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1.
Front Immunol ; 14: 1105180, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37234164

RESUMO

Colorectal cancer (CRC) is a deadly form of cancer worldwide. Patients with locally advanced rectal cancer and metastatic CRC have a poor long-term prognosis, and rational and effective treatment remains a major challenge. Common treatments include multi-modal combinations of surgery, radiotherapy, and chemotherapy; however, recurrence and metastasis rates remain high. The combination of radiotherapy and immunotherapy (radioimmunotherapy [RIT]) may offer new solutions to this problem, but its prospects remain uncertain. This review aimed to summarize the current applications of radiotherapy and immunotherapy, elaborate on the underlying mechanisms, and systematically review the preliminary results of RIT-related clinical trials for CRC. Studies have identified several key predictors of RIT efficacy. Summarily, rational RIT regimens can improve the outcomes of some patients with CRC, but current study designs have limitations. Further studies on RIT should focus on including larger sample sizes and optimizing the combination therapy regimen based on underlying influencing factors.


Assuntos
Neoplasias Colorretais , Radioimunoterapia , Humanos , Radioimunoterapia/métodos , Terapia Combinada , Imunoterapia , Resultado do Tratamento , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia
2.
Nat Commun ; 14(1): 2109, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-37055410

RESUMO

Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1's role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Radioimunoterapia , Células Mieloides , Quimiocina CXCL16 , Microambiente Tumoral , Fator de Transcrição STAT1/genética
4.
ACS Nano ; 17(8): 7837-7846, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37022191

RESUMO

Atomically precise gold clusters play an important role in the development of high-Z-element-based radiosensitizers, due to their intriguing structural diversity and advantages in correlating structures and properties. However, the synthesis of gold clusters with both water-solubility and single-crystal structure remains a challenge. In this study, atomically precise Au25(S-TPP)18 clusters (TPP-SNa = sodium 3-(triphenylphosphonio)propane-1-thiolate bromide) showing both mitochondria-targeting ability and water-solubility were obtained via ligand design for enhanced radioimmunotherapy. Compared with Au25(SG)18 clusters (SG = glutathione), Au25(S-TPP)18 exhibited higher radiosensitization efficiency due to its mitochondria-targeting ability, higher ROS production capacity, and obvious inhibition upon thioredoxin reductase (TrxR). In addition, the enhanced radiotherapy-triggered abscopal effect in combination with checkpoint blockade displayed effective growth inhibition of distant tumors. This work reveals the ligand-regulated organelle targeting ability of metal clusters by which feasible strategies to promote their application in precise theranostics could be realized.


Assuntos
Radioimunoterapia , Água , Água/química , Ligantes , Ouro/química , Mitocôndrias
5.
Clin Cancer Res ; 29(10): 1916-1928, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36917693

RESUMO

PURPOSE: Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. EXPERIMENTAL DESIGN: [225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. RESULTS: Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 µCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi. CONCLUSIONS: [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.


Assuntos
Neoplasias da Próstata , Radioisótopos , Camundongos , Masculino , Animais , Humanos , Radioisótopos/uso terapêutico , Actínio/uso terapêutico , Bismuto , Radioimunoterapia , Partículas alfa/uso terapêutico , Distribuição Tecidual , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/tratamento farmacológico , Proteína Cofatora de Membrana
6.
Ann Hematol ; 102(5): 1149-1158, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36995403

RESUMO

Yttrium-90 ibritumomab tiuxetan (90YIT) is a radioimmunotherapy agent in which the radioisotope yttrium-90 is bound to ibritumomab via tiuxetan as a chelating agent, and is used for relapsed or refractory low-grade B-cell non-Hodgkin's lymphoma (rr-B-NHL). We conducted a joint study to evaluate the clinical outcome of 90YIT. The J3Zi study is composed of data from patients receiving 90YIT for rr-B-NHL from the top three institutions with 10 years of 90YIT treatment experience from October 2008 to May 2018 in Japan. The efficacy, prognostic factors and safety of 90YIT were retrospectively evaluated. Data from 316 patients were analyzed; the mean age was 64.6 years and the median number of prior treatments was 2. The median PFS was 3.0 years, the final OS rate was over 60%, and the median OS was not reached during the study period. Significant factors influencing PFS were sIL-2R ≤ 500 (U/mL) and no disease progression within 24 months of first treatment. Significant factors influencing OS were number of prior treatments ≤ 2 and sIL-2R ≤ 500 (U/mL). The PFS and OS rates were found to be significantly higher in the late half era (2013 to 2018) than in the early half era (2008 to 2013) during the study period. Prognosis following 90YIT treatment was improved in the late half era compared to the early half era. As treatment using 90YIT increased, administration of 90YIT shifted to the earlier treatment line. This may have contributed to the improvement of prognosis found in the late era. (UMIN000037105).


