Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 29, 2022

Abstract Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which called abscopal effect. The view RT as a simple treatment has dramatically changed in recent years, it now widely accepted that provoke immune response gives strong rationale the combination immunotherapy (iRT). Nevertheless, several points remain to be addressed such interaction system, identification best schedules with (IO), expansion mechanism amplify iRT. To answer these crucial questions, we roundly summarize underlying showing whole landscape clinical trials attempt identify In consideration rarity effect, propose occurrence induced by radiation promoted 100% molecular genetic level. Furthermore, “radscopal effect” refers using low-dose reprogram microenvironment may overcome resistance Taken together, could regarded trigger antitumor response, help IO used radical added into current standard regimen patients metastatic cancer.

Language: Английский

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Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Journal for ImmunoTherapy of Cancer, Journal Year: 2021, Volume and Issue: 9(4), P. e002038 - e002038

Published: April 1, 2021

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in delivery techniques allow hypofractionated of conformal radiotherapy. Hypofractionation or other modifications standard fractionation may improve radiation's ability promote Other novel options also affect responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding the immunological impact unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, differences result distinct immune-modulatory effects. Radiation oncologists immunologists convened a virtual consensus discussion identify current deficiencies, challenges, pitfalls critical gaps when combining with immunotherapy making recommendations field advise National Cancer Institute on new directions initiatives will help further development two fields.This commentary aims raise awareness this complexity so need study dose, fractionation, type volume understood valued by immuno-oncology research community. Divergence approaches findings between preclinical studies clinical trials highlights for evaluating design future particular emphasis dose biomarkers selecting appropriate end points combination radiation/immune modulator trials, recognizing direct effect tumor potential abscopal well be different. Similarly, should designed much possible model intended setting. This article describes conceptual framework testing different therapy regimens separate models how itself functions an immunomodulatory 'drug' provide alternatives widely adopted 'one-size-fits-all' strategy frequently used 8 Gy×3 immunomodulation.

Language: Английский

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Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: March 21, 2022

Abstract Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) immune checkpoint CD47 is dominant in recurrent GBM patients poor prognosis. A glycolysis-to-FAO metabolic rewiring associated anti-phagocytosis radioresistant cells regrown radiation syngeneic mice. Inhibition FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A −/− , ACAD9 demonstrate FAO-derived acetyl-CoA upregulates transcription via NF-κB/RelA acetylation. Blocking impairs tumor growth reduces anti-phagocytosis. Etomoxir combined anti-CD47 antibody synergizes control tumors boosted macrophage phagocytosis. These results enhanced fat metabolism promotes aggressive CD47-mediated evasion. The FAO-CD47 axis may be targeted improve eliminating phagocytosis-proofing radioimmunotherapy.

Language: Английский

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Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Feb. 8, 2023

RIG-I-like receptors (RLRs) are intracellular pattern recognition that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated 5 (MDA5) laboratory of genetics physiology 2 (LGP2) have distinctive features. These not only recognize RNA intermediates from viruses bacteria, but also interact with endogenous such as the mislocalized mitochondrial RNA, aberrantly reactivated repetitive transposable elements in human genome. Evasion RLRs-mediated response may lead to sustained infection, defective immunity carcinogenesis. Therapeutic targeting provoke anti-infection effects, anticancer sensitize "immune-cold" tumors checkpoint blockade. In this review, we summarize current knowledge signaling discuss rationale for therapeutic cancer. We describe how can be activated by synthetic oncolytic viruses, mimicry radio-chemotherapy, agonists systemically delivered vivo. integration agonism interference CAR-T cells provides new dimensions complement cancer immunotherapy. Moreover, update progress recent clinical trials therapy involving activation modulation. Further studies mechanisms underlying will shed light on development therapeutics. Manipulation represents an opportunity clinically relevant therapy. Addressing challenges field help develop future generations

Language: Английский

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Identification of hub genes and potential molecular mechanisms related to radiotherapy sensitivity in rectal cancer based on multiple datasets

