RESUMEN

Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.

Asunto(s)

Ferroptosis , Radioisótopos de Yodo , Radiofármacos , Ferroptosis/efectos de los fármacos , Animales , Radiofármacos/química , Radiofármacos/uso terapéutico , Ratones , Radioisótopos de Yodo/uso terapéutico , Radioisótopos de Yodo/química , Línea Celular Tumoral , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Hierro/química , Ratones Endogámicos BALB C , Inmunoterapia/métodos , Radioinmunoterapia/métodos , Femenino , Neoplasias/terapia

RESUMEN

Radioimmunotherapy (RIT) is a novel and promising cancer treatment method, with ongoing research focusing on RIT antibody selection, radionuclides, treatment options, and benefited patient groups. As we dive into the mechanisms of tumor biology, a deeper exploration of how RIT affects tumor tissue is needed to provide new ways to improve clinical treatment outcome and patient prognosis. We labeled the anti-PD-L1 monoclonal antibody atezolizumab with iodine-131 (131I), separated and purified the labeled mAb with Sephadex G-25 medium gel filtration resin, and tested product stability. We detected the in vivo activity of 131I-PD-L1 mAb by analyzing its in vivo biodistribution and performing SPECT imaging and then set different treatment groups to study the effect of 131I-atezolizumab on the survival of tumor-bearing mice. Western blot, real-time quantitative PCR, and immunohistochemistry were used to detect the expression level of Caspase8 and Nlrp3 in tumor. TUNEL fluorescence staining was used to detect the apoptosis in the tumor. The radiopharmaceutical molecular probe 131I-atezolizumab showed high stability and in vivo biological activity. The treatment regimen adopted had a positive effect on the survival of tumor-bearing mice. 131I internal irradiation upregulated Caspase8 in tumor and ultimately inhibited solid tumor growth by activating apoptosis pathways. We also found a significant increase in the expression of NLRP3, which plays an important role in the pyroptosis pathway, in tumor. In summary, our data demonstrated that radiopharmaceuticals combined with immunotherapy affected tumor tissue by modulating relevant biological pathways, thereby achieving better antitumor effects compared with single therapy and providing new insights for promoting better patient prognosis and combination treatment strategies.

Asunto(s)

Apoptosis , Caspasa 8 , Radioisótopos de Yodo , Radioinmunoterapia , Animales , Apoptosis/efectos de los fármacos , Ratones , Humanos , Línea Celular Tumoral , Radioinmunoterapia/métodos , Caspasa 8/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Distribución Tisular , Femenino , Regulación hacia Arriba/efectos de los fármacos , Ratones Endogámicos BALB C , Neoplasias/radioterapia , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Radiofármacos/farmacología

RESUMEN

In the1980s, radiolabeled cells helped understand the pathology of hemato-oncology. In the 1990s, preclinical trials evaluated radiolabeled immunotherapy with monoclonal antibodies (MoAbs) such as anti-CD20 agents labeled with Iodine-131 (Bexxar) or Yttrium-90 (Zevalin). Due to the safe and durable responses of radiolabeled MoAbs, the Food and Drug Administration approved these agents in the 2000s. Despite radioimmunotherapy's long journey, its application has recently decreased. This review will discuss the historical timeline of radioimmunotherapy, debate on advantages and difficulties, and explore trials. We will examine future directions of radioligand therapy in hemato-oncology, considering emerging molecules that may become the next theragnostic trend.

Asunto(s)

Linfoma , Radioinmunoterapia , Radiofármacos , Humanos , Anticuerpos Monoclonales/uso terapéutico , Historia del Siglo XX , Historia del Siglo XXI , Radioisótopos de Yodo/uso terapéutico , Linfoma/radioterapia , Linfoma/diagnóstico por imagen , Radioinmunoterapia/métodos , Radiofármacos/uso terapéutico , Radioisótopos de Itrio/uso terapéutico

RESUMEN

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors.

