Low-Dose Radiotherapy Leads to a Systemic Anti-Inflammatory Shift in the Pre-Clinical K/BxN Serum Transfer Model and Reduces Osteoarthritic Pain in Patients

Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease.

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.

Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy

High doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes. Graphical Abstract

Platelet Membranes Coated Gold Nanocages for Tumor Targeted Drug Delivery and Amplificated Low-Dose Radiotherapy

Continuous high doses of radiation can cause irreversible side effects and radiation resistance; thus, advanced radiosensitizers are urgently needed. To overcome this problem, we developed a nano platelet radiosensitization system (PCA) by coating the chemotherapeutic drug cisplatin (CDDP) loaded gold nanocages (AuNs) within the platelet membrane. The developed PCA system may enable AuNs to have immune escape and targeting capabilities. After administration, PCA will actively target tumor cells and avoid being cleared by the immune system. Subsequently, CDDP, which destroys tumor cell DNA, can not only kill tumor cells directly but also combine with AuNs, which deposit radiation energy into tumor tissues, reducing RT resistance. In vivo and in vitro studies revealed that the combination of PCA with RT (2Gy) efficiently inhibits tumor proliferation without causing side effects such as inflammation. To conclude, this is the first attempt to use platelet membranes to correctly transport AuNs while also accomplishing low-dose RT, which could help AuNs-based tumor RT become more effective.

Injectable Hydrogel for Synergetic Low Dose Radiotherapy, Chemodynamic Therapy and Photothermal Therapy

Higher doses of radiotherapy (RT) are associated with resistance induction, therefore highly selective and controllable radiosensitizers are urgently needed. To address this issue, we developed a FeGA-based injectable hydrogel system (FH) that can be used in combination with low-dose radiation. Our FH can deliver FeGA directly to the tumor site via intratumoral injection, where it is a reservoir-based system to conserve FeGA. The photothermal properties of FeGA steadily dissolve FH under laser irradiation, and, simultaneously, FeGA reacts with a large amount of H2O2 in the cell to produce OH (Fenton reaction) which is highly toxic to mitochondria, rendering the cell inactive and reducing radiotherapy resistance. In vivo and in vitro studies suggest that combining the FH and NIR irradiation with RT (2Gy) can significantly reduce tumor proliferation without side effects such as inflammation. To conclude, this is the first study to achieve combined chemodynamic therapy (CDT) and photothermal therapy (PTT) in situ treatment, and the best therapeutic effect can be obtained with a low-dose radiation combination, thus expanding the prospects of FeGA-based tumor therapy.

Metabolic Tumor Volume and Total Lesion Glycolysis Can Predict Response to Very Low Dose Radiotherapy (4 Gy) in Indolent B-Cell Lymphomas