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: March 6, 2023

Abstract Background Radiotherapy resistance is the main cause of low tumor regression for locally advanced rectum adenocarcinoma (READ). The biomarkers correlated to radiotherapy sensitivity and potential molecular mechanisms have not been completely elucidated. Methods A mRNA expression profile a gene dataset READ (GSE35452) were acquired from Cancer Genome Atlas (TCGA) Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) between responder non-responder screened out. ontology (GO) analysis Kyoto Encyclopedia Genes Genomes (KEGG) pathway DEGs performed. Random survival forest was used identified hub by randomForestSRC package. Based on CIBERSORT algorithm, Genomics Drug Sensitivity in (GDSC) database, set variation (GSVA), enrichment (GSEA), nomogram, motif non-coding RNA network analyses, associations immune cell infiltration, drug sensitivity, specific signaling pathways, prognosis prediction TF – miRNA regulatory ceRNA investigated. expressions clinical samples displayed with online Human Protein (HPA). Results In total, 544 up-regulated 575 down-regulated enrolled. Among that, three hubs including PLAGL2 , ZNF337 ALG10 identified. These significantly associated different immune-related chemotherapeutic drugs. Also, they various disease-related genes. addition, GSVA GSEA revealed that levels affected pathways related disease progression. nomogram calibration curves based showed excellent predictive performance. And then, transcription factor ( ZBTB6 ) - (has-miR-133b) lncRNA established. Finally, results HPA database demonstrated protein PLAGL2, varied widely patients. Conclusion findings indicated up-regulation response involved multiple process cellular biology tumor. They might be READ.

Language: Английский

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Mitochondrial CPT1A: Insights into structure, function, and basis for drug development

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: March 23, 2023

Carnitine Palmitoyl-Transferase1A (CPT1A) is the rate-limiting enzyme in fatty acid β-oxidation, and its deficiency or abnormal regulation can result diseases like metabolic disorders various cancers. Therefore, CPT1A a desirable drug target for clinical therapy. The deep comprehension of human crucial developing therapeutic inhibitors Etomoxir. an appealing druggable cancer therapies since it essential survival, proliferation, resistance cells. It will help to lower risk recurrence metastasis, reduce mortality, offer prospective therapy options treatment if effects on lipid metabolism cells are inhibited. Targeted inhibition be developed as effective strategy cancers from perspective. However, pathogenic mechanism recent progress have not been systematically summarized. Here we discuss functions health diseases, targeting CPT1A. This review summarizes current knowledge CPT1A, hoping prompt further understanding it, provide foundation CPT1A-targeting development.

Language: Английский

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Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors

JAMA Oncology, Journal Year: 2023, Volume and Issue: 9(9), P. 1205 - 1205

Published: July 6, 2023

Importance Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand have improved the outcome for many cancer types, majority of patients fails to respond ICI monotherapy. Hypofractionated radiotherapy has potential improve therapeutic ratio ICIs. Objective To assess addition ICIs compared with monotherapy in advanced solid tumors. Design, Setting, Participants This open-label, multicenter, randomized phase 2 trial was conducted 5 Belgian hospitals enrolled participants between March 2018 October 2020. Patients 18 years or older locally metastatic melanoma, renal carcinoma, urothelial head neck squamous non–small lung carcinoma were eligible. A total 99 randomly assigned either control arm (n = 52) experimental 47). Of those, 3 (1 vs arm) withdrew consent thus not included analysis. Data analyses performed April 2022 2023. Interventions (1:1) receive anti–PD-1/PD-1 alone as per standard care (control combined stereotactic body × 8 gray a maximum lesions prior second third cycle, depending on frequency administration (experimental arm). Randomization stratified according tumor histologic findings disease burden (3 fewer more than lesions). Main Outcomes Measures The primary end point progression-free survival (PFS) Response Evaluation Criteria Solid Tumors. Key secondary points overall (OS), objective response rate, local toxic effects. Efficacy assessed intention-to-treat population, while safety evaluated as-treated population. Results Among 96 analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had 65 (68%) received at least previous line systemic treatment time inclusion. Seven allocated did complete study-prescribed course due early progression 5) intercurrent illness 2). With median (range) follow-up 12.5 (0.7-46.2) months, PFS 2.8 months 4.4 (hazard ratio, 0.95; 95% CI, 0.58-1.53; P .82). Between arms, no improvement OS observed (11.0 14.3 months; hazard 0.82; 0.48-1.41; .47), rate statistically significantly different (22% 27%; .56), despite 75% irradiated patients. Acute treatment-related effects any grade higher occurred 79% 18% 78% arm, respectively. No adverse events occurred. Conclusions Relevance clinical demonstrated that safe, adding subablative limited number failed show OS. Trial Registration ClinicalTrials.gov Identifier: NCT03511391