Asunto(s)

Inmunoterapia , Animales , Ratones , Inmunoterapia/métodos , Línea Celular Tumoral , Femenino , Terapia Combinada , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Interleucina-12 , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Radioinmunoterapia/métodos , Interleucina-2 , Ratones Endogámicos BALB C , Memoria Inmunológica , Estadificación de Neoplasias , Neoplasias del Colon/terapia , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología

RESUMEN

In Greek mythology, The Phoenix is an immortal bird that dies, but then achieves new life by rising from the ashes of its predecessor. Radioimmunotherapy (RIT) of B-cell Non-Hodgkin lymphoma (NHL) is a field which once began to fly high-with FDA approval of the anti-CD20 RITs Zevalin® and Bexxar® in 2002 and 2003 respectively, as safe and effective therapies of NHL. However, despite their therapeutic efficacy, Bexxar® was withdrawn from the market by the manufacturer in 2014 due to limited commercial demand and Zevalin® has had very limited to no availability of late. I-131 rituximab is used to a limited extent in Australia, India and other countries, as well. But has RIT of NHL been (perhaps prematurely) left for dead by many? Given the current great clinical and commercial interest in radiopharmaceutical therapies of cancer, notably PSMA and SSTR targeting agents in prostate and neuroendocrine cancers, can radioimmunotherapy of NHL-like the mythical Phoenix-now rise from its ashes in an even better form to fly higher, faster, farther and longer than before?

Asunto(s)

Linfoma no Hodgkin , Medicina Nuclear , Radioinmunoterapia , Radioinmunoterapia/métodos , Humanos , Linfoma no Hodgkin/radioterapia

RESUMEN

Radiotheranostics is a rapidly growing approach in personalized medicine, merging diagnostic imaging and targeted radiotherapy to allow for the precise detection and treatment of diseases, notably cancer. Radiolabeled antibodies have become indispensable tools in the field of cancer theranostics due to their high specificity and affinity for cancer-associated antigens, which allows for accurate targeting with minimal impact on surrounding healthy tissues, enhancing therapeutic efficacy while reducing side effects, immune-modulating ability, and versatility and flexibility in engineering and conjugation. However, there are inherent limitations in using antibodies as a platform for radiopharmaceuticals due to their natural activities within the immune system, large size preventing effective tumor penetration, and relatively long half-life with concerns for prolonged radioactivity exposure. Antibody engineering can solve these challenges while preserving the many advantages of the immunoglobulin framework. In this review, the goal is to give a general overview of antibody engineering and design for tumor radiotheranostics. Particularly, the four ways that antibody engineering is applied to enhance radioimmunoconjugates: pharmacokinetics optimization, site-specific bioconjugation, modulation of Fc interactions, and bispecific construct creation are discussed. The radionuclide choices for designed antibody radionuclide conjugates and conjugation techniques and future directions for antibody radionuclide conjugate innovation and advancement are also discussed.

Asunto(s)

Neoplasias , Radioinmunoterapia , Humanos , Neoplasias/inmunología , Neoplasias/radioterapia , Neoplasias/terapia , Radioinmunoterapia/métodos , Radiofármacos/uso terapéutico , Animales , Inmunoconjugados/química , Ingeniería de Proteínas/métodos

RESUMEN

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 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 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 [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [225Ac]AcBLPhen significantly increased the delivery of [225Ac]Ac3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [225Ac]Ac3+ 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.

Asunto(s)

Actinio , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Actinio/química , Humanos , Línea Celular Tumoral , Animales , Partículas alfa/uso terapéutico , Ratones , Femenino , Materiales Biocompatibles/química , Neoplasias de la Mama/tratamiento farmacológico , Radioinmunoterapia/métodos