Assuntos
Linfoma de Células B , Linfoma não Hodgkin , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/radioterapia , Linfoma de Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Radioisótopos de Ítrio/uso terapêutico , Radioimunoterapia
7.
J Exp Clin Cancer Res ; 42(1): 61, 2023 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-36906664

RESUMO

We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Radioimunoterapia , Masculino , Animais , Humanos , Radioimunoterapia/métodos , Chumbo , Partículas alfa , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Radioisótopos de Chumbo/uso terapêutico , Proteína Cofatora de Membrana
8.
EMBO Mol Med ; 15(4): e16732, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-36876343

RESUMO

Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastatic cancers. Most current approaches rely on the use of vectors to deliver radionuclides to tumor cells, targeting membrane-bound cancer-specific moieties. Here, we report the embryonic navigation cue netrin-1 as an unanticipated target for vectorized radiotherapy. While netrin-1, known to be re-expressed in tumoral cells to promote cancer progression, is usually characterized as a diffusible ligand, we demonstrate here that netrin-1 is actually poorly diffusible and bound to the extracellular matrix. A therapeutic anti-netrin-1 monoclonal antibody (NP137) has been preclinically developed and was tested in various clinical trials showing an excellent safety profile. In order to provide a companion test detecting netrin-1 in solid tumors and allowing the selection of therapy-eligible patients, we used the clinical-grade NP137 agent and developed an indium-111-NODAGA-NP137 single photon emission computed tomography (SPECT) contrast agent. NP137-111 In provided specific detection of netrin-1-positive tumors with an excellent signal-to-noise ratio using SPECT/CT imaging in different mouse models. The high specificity and strong affinity of NP137 paved the way for the generation of lutetium-177-DOTA-NP137, a novel vectorized radiotherapy, which specifically accumulated in netrin-1-positive tumors. We demonstrate here, using tumor cell-engrafted mouse models and a genetically engineered mouse model, that a single systemic injection of NP137-177 Lu provides important antitumor effects and prolonged mouse survival. Together, these data support the view that NP137-111 In and NP137-177 Lu may represent original and unexplored imaging and therapeutic tools against advanced solid cancers.


Assuntos
Neoplasias , Radioimunoterapia , Animais , Camundongos , Linhagem Celular Tumoral , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Radioimunoterapia/métodos , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Netrina-1/metabolismo
9.
Nat Cancer ; 4(2): 165-180, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36806801

RESUMO

Monoclonal antibodies are a growing class of targeted cancer therapeutics, characterized by exquisite specificity, long serum half-life, high affinity and immune effector functions. In this review, we outline key advances in the field with a particular focus on recent and emerging classes of engineered antibody therapeutic candidates, discuss molecular structure and mechanisms of action and provide updates on clinical development and practice.


Assuntos
Anticorpos Monoclonais , Neoplasias , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Neoplasias/tratamento farmacológico , Radioimunoterapia
10.
Adv Mater ; 35(17): e2208546, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36745572

RESUMO

Immunotherapy shows immense promise for improving cancer treatment. Combining immunotherapy with radiotherapy provides a conspicuous advantage due to its enhanced abscopal effect. However, established immune tolerance mechanisms in the tumor microenvironment can hamper the generation of a sufficient abscopal effect. Herein, a type of DNA nanocluster (DNAnc) that is self-assembled by a CpG-ODNs-loaded Y-shaped double-stranded DNA vector based on the unique complementary base-pairing rules is designed. The unique structure of DNAnc makes it load more than ≈8125.5 ± 822.5 copies of CpG ODNs within one single nanostructure, which effectively increases resistance to nuclease degradation and elevates the efficiency of repolarizing macrophages to an M1-like phenotype. Mechanistic studies reveal that more DNAncs are endocytosed by macrophages in the cancer tissue and repolarized macrophages to elicit a robust abscopal effect with the accumulation of macrophages induced by radiotherapy, generating potent, long-term, and durable antitumor immunity for the inhibition of tumor metastasis and the prevention of tumor recurrence, which provides a novel strategy to boost cancer immunotherapy.