Language: Английский

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Recent advances in the metal/organic hybrid nanomaterials for cancer theranostics

Coordination Chemistry Reviews, Journal Year: 2024, Volume and Issue: 504, P. 215654 - 215654

Published: Jan. 20, 2024

Language: Английский

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Synthesis and Bioapplication of Emerging Nanomaterials of Hafnium

ACS Nano, Journal Year: 2024, Volume and Issue: 18(2), P. 1289 - 1324

Published: Jan. 2, 2024

A significant amount of progress in nanotechnology has been made due to the development engineered nanoparticles. The use metallic nanoparticles for various biomedical applications extensively investigated. Biomedical research is highly focused on them because their inert nature, nanoscale structure, and similar size many biological molecules. intrinsic characteristics these particles, including electronic, optical, physicochemical, surface plasmon resonance, that can be altered by altering size, shape, environment, aspect ratio, ease synthesis, functionalization properties, have led numerous applications. Targeted drug delivery, sensing, photothermal photodynamic therapy, imaging are some these. promising clinical results NBTXR3, a high-Z radiosensitizing nanomaterial derived from hafnium, demonstrated translational potential this metal. This radiosensitization approach leverages dependence energy attenuation atomic number enhance energy-matter interactions conducive radiation therapy. High-Z nanoparticle localization tumor issue differentially increases effect ionizing cancer cells versus nearby healthy ones mitigates adverse effects reducing overall burden. principle enables material multifunctionality as contrast agents X-ray-based imaging. physiochemical properties hafnium (Z = 72) particularly advantageous well-placed K-edge absorption high mass coefficient compared elements human tissue across ranges leads attenuation. Chemical reactivity allows variety composition, functionalization. Nanoparticles such oxide exhibit excellent biocompatibility inertness prior incidence with radiation. Additionally, optical electronic applicable biosensing, component coatings, semiconductors. wide interest prompted extensive design synthesis facilitate property fine-tuning. review summarizes synthetic methods hafnium-based nanomaterials imaging, biosensing mechanistic focus. discussion future perspective section highlights elaborates current challenges. By focusing factors impacting applicational effectiveness examining limitations aims support researchers expedite translation nanomedicine.

Language: Английский

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Radiotherapy and the immune system: More than just immune suppression

Stem Cells, Journal Year: 2021, Volume and Issue: 39(9), P. 1155 - 1165

Published: May 18, 2021

Abstract Radiotherapy (RT) is still one of the standard cancer therapies, with up to two third all patients solid tumors being irradiated in course their disease. The aim using ionizing radiation fractionated treatment schedules was always achieve local tumor control by inducing DNA damage which can be repaired surrounding normal tissue but leads cell death cells. Meanwhile, it known that RT also has immunological effects reshaping microenvironment. Nevertheless, alone often fails elicit potent antitumor immune responses as these immunostimulatory well immunosuppressive. Here, we discuss how immunotherapies exploited combined therapies boost RT-induced or counteract preexisting and RT-mediated immunosuppression improve systemic control. Furthermore, highlight some parameters radioimmunotherapies (RITs) are under investigation for potential optimizations RIT approaches tested first phases II III trials. Finally, might affect stem

Language: Английский

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