RESUMEN

Molecular radiotherapy (MRT), also known as radioimmunotherapy or targeted radiotherapy, is the delivery of radionuclides to tumours by targeting receptors overexpressed on the cancer cell. Currently it is used in the treatment of a few cancer types including lymphoma, neuroendocrine, and prostate cancer. Recently reported outcomes demonstrating improvements in patient survival have led to an upsurge in interest in MRT particularly for the treatment of prostate cancer. Unfortunately, between 30% and 40% of patients do not respond. Further normal tissue exposure, especially kidney and salivary gland due to receptor expression, result in toxicity, including dry mouth. Predictive biomarkers to select patients who will benefit from MRT are crucial. Whilst pre-treatment imaging with imaging versions of the therapeutic agents is useful in demonstrating tumour binding and potentially organ toxicity, they do not necessarily predict patient benefit, which is dependent on tumour radiosensitivity. Transcript-based biomarkers have proven useful in tailoring external beam radiotherapy and adjuvant treatment. However, few studies have attempted to derive signatures for MRT response prediction. Here, transcriptomic studies that have identified genes associated with clinical radionuclide exposure have been reviewed. These studies will provide potential features for seeding multi-component biomarkers of MRT response.

Asunto(s)

Biomarcadores de Tumor , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Radioinmunoterapia/métodos , Masculino , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias/radioterapia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Radioisótopos/uso terapéutico

RESUMEN

BACKGROUND: Glioblastoma (GB), the most aggressive brain cancer, remains a critical clinical challenge due to its resistance to conventional treatments. Here, we introduce a locoregional targeted-α-therapy (TAT) with the rat monoclonal antibody 9E7.4 targeting murine syndecan-1 (SDC1) coupled to the α-emitter radionuclide astatine-211 (211At-9E7.4). METHODS: We orthotopically transplanted 50,000 GL261 cells of murine GB into the right striatum of syngeneic female C57BL/6JRj mice using stereotaxis. After MRI validation of tumour presence at day 11, TAT was injected at the same coordinates. Biodistribution, efficacy, toxicity, local and systemic responses were assessed following application of this protocol. The 9E7.4 monoclonal antibody was labelled with iodine-125 (125I) for biodistribution and with astatine-211 (211At) for the other experiments. FINDINGS: The 211At-9E7.4 TAT demonstrated robust efficacy in reducing orthotopic tumours and achieved improved survival rates in the C57BL/6JRj model, reaching up to 70% with a minimal activity of 100 kBq. Targeting SDC1 ensured the cerebral retention of 211At over an optimal time window, enabling low-activity administration with a minimal toxicity profile. Moreover, TAT substantially reduced the occurrence of secondary tumours and provided resistance to new tumour development after contralateral rechallenge, mediated through the activation of central and effector memory T cells. INTERPRETATION: The locoregional 211At-9E7.4 TAT stands as one of the most efficient TAT across all preclinical GB models. This study validates SDC1 as a pertinent therapeutic target for GB and underscores 211At-9E7.4 TAT as a promising advancement to improve the treatment and quality of life for patients with GB. FUNDING: This work was funded by the French National Agency for Research (ANR) "France 2030 Investment Plan" Labex Iron [ANR-11-LABX-18-01], The SIRIC ILIAD [INCa-DGOS-INSERM-18011], the French program "Infrastructure d'Avenir en Biologie-Santé" (France Life Imaging) [ANR-11-INBS-0006], the PIA3 of the ANR, integrated to the "France 2030 Investment Plan" [ANR-21-RHUS-0012], and support from Inviscan SAS (Strasbourg, France). It was also related to: the ANR under the frame of EuroNanoMed III (project GLIOSILK) [ANR-19-ENM3-0003-01]; the "Région Pays-de-la-Loire" under the frame of the Target'In project; the "Ligue Nationale contre le Cancer" and the "Comité Départemental de Maine-et-Loire de la Ligue contre le Cancer" (CD49) under the frame of the FusTarG project and the "Tumour targeting, imaging and radio-therapies network" of the "Cancéropôle Grand-Ouest" (France). This work was also funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Nantes, and the University of Angers.