Assuntos
Neoplasias , Radioimunoterapia , Radioimunoterapia/métodos , DNA/química , DNA/genética , Nanoestruturas , Humanos , Animais , Camundongos , Linhagem Celular , Fenômenos Químicos , Memória Imunológica , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia
11.
Small Methods ; 7(5): e2201401, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36811166

RESUMO

In cancer treatment, traditional radiotherapy (RT) is routinely conducted in local tumors and limited by radioresistance, while recently emerged immunotherapy is confronted with low response rate, high cost, and cytokine release syndrome. Logically, the combination of the two therapeutic modalities into radioimmunotherapy is promising to complement with each other for systemic elimination of cancer cells with high specificity, efficiency, and safety. Especially, RT-induced immunogenic cell death (ICD) plays an imperative role in radioimmunotherapy to evoke systemic immune response against cancer, including elevating the immunity of tumor antigens, recruiting and activating antigen-presenting cells, and priming cytotoxic T lymphocytes for tumoral infiltration and cancer cell eradication. This review first retrospects the origin and concept of ICD, summarizes the major damage-associated molecular patterns and signaling pathways, and highlights the characteristics of RT-induced ICD. Subsequently, therapeutic strategies enhancing RT-induced ICD for radioimmunotherapy are reviewed from the perspectives of enhancing RT itself, combination with other treatments, and stimulating the holistic immune system. On the basis of these published research and underlying mechanism, this work attempts to forecast possible directions for RT-induced ICD enhancement to promote clinical applications.


Assuntos
Neoplasias , Radioimunoterapia , Humanos , Morte Celular Imunogênica , Imunoterapia , Neoplasias/radioterapia , Linfócitos T Citotóxicos
12.
Clin Lymphoma Myeloma Leuk ; 23(4): 259-265, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36775698

RESUMO

BACKGROUND: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine + rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. PATIENTS AND METHODS: We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N = 51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N = 92). RESULTS: Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P = .18), complete response rate (94% vs. 95%, P = .91), or 5 years progression-free survival (76% vs. 75%, P = .63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. CONCLUSION: The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Linfoma Folicular , Humanos , Rituximab/farmacologia , Rituximab/uso terapêutico , Cloridrato de Bendamustina/farmacologia , Cloridrato de Bendamustina/uso terapêutico , Análise Custo-Benefício , Radioimunoterapia , Radioisótopos de Ítrio/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/radioterapia , Linfoma Folicular/patologia , Linfoma de Zona Marginal Tipo Células B/patologia
13.
ACS Nano ; 17(4): 3225-3258, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36746639

RESUMO

The immune checkpoint blockade (ICB) therapy has revolutionized the field of cancer treatment, while low response rates and systemic toxicity limit its clinical outcomes. With the rapid advances in nanotechnology and materials science, various types of biomaterials have been developed to maximize therapeutic efficacy while minimizing side effects by increasing tumor antigenicity, reversing immunosuppressive microenvironment, amplifying antitumor immune response, and reducing extratumoral distribution of checkpoint inhibitors as well as enhancing their retention within target sites. In this review, we reviewed current design strategies for different types of biomaterials to augment ICB therapy effectively and then discussed present representative biomaterial-assisted immune modulation and targeted delivery of checkpoint inhibitors to boost ICB therapy. Current challenges and future development prospects for expanding the ICB with biomaterials were also summarized. We anticipate this review will be helpful for developing emerging biomaterials for ICB therapy and promoting the clinical application of ICB therapy.


Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Imunoterapia , Nanotecnologia , Radioimunoterapia , Microambiente Tumoral
14.
Expert Rev Anticancer Ther ; 23(2): 135-145, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36803369

RESUMO

INTRODUCTION: Oncological treatments are changing rapidly due to the advent of several targeted anticancer drugs and regimens. The primary new area of research in oncological medicine is the implementation of a combination of novel therapies and standard care. In this scenario, radioimmunotherapy is one of the most promising fields, as proven by the exponential growth of publications in this context during the last decade. AREAS COVERED: This review provides an overview of the synergistic use of radiotherapy and immunotherapy and addresses questions like the importance of this subject, aspects clinicians look for in patients to administer this combined therapy, individuals who would benefit the most from this treatment, how to achieve abscopal effect and when does radio-immunotherapy become standard clinical practice. EXPERT OPINION: Answers to these queries generate further issues that need to be addressed and solved. The abscopal and bystander effects are not utopia, rather physiological phenomena that occur in our bodies. Nevertheless, substantial evidence regarding the combination of radioimmunotherapy is lacking. In conclusion, joining forces and finding answers to all these open questions is of paramount importance.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Neoplasias/radioterapia , Imunoterapia , Radioimunoterapia , Terapia Combinada
15.
Front Immunol ; 14: 1128774, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36798129

