Search

Diffusing alpha-emitting radiation therapy (DaRT) employs intratumoral Ra-224-coated seeds that efficiently destroy solid tumors by slowly releasing alpha-emitting atoms inside the tumor. In immunogenic tumor models, DaRT was shown to activate systemic antitumor immunity. Agonists of the membrane-bound toll-like receptors (TLRs) enhanced these effects and led to tumor rejection. Here, we examined the combination of DaRT with agents that activate a different type of pattern recognition receptors, the cytoplasmatic RIG1-like receptors (RLRs). In response to cytoplasmatic viral dsRNA, RLRs activate an antiviral immune response that includes the elevation of antigen presentation. Thus, it was postulated that in low-immunogenic tumor models, RLR activation in tumor cells prior to the induction of their death by DaRT will be superior compared to TLR activation. Intratumoral cytoplasmatic delivery of the dsRNA mimic polyIC by polyethylenimine (PEI), was used to activate RLR, while polyIC without PEI was used to activate TLR. PolyIC(PEI) prior to DaRT synergistically retarded 4T1 triple-negative breast tumors and metastasis development more efficiently than polyIC and rejected panc02 pancreatic tumors in some of the treated mice. Splenocytes from treated mice, adoptively transferred to naive mice in combination with 4T1 tumor cells, delayed tumor development compared to naïve splenocytes. Low-dose cyclophosphamide, known to reduce T regulatory cell number, enhanced the effect of DaRT and polyIC(PEI) and led to high long-term survival rates under neoadjuvant settings, which confirmed metastasis clearance. The epigenetic drug decitabine, known to activate RLR in low doses, was given intraperitoneally prior to DaRT and caused tumor growth retardation, similar to local polyIC(PEI). The systemic and/or local administration of RLR activators was also tested in the squamous cell carcinoma (SCC) tumor model SQ2, in which a delay in tumor re-challenge development was demonstrated. We conclude that RIG-I-like activation prior to intratumoral alpha radiation may serve as a potent combination technique to reduce both tumor growth and the spread of distant metastases in low-immunogenic and metastatic tumor models. [ABSTRACT FROM AUTHOR]

Diffusing alpha-emitters radiation therapy (DaRT) is the only known method for treating solid tumors with highly destructive alpha radiation. More importantly, as a monotherapy, DaRT has been shown to induce a systemic antitumor immune response following tumor ablation. Here, immunomodulatory strategies to boost the antitumor immune response induced by DaRT, and the response specificity, were investigated in the colon cancer CT26 mouse model. Local treatment prior to DaRT, with the TLR3 agonist poly I:C, was sufficient to inhibit tumor growth relative to poly I:C or DaRT alone. DaRT used in combination with the TLR9 agonist CpG, or with the TLR1/2 agonist XS15 retarded tumor growth and increased tumor-rejection rates, compared to DaRT alone, curing 41% and 20% of the mice, respectively. DaRT in combination with CpG, the Treg inhibitor cyclophosphamide, and the MDSC inhibitor sildenafil, cured 51% of the animals, compared to only 6% and 0% cure when immunomodulation or DaRT was used alone, respectively. Challenge and Winn assays revealed that these high cure rates involved a specific immunological memory against CT26 antigens. We suggest that DaRT acts in synergy with immunomodulation to induce a specific and systemic antitumor immune response. This strategy may serve as a safe and efficient method not only for tumor ablation, but also for in situ vaccination of cancer patients. [ABSTRACT FROM AUTHOR]

Many biomedical applications require concentration measurements of biological compounds, which may be achieved using targeted fluorescent probes. It has been shown that the ratio between amyloid-Beta and tau protein in the cerebrospinal fluid (CSF) is a good indicator of incipient Alzheimer’s disease (AD). We have previously proposed a method that can accurately estimate the concentration ratio of these two proteins without the need to collect CSF samples: Fluorescent probes are injected to the blood and bind to the CSF biomarkers. A miniature needle with an optical fiber excites the fluorescent probes and collects the fluorescence emission. The concentration ratio between the proteins is estimated, and used for diagnosis of incipient AD. We present here the results of the method’s concentration ratio estimation during trials performed on mice. Miniature tubes containing two fluorescent probes in several concentration ratios were implanted in two locations in the mice: subcutaneously, and deeper in the abdomen. The fluorescent probes were excited and the fluorescence intensity was measured. The concentration ratios were estimated from the fluorescence intensities with an average error of less than 20%. This study is a step towards the demonstration of the method in in vivo studies in mice with markers in the bloodstream/CSF. [ABSTRACT FROM AUTHOR]