Asunto(s)

Astato , Neoplasias Encefálicas , Glioblastoma , Sindecano-1 , Animales , Femenino , Ratones , Sindecano-1/metabolismo , Glioblastoma/terapia , Glioblastoma/inmunología , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/tratamiento farmacológico , Astato/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Memoria Inmunológica , Modelos Animales de Enfermedad , Distribución Tisular , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Ratones Endogámicos C57BL , Ratas , Radioinmunoterapia/métodos

RESUMEN

Radiotherapy demonstrates a synergistic effect with immunotherapy by inducing a transformation of "immune cold" tumors into "immune hot" tumors in triple negative breast cancer (TNBC). Nevertheless, the effectiveness of immunotherapy is constrained by low expression of tumor-exposed antigens, inadequate inflammation, and insufficient tumor infiltrating lymphocyte (TILs). To address this predicament, novel lutecium-based rare earth nanoparticles (RENPs) are synthesized with the aim of amplifying radiation effect and tumor immune response. The nanoprobe is characterized by neodymium-based down-conversion fluorescence, demonstrating robust photostability, biocompatibility, and targetability. The conjugation of RENPs with a CXCR4 targeted drug enables precise delineation of breast tumors using a near-infrared imaging system and improves radiation efficacy via lutetium-based radio-sensitizer in vivo. Furthermore, the study shows a notable enhancement of immune response through the induction of immunogenic cell death and recruitment of TILs, resulting in the inhibition of tumor progression both in vitro and in vivo models following the administration of nanoparticles. Hence, the novel multifunctional nanoprobes incorporating various lanthanide elements offer the potential for imaging-guided tumor delineation, radio-sensitization, and immune activation post-radiation, thus presenting an efficient radio-immunotherapeutic approach for TNBC.

Asunto(s)

Nanopartículas , Radioinmunoterapia , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/radioterapia , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Animales , Ratones , Femenino , Radioinmunoterapia/métodos , Nanopartículas/química , Humanos , Modelos Animales de Enfermedad , Metales de Tierras Raras/química , Línea Celular Tumoral

RESUMEN

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab's clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs ß-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

Asunto(s)

Inmunoconjugados , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Pulmonares , Radioinmunoterapia , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/radioterapia , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Radioinmunoterapia/métodos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Proteínas de la Membrana/metabolismo , Inmunoterapia/métodos , Medicina de Precisión , Terapia Molecular Dirigida

RESUMEN

Combining radiotherapy with immune checkpoint blockade therapy offers a promising approach to treat glioblastoma multiforme (GBM), yet challenges such as limited effectiveness and immune-related adverse events (irAEs) persist. These issues are largely due to the failure in targeting immunomodulators directly to the tumor microenvironment. To address this, a biomimetic nanoplatform that combines a genetically modified mesenchymal stem cell (MSC) membrane with a bioactive nanoparticle core for chemokine-directed radioimmunotherapy of GBM is developed. The CC chemokine receptor 2 (CCR2)-overexpressing MSC membrane acts as a tactical tentacle to achieve radiation-induced tropism toward the abundant chemokine (CC motif) ligand 2 (CCL2) in irradiated gliomas. The nanoparticle core, comprising diselenide-bridged mesoporous silica nanoparticles (MSNs) and PD-L1 antibodies (αPD-L1), enables X-ray-responsive drug release and radiosensitization. In two murine models with orthotopic GBM tumors, this nanoplatform reinvigorated immunogenic cell death, and augmented the efficacy and specificity of GBM radioimmunotherapy, with reduced occurrence of irAEs. This study suggests a promising radiation-induced tropism strategy for targeted drug delivery, and presents a potent nanoplatform that enhances the efficacy and safety of radio-immunotherapy.