RESUMO

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate, and is a major burden on human health worldwide. Gut microbiota regulate human immunity and metabolism through producing numerous metabolites, which act as signaling molecules and substrates for metabolic reactions in various biological processes. The importance of host-gut microbiota interactions in immunometabolic mechanisms in CRC is increasingly recognized, and interest in modulating the microbiota to improve patient's response to therapy has been raising. However, the specific mechanisms by which gut microbiota interact with immunotherapy and radiotherapy remain incongruent. Here we review recent advances and discuss the feasibility of gut microbiota as a regulatory target to enhance the immunogenicity of CRC, improve the radiosensitivity of colorectal tumor cells and ameliorate complications such as radiotoxicity. Currently, great breakthroughs in the treatment of non-small cell lung cancer and others have been achieved by radioimmunotherapy, but radioimmunotherapy alone has not been effective in CRC patients. By summarizing the recent preclinical and clinical evidence and considering regulatory roles played by microflora in the gut, such as anti-tumor immunity, we discuss the potential of targeting gut microbiota to enhance the efficacy of radioimmunotherapy in CRC and expect this review can provide references and fresh ideas for the clinical application of this novel strategy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Colorretais , Microbioma Gastrointestinal , Neoplasias Pulmonares , Humanos , Microbioma Gastrointestinal/fisiologia , Radioimunoterapia/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/complicações , Neoplasias Pulmonares/complicações , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/metabolismo
16.
Adv Sci (Weinh) ; 10(11): e2206979, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36793141

RESUMO

Radioimmunotherapy (RIT) is an advanced physical therapy used to kill primary cancer cells and inhibit the growth of distant metastatic cancer cells. However, challenges remain because RIT generally has low efficacy and serious side effects, and its effects are difficult to monitor in vivo. This work reports that Au/Ag nanorods (NRs) enhance the effectiveness of RIT against cancer while allowing the therapeutic response to be monitored using activatable photoacoustic (PA) imaging in the second near-infrared region (NIR-II, 1000-1700 nm). The Au/Ag NRs can be etched using high-energy X-ray to release silver ions (Ag+ ), which promotes dendritic cell (DC) maturation, enhances T-cell activation and infiltration, and effectively inhibits primary and distant metastatic tumor growth. The survival time of metastatic tumor-bearing mice treated with Au/Ag NR-enhanced RIT is 39 days compared with 23 days in the PBS control group. Furthermore, the surface plasmon absorption intensity at 1040 nm increases fourfold after Ag+ are released from the Au/Ag NRs, allowing X-ray activatable NIR-II PA imaging to monitor the RIT response with a high signal-to-background ratio of 24.4. Au/Ag NR-based RIT has minimal side effects and shows great promise for precise cancer RIT.


Assuntos
Nanotubos , Neoplasias , Técnicas Fotoacústicas , Animais , Camundongos , Raios X , Radioimunoterapia
17.
Expert Rev Anti Infect Ther ; 21(4): 365-374, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36815406

RESUMO

INTRODUCTION: Corona Virus Disease of 2019 (COVID-19) pandemic has renewed interest in monoclonal antibodies for treating infectious diseases. During last two decades experimental data has been accumulated showing the potential of radioimmunotherapy (RIT) of infectious diseases. In addition, COVID-19 pandemic has created a novel landscape for opportunistic fungal infections in post-COVID-19 patients resulting from severe immune suppression. AREAS COVERED: We analyze recent results on targeting "pan-antigens" shared by fungal pathogens in mouse models and in healthy dogs; on developing RIT of prosthetic joint infections (PJI); examine RIT as potential human immunodeficiency virus (HIV) cure strategy and analyze its mechanisms and safety. Literature review was performed using PubMed and Google Scholar and includes relevant articles from 2000 to 2022. EXPERT OPINION: Some of the RIT of infection applications can, hopefully, be moved into the clinic earlier than others after preclinical development: (1) RIT of opportunistic fungal infections might contribute to saving lives as current antifungal drugs do not work in severely immunocompromised patients; (2) RIT of patients with PJI. Success of RIT in these patients will allow to expand the application of RIT to other similarly vulnerable patients' populations such as cancer patients with weakened immune system and organ transplant recipients.