It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG. Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with a MDSC inhibitor (sildenafil), Treg inhibitor (cyclophosphamide at low dose), and the immunostimulant, CpG. Combination of all four therapies led to a complete rejection of primary tumors (in 3 out of 20 tumor-bearing mice) and to the elimination of lung metastases. The treatment with DaRT and Treg or MDSC inhibitors (without CpG) also resulted in a significant reduction in tumor size, reduced the lung metastatic burden, and extended survival compared to the corresponding controls. We suggest that the therapy with DaRT combined with the inhibition of immunosuppressive cells and CpG reinforced both local and systemic anti-tumor immune responses and displayed a significant anti-tumor effect in tumor-bearing mice. [ABSTRACT FROM AUTHOR]

Introduction: The current systemic anti-metastatic treatment is chemotherapy. Chemotherapy reacts mostly against replicating cells, which makes this therapy not specific. Moreover, resting cancer cells will not be destroyed. A better alternative is an engagement of the host immune system to react against tumor-associated antigens. An efficient immune-stimulating technique is an ablation of the tumor that results in the release of tumor antigens. Our ablation strategy is an innovative alpha-radiation-based technology, diffusing alpha-emitters radiation therapy (DaRT), which efficiently destroys local tumors and provides thereby an antigenic supply for antigen-presenting cells to stimulate T cells. Methods: Mice bearing weakly immunogenic DA3 adenocarcinoma or highly immunogenic CT26 colon carcinoma were treated by DaRT. Anti-tumor immune responses following tumor destruction were evaluated by (1) the resistance to a tumor challenge; (2) scanning by a CT imaging device for elimination of lung metastases; (3) improved tumor control when combining DaRT with an immunoadjuvant (CpG). Results: CT26 model: 63-77 % of DaRT-treated mice became resistant to a re-inoculated tumor compared to 29-33 % resistant mice in the control. DA3 model: (1) The growth rate of challenge tumors was the lowest in mice which their primary tumor was treated by DaRT. (2) Most (93 %) mice in the control group developed lung metastases compared to 56 % in the DaRT group. (3) Combining DaRT with CpG resulted in a better control of the primary tumor. Our study offers a technique to eliminate local and distant malignant cells, regardless of their replication status, by stimulating specific anti-tumor immunity through the supply of tumor antigens from the destroyed tumor. [ABSTRACT FROM AUTHOR]

Purpose: We developed 224Ra-loaded wires, which release by recoil alpha emitting nuclei into solid tumors and cause tumor cell killing. This research examined if the major damage was inflicted by alpha particles emitted from these atoms or by direct gamma and beta emissions from the inserted wires. We also examined the efficacy of this treatment against colon cancer in combination with chemotherapy. Materials and methods: Mouse colon carcinomas (CT-26 xenografts), treated by intra-tumoral radioactive wires loaded with 224Ra atoms were monitored for effects on tumor growth, intratumoral tissue damage and distribution of alpha emitting atoms. The effects were compared with those of 224Ra-loaded wires coated with poly methyl methacrylate (PMMA), which blocks atom recoil. Similar experiments were performed with radioactive wires combined with systemic 5-FU. Results: 224Ra-loaded wires inhibited tumor growth and formed necrotic areas inside the tumor. PMMA coated wires did not inhibit tumor growth, and caused minor intratumoral damage. Autoradiography images of tumors treated with 224Ra-loaded wires revealed a spread of alpha emitters over several mm, whereas PMMA-coated wires showed no such spread. Injection of 5-FU with 224Ra-loaded wires augmented tumor growth retardation and cure. Conclusions: 224Ra-loaded wires ablate solid tumors by the release of alpha-particle emitting atoms inside the tissue, an effect that can be enhanced by combining this method with chemotherapy. [ABSTRACT FROM AUTHOR]

The article presents a study which probes the effect of radiation therapy and cisplatin on the growth of tumor. Methods used in the study were the treatment of BALB/c mice with squamous cell carcinoma tumors with radium 224. Results show the substantial improvement of the overall endurance and antitumor activity of tumor-bearing mice through combination of treatment.