Asunto(s)

Glioblastoma , Nanopartículas , Radioinmunoterapia , Glioblastoma/radioterapia , Glioblastoma/terapia , Glioblastoma/patología , Animales , Radioinmunoterapia/métodos , Ratones , Nanopartículas/química , Humanos , Línea Celular Tumoral , Células Madre Mesenquimatosas , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Dióxido de Silicio/química

Asunto(s)

Sarcoma , Humanos , Sarcoma/terapia , Sarcoma/patología , Neoplasias de los Tejidos Blandos/terapia , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/secundario , Radioinmunoterapia/métodos , Metástasis de la Neoplasia

Asunto(s)

Sarcoma , Humanos , Sarcoma/terapia , Sarcoma/patología , Masculino , Femenino , Persona de Mediana Edad , Radioinmunoterapia/métodos , Resultado del Tratamiento , Adulto , Anciano , Metástasis de la Neoplasia , Neoplasias de los Tejidos Blandos/terapia , Neoplasias de los Tejidos Blandos/secundario , Neoplasias de los Tejidos Blandos/patología

RESUMEN

Radiation therapy may induce off-target antitumor "abscopal" immunostimulatory and immunosuppressive effects. Several preclinical and early clinical studies revealed promising results when combining radiation therapy with immunostimulatory agents. Most radioimmunotherapy randomized trials showed disappointing results in patients with advanced tumors. In contrast, outcomes were encouraging when immunotherapy was delivered on top of gross disease elimination with curative-intent radiation therapy. In this review, we highlight available results from randomized trials and discuss the potential impact of overall tumor burden on the observed efficacy of radioimmunotherapy.

Asunto(s)

Neoplasias , Radioinmunoterapia , Humanos , Radioinmunoterapia/métodos , Neoplasias/radioterapia , Neoplasias/inmunología , Inmunoterapia/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Carga Tumoral/efectos de la radiación

RESUMEN

Genome editing has the potential to improve the unsatisfactory therapeutic effect of antitumor immunotherapy. However, the cell plasma membrane prevents the entry of almost all free genome-manipulation agents. Therefore, a system can be spatiotemporally controlled and can instantly open the cellular membrane to allow the entry of genome-editing agents into target cells is needed. Here, inspired by the ability of T cells to deliver cytotoxins to cancer cells by perforation, an ultrasound (US)-controlled perforation system (UPS) is established to enhance the delivery of free genome-manipulating agents. The UPS can perforate the tumor cell membrane while maintaining cell viability via a controllable lipid peroxidation reaction. In vitro, transmembrane-incapable plasmids can enter cells and perform genome editing with the assistance of UPS, achieving an efficiency of up to 90%. In vivo, the UPS is biodegradable, nonimmunogenic, and tumor-targeting, enabling the puncturing of tumor cells under US. With the application of UPS-assisted genome editing, gasdermin-E expression in 4T1 tumor-bearing mice is successfully restored, which leads to pyroptosis-mediated antitumor immunotherapy via low-dose X-ray irradiation. This study provides new insights for designing a sonoporation system for genome editing. Moreover, the results demonstrate that restoring gasdermin expression by genome editing significantly improves the efficacy of radioimmunotherapy.

Asunto(s)

Piroptosis , Radioinmunoterapia , Linfocitos T , Animales , Ratones , Línea Celular Tumoral , Humanos , Radioinmunoterapia/métodos , Linfocitos T/metabolismo , Rayos X , Edición Génica , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Femenino , Ondas Ultrasónicas , Gasderminas

RESUMEN

Intrinsic or acquired radioresistance remained an important challenge in the successful management of cancer. Herein, a novel "smart" multifunctional copper-based nanocomposite (RCL@Pd@CuZ) to improve radiotherapy (RT) sensitivity is designed and developed. In this nanoplatform, DSPE-PEG-RGD modified on the liposome surface enhanced tumor targeting and permeability; capsaicin inserted into the phospholipid bilayer improved the hypoxic conditions in the tumor microenvironment (TME) by inhibiting mitochondrial respiration; a Cu MOF porous cube encapsulated in liposome generated highly active hydroxyl radicals (OH·), consumed GSH and promoted cuproptosis by releasing Cu2+; the ultrasmall palladium (Pd) nanozyme within the cubes exhibited peroxidase activity, catalyzing toxic OH· generation and releasing oxygen from hydrogen peroxide; and lastly, Pd, as an element with a relatively high atomic number (Z) enhanced the photoelectric and Compton effects of X-rays. Therefore, RCL@Pd@CuZ enhance RT sensitivity by ameliorating hypoxia, promoting cuproptosis, depleting GSH, amplifying oxidative stress, and enhancing X-ray absorption  , consequently potently magnifying immunogenic cell death (ICD). In a mouse model , RCL@Pd@CuZ combined with RT yielded >90% inhibition compared with that obtained by RT alone in addition to a greater quantity of DC maturation and CD8+ T cell infiltration. This nanoplatform offered a promising remedial modality to facilitate cuproptosis-related cancer radioimmunotherapy.