Assuntos
COVID-19 , Doenças Transmissíveis , Micoses , Camundongos , Humanos , Animais , Cães , Radioimunoterapia/métodos , Pandemias , Doenças Transmissíveis/terapia
18.
Eur J Nucl Med Mol Imaging ; 50(6): 1671-1688, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36622406

RESUMO

Immune checkpoint inhibitors (ICIs) achieve a milestone in cancer treatment. Despite the great success of ICI, ICI therapy still faces a big challenge due to heterogeneity of tumor, and therapeutic response is complicated by possible immune-related adverse events (irAEs). Therefore, it is critical to assess the systemic immune response elicited by ICI therapy to guide subsequent treatment regimens. Positron emission tomography (PET) molecular imaging is an optimal approach in cancer diagnosis, treatment effect evaluation, follow-up, and prognosis prediction. PET imaging can monitor metabolic changes of immunocytes and specifically identify immuno-biomarkers to reflect systemic immune responses. Here, we briefly review the application of PET molecular imaging to date of systemic immune responses following ICI therapy and the associated rationale.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Radioimunoterapia , Imagem Molecular
19.
J Immunother Cancer ; 11(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36631161

RESUMO

BACKGROUND: Radioimmunotherapy combines irradiation of tumor lesions with immunotherapy to achieve local and abscopal control of cancer. Most immunotherapy agents are given systemically, but strategies for delivering immunotherapy locally are under clinical scrutiny to maximize efficacy and avoid toxicity. Local immunotherapy, by injecting various pathogen-associated molecular patterns, has shown efficacy both preclinically and clinically. BO-112 is a viral mimetic based on nanoplexed double-stranded RNA (poly I:C) which exerts immune-mediated antitumor effects in mice and humans on intratumoral delivery. BO-112 and focal irradiation were used to make the proof-of-concept for local immunotherapy plus radiation therapy combinations. METHODS: Murine transplantable tumor cell lines (TS/A, MC38 and B16-OVA) were used to show increased immunogenic features under irradiation, as well as in bilateral tumor models in which only one of the lesions was irradiated or/and injected with BO-112. Flow cytometry and multiplex tissue immunofluorescence were used to determine the effects on antitumor immunity. Depletions of immune cell populations and knockout mice for the IFNAR and BATF-3 genes were used to delineate the immune system requirements for efficacy. RESULTS: In cultures of TS/A breast cancer cells, the combination of irradiation and BO-112 showed more prominent features of immunogenic tumor cell death in terms of calreticulin exposure. Injection of BO-112 into the tumor lesion receiving radiation achieved excellent control of the treated tumor and modest delays in contralateral tumor progression. Local effects were associated with more prominent infiltrates of antitumor cytotoxic tumor lymphocytes (CTLs). Importantly, local irradiation plus BO-112 in one of the tumor lesions that enhanced the therapeutic effects of radiotherapy on distant irradiated lesions that were not injected with BO-112. Hence, this beneficial effect of local irradiation plus BO-112 on a tumor lesion enhanced the therapeutic response to radiotherapy on distant non-injected lesions. CONCLUSION: This study demonstrates that local BO-112 immunotherapy and focal irradiation may act in synergy to achieve local tumor control. Irradiation plus BO-112 in one of the tumor lesions enhanced the therapeutic effects on distant irradiated lesions that were not injected with BO-112, suggesting strategies to treat oligometastatic patients with lesions susceptible to radiotherapy and with at least one tumor accessible for repeated BO-112 intratumoral injections.


Assuntos
Linfócitos T CD8-Positivos , Poli I-C , Radioimunoterapia , Animais , Camundongos , Adjuvantes Imunológicos/metabolismo , Imunoterapia , Poli I-C/metabolismo
20.
Semin Nucl Med ; 53(3): 413-425, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36635112

RESUMO

Systemic radioimmunotherapy (RIT) is arguably the most effective and least toxic anticancer treatment for non-Hodgkin lymphoma (NHL). In treatment-naïve patients with indolent NHL, the efficacy of a single injection of RIT compares with that of multiple cycles of combination chemotherapy. However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates 90Y-Ibritumomab-tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Notwithstanding this, the development of RIT has continued. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments.


Assuntos
Linfoma de Células B , Linfoma não Hodgkin , Radioimunoterapia , Humanos , Linfoma de Células B/radioterapia , Linfoma de Células B/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Linfoma não Hodgkin/tratamento farmacológico , Radioisótopos de Ítrio/uso terapêutico
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