Numerous studies have established the role of very low dose radiotherapy (VLDRT), only 4 Gy in 2 fractions, in the management of indolent non-Hodgkin's lymphoma (NHL). While objective response rates to VLDRT are excellent, there are no widely accepted biomarkers of the depth and the durability of response after VLDRT. Radiosensitivity to VLDRT is not clearly linked to clinical features, such as tumor grade, histology, prior treatments or [18F]-FDG-PET standardized uptake values (SUV). Our group has recently demonstrated that pre-treatment tumor size greater than 6 cm may predict suboptimal response to VLDRT; however, this remains an imperfect predictor, and the majority of patients selected for VLDRT have lesions smaller than 6 cm. [18F]-FDG-PET metrics like baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are shown to stratify patient response to chemotherapy for some NHLs, but neither has been shown to predict radiotherapy response to VLDRT. Therefore, we aimed to determine if these features could predict response to VLDRT in indolent B-cell NHLs. Between 2005 and 2018, 250 patients with follicular or marginal zone lymphoma were locally irradiated to 299 sites using 2 Gy x2. Response was assessed within 1.5-6 months of VLDRT (n=231), and local failure (LF) was assessed over a median follow-up of 29 months. Out of the 299 treated sites, 254 (85%) had a corresponding [18F]-FDG-PET/CT scan performed prior to radiotherapy. PET scans were imported into MIM, a radiotherapy contouring and planning software program, and pre-radiotherapy disease was manually defined. A uniform expansion of 0.5 cm was performed to define a larger region of interest containing the contoured lesion but accounting for technical variability in defining the tumor edges. Of the 254 lesions, 207 (81%) had a maximum SUV (SUVmax) greater than 2.5 and were considered for further analysis. PET parameters were obtained using an SUV of 2.5 as a cutoff for MTV (MTV2.5) and TLG (TLG2.5), which capture lesion bulk, and using 41% of the SUVmax as a cutoff for MTV (MTV41%) and TLG (TLG41%), which capture the most metabolically active parts of a lesion. Maximum lesion size was analyzed using 4 cm and 6 cm as predetermined cutoffs. Lesion response was analyzed using multivariate logistic LASSO regression to account for predictor multicollinearity, and receiver operating characteristic curve analysis to obtain estimates of the area under the curve (AUC). To analyze time to LF, we performed Cox proportional hazards multivariate regression using stepwise selection. PET parameters were divided in quartiles to aid in interpretability. Estimates are shown with 95% confidence intervals. A complete response (CR) was seen in 156 (68%) lesions and LF was seen in 81 (27%) lesions after VLDRT. Using size alone had similar predictive value for response (AUC: 0.57(0.49-0.65) compared to MTV2.5 (AUC:0.66 (0.57-0.74)), MTV41% (AUC:0.64 (0.56-0.73)), TLG2.5 (AUC:0.64 (0.54-0.74)), and TLG41% (AUC:0.64 (0.54,0.75)). Through LASSO logistic regression, we determined that only MTV41% > 75 th percentile was associated with lower odds of CR (odds ratio (OR):0.21 (0.08-0.53)) versus size ≥4 (OR: 0.94 (0.32, 2.73) ) with no interaction noted. Likewise, in a multivariate model of LF, TLG2.5> 75 th percentile was shown to be a better predictor of worse LF (HR: 2.44 (1.32, 4.52)) than size when considering lesions < 6 cm. In stratifying response and local control for patients receiving VLDRT for indolent lymphomas, MTV and TLG may aid in patient selection, especially for lesions smaller than 6 cm. As PET-based radiotherapy planning is routinely performed in the treatment of indolent lymphomas, these parameters are easily attained after contouring and may have immediate clinical utility. These findings may also be applicable to radiotherapy response with higher doses, and the incorporation of [18F]-FDG-PET metrics into treatment decisions is an area of active research. It remains to be seen in ongoing work whether higher-order PET radiomic features (which for instance capture heterogeneity of tumor glucose metabolism) can further improve the accuracy of [18F]-FDG-PET-based radiotherapy outcome prediction. Disclosures Mayerhoefer: Siemens: Other: Speaker Honoraria; General Electric: Other: Speaker Honoraria; Bristol Myers Squibb: Other: Speaker Honoraria.

ArthroRad trial: multicentric prospective and randomized single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis depending on the dose—results after 3 months’ follow-up

Purpose Randomized comparison of the effect of radiotherapy on painful osteoarthritis (OA) applying a standard-dose vs. a very-low-dose regime Patients and methods Patients with OA of the hand and knee joints were included. Further inclusion criteria: symptoms for more than 3 months, favorable general health status, age above 40 years. Patients with prior local radiotherapy, trauma, rheumatoid arthritis, or vascular diseases were excluded. After randomization (every joint was randomized separately), the following protocols were applied: standard arm: total dose 3.0 Gy, single fractions of 0.5 Gy twice weekly; experimental arm: total dose 0.3 Gy, single fractions of 0.05 Gy twice weekly. The dosage was not known to the patients. The patients were examined 3 and 12 months after radiotherapy. Scores like VAS (visual analogue scale), KOOS-SF (the knee injugy and osteoarthritis outcome score), SF-SACRAH (short form score for the assessment and quantification of chronic rheumatic affections of the hands), and SF-12 (short form 12) were used. Results A total of 64 knees and 172 hands were randomized. 3.0 Gy was applied to 87 hands and 34 knees, 0.3 Gy was given to 85 hands and 30 knees. After 3 months, we observed good pain relief after 3 Gy and after 0.3 Gy, there was no statistically significant difference. Side effects were not recorded. The trial was closed prematurely due to slow recruitment. Conclusion We found favorable pain relief and a limited response in the functional and quality of life scores in both arms. The effect of low doses such as 0.3 Gy on pain is widely unknown. Further trials are necessary to compare a conventional dose to placebo and to further explore the effect of low doses on inflammatory disorders.