Asunto(s)

Cobre , Radioinmunoterapia , Animales , Radioinmunoterapia/métodos , Cobre/química , Ratones , Respiración de la Célula/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Humanos , Línea Celular Tumoral , Paladio/química , Paladio/farmacología , Liposomas/química , Nanocompuestos/química , Nanocompuestos/uso terapéutico

RESUMEN

PURPOSE: Gastric cancer (GC), one of the most prevalent and deadliest tumors worldwide, is often diagnosed at an advanced stage with limited treatment options and poor prognosis. The development of a CLDN18.2-targeted radioimmunotherapy probe is a potential treatment option for GC. METHODS: The CLDN18.2 antibody TST001 (provided by Transcenta) was conjugated with DOTA and radiolabeled with the radioactive nuclide 177Lu. The specificity and targeting ability were evaluated by cell uptake, imaging and biodistribution experiments. In BGC823CLDN18.2/AGSCLDN18.2 mouse models, the efficacy of [177Lu]Lu-TST001 against CLDN18.2-expressing tumors was demonstrated, and toxicity was evaluated by H&E staining and blood sample testing. RESULTS: [177Lu]Lu-TST001 was labeled with an 99.17%±0.32 radiochemical purity, an 18.50 ± 1.27 MBq/nmol specific activity and a stability of ≥ 94% after 7 days. It exhibited specific and high tumor uptake in CLDN18.2-positive xenografts of GC mouse models. Survival studies in BGC823CLDN18.2 and AGSCLDN18.2 tumor-bearing mouse models indicated that a low dose of 5.55 MBq and a high dose of 11.10 MBq [177Lu]Lu-TST001 significantly inhibited tumor growth compared to the saline control group, with the 11.1 MBq group showing better therapeutic efficacy. Histological staining with hematoxylin and eosin (H&E) and Ki67 immunohistochemistry of residual tissues confirmed tumor tissue destruction and reduced tumor cell proliferation following treatment. H&E showed that there was no significant short-term toxicity observed in the heart, spleen, stomach or other important organs when treated with a high dose of [177Lu]Lu-TST001, and no apparent hematotoxicity or liver toxicity was observed. CONCLUSION: In preclinical studies, [177Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.

Asunto(s)

Antineoplásicos , Neoplasias Gástricas , Humanos , Animales , Ratones , Radioinmunoterapia/métodos , Xenoinjertos , Neoplasias Gástricas/radioterapia , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto , Anticuerpos Monoclonales/uso terapéutico , Línea Celular Tumoral , Lutecio/uso terapéutico , Claudinas

RESUMEN

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.

Asunto(s)

Neoplasias Peritoneales , Radioinmunoterapia , Humanos , Animales , Ratones , Radioinmunoterapia/métodos , Ratones Desnudos , Neoplasias Peritoneales/diagnóstico por imagen , Neoplasias Peritoneales/radioterapia , Neoplasias Peritoneales/tratamiento farmacológico , Radioisótopos/uso terapéutico , Línea Celular Tumoral

RESUMEN

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using ß-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Asunto(s)

Linfoma de Células B , Linfoma Folicular , Linfoma no Hodgkin , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/radioterapia , Medicina de Precisión , Tomografía Computarizada por Tomografía de Emisión de Positrones , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/radioterapia , Radioinmunoterapia/métodos , Radioisótopos de Itrio/uso terapéutico