-024-01048-0 -
Cell Reports. Medicine Jun 2024RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression...
RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.
Topics: Leukemia, Myelomonocytic, Chronic; Myeloid Cell Leukemia Sequence 1 Protein; Humans; Apoptosis; Animals; Mutation; Mice; Signal Transduction; Hematopoietic Stem Cells; Disease Progression; Sulfonamides; NF-kappa B; DNA Methylation; Bridged Bicyclo Compounds, Heterocyclic; Blast Crisis
PubMed: 38781960
DOI: 10.1016/j.xcrm.2024.101585