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Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source. We examined the IFN1 response and expression of immune susceptibility markers in B78 and B16 melanomas and MOC2 head and neck cancer murine models using qPCR and western blot. For TRT, we used Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2. We observed significant IFN1 activation in all cell lines, with peak activation in B78, B16, and MOC2 cell lines occurring 7, 7, and 1 days, respectively, following RT for all doses. This effect was STING-dependent. Select IFN response genes remained upregulated at 14 days following RT. IFN1 activation following STING agonist treatment was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. delivery of EBRT and TRT to B78 and MOC2 tumors resulted in a comparable time course and magnitude of IFN1 activation. In the MOC2 model, the combination of Y-NM600 and dual checkpoint blockade therapy reduced tumor growth and prolonged survival compared to single agent therapy and cumulative dose equivalent combination EBRT and dual checkpoint blockade therapy. We report the time course of the STING-dependent IFN1 response following radiation in multiple murine tumor models. We show the potential of TRT to stimulate IFN1 activation that is comparable to that observed with EBRT and this may be critical to the therapeutic integration of TRT with immunotherapies.

This work describes the development and validation of a patient-specific Monte Carlo internal dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry). RAPID utilizes serial PET/CT or SPECT/CT images to calculate voxelized three-dimensional (3D) internal dose distributions with the Monte Carlo code Geant4. RAPID's dosimetry calculations were benchmarked against previously published S-values and specific absorbed fractions (SAFs) calculated for monoenergetic photon and electron sources within the Zubal phantom and for S-values calculated for a variety of radionuclides within spherical tumor phantoms with sizes ranging from 1 to 1000 g. The majority of the S-values and SAFs calculated in the Zubal Phantom were within 5% of the previously published values with the exception of a few 10 keV photon SAFs that agreed within 10%, and one value within 16%. The S-values calculated in the spherical tumor phantoms agreed within 2% for 177Lu, 131I, 125I, 18F, and 64Cu, within 3.5% for 211At and 213Bi, within 6.5% for 153Sm, 111In, 89Zr, and 223Ra, and within 9% for 90Y, 68Ga, and 124I. In conclusion, RAPID is capable of calculating accurate internal dosimetry at the voxel-level for a wide variety of radionuclides and could be a useful tool for calculating patient-specific 3D dose distributions.

Radiation therapy can modulate the tumor microenvironment (TME), influencing antitumor immune responses. This study compared the immunomodulatory effects of alpha-emitting ( Ac) and beta-emitting ( Lu) radiopharmaceutical therapies (RPT) using NM600 in murine prostate cancer models. We assessed immunological changes in TRAMP-C1 and Myc-CaP tumor models treated with Ac-NM600 or Lu-NM600. Flow cytometry was used to profile immune cell populations, activation markers, and checkpoint molecules, while multiplex assays analyzed cytokine and chemokine expression. In general, Ac-NM600 elicited stronger immunomodulatory effects than Lu-NM600, including cell line dependent increased CD8/Treg ratios, activation of effector and memory T cells, and depletion of suppressive Tregs and MDSCs. The treatment elevated Th1 cytokines, pro-inflammatory chemokines, and checkpoint molecules like PD-1 on CD8+ T cells and PD-L1 on MDSCs, creating a more \"hot\" TME. Alpha-emitting Ac-NM600 demonstrated superior ability to enhance antitumor immunity compared to beta-emitting Lu-NM600. These findings support the use of Ac-NM600 in combination with immunotherapies for advanced prostate cancer treatment.

Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced cancer. The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed. The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT. The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.

Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose–response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT.

To evaluate the overall robustness of a novel cellular irradiator we performed a series of well-characterized, dose-responsive assays to assess the consequences of DNA damage. We used a previously described novel irradiation system and a traditional 137Cs source to irradiate a cell line. The generation of reactive oxygen species was assessed using chloromethyl-H2DCFDA dye, the induction of DNA DSBs was observed using the comet assay, and the initiation of DNA break repair was assessed through γH2AX image cytometry. A high correlation between physical absorbed dose and biologic dose was seen for the production of intracellular reactive oxygen species, physical DNA double strand breaks, and modulation of the cellular double stand break pathway. The results compared favorably to irradiation with a traditional 137Cs source. The rapid, straightforward tests described form a reasonable approach for biologic characterization of novel irradiators. These additional testing metrics go beyond standard physics testing such as Monte Carlo simulation and thermo-luminescent dosimeter evaluation to confirm that a novel irradiator can produce the desired dose effects in vitro. Further, assessment of these biological metrics confirms that the physical handling of the cells during the irradiation process results in biologic effects that scale appropriately with dose.

Purpose The rapid expansion of radiopharmaceutical therapy (RPT) development demands scalable preclinical dosimetry methods. While PET and SPECT remain the gold standards, their low throughput and high cost limit large-cohort studies. Cherenkov luminescence imaging (CLI) offers a high-throughput alternative but suffers from depth-dependent attenuation and photon scatter that compromise quantitative accuracy. This work develops and validates a quantitative CLI methodology incorporating attenuation and scatter corrections to enable accurate preclinical dosimetry. Methods Depth-dependent attenuation was characterized using a tissue-mimicking phantom to derive calibration coefficients. Photon scatter was modeled using GEANT4-generated Cherenkov spread functions (CSFs), applied in a depth-weighted iterative Richardson–Lucy deconvolution/reconvolution framework. The method was evaluated in NU/NU mice (n = 4) bearing MC38 tumors after injection of 86 Y-NM600, an isotope suitable for both PET and CLI. Liver and tumor activities were quantified at four timepoints using PET and the proposed CLI method. Voxelized Monte Carlo dosimetry was performed for both modalities. Results CLI–PET activity quantification yielded mean errors of 15.4% (liver) and 10.3% (tumor) over the first three timepoints. Tumor absorbed doses from CLI-derived synthetic PET images (3.4 ± 0.3 Gy/MBq) were statistically indistinguishable from PET-based estimates (3.2 ± 0.2 Gy/MBq, p  = 0.31). Discrepancies increased at late timepoints due to low activity and background auto-luminescence. Conclusions With appropriate depth-dependent optical attenuation calibration and Monte Carlo–derived ionizing scatter correction, CLI can provide quantitative biodistribution and dosimetry estimates comparable to PET. This approach enables high-throughput, low-cost in vivo dosimetry, expanding the feasibility of large-scale preclinical RPT studies and supporting translational radiopharmaceutical development.

BackgroundSystemic radiation treatments that preferentially irradiate cancer cells over normal tissue, known as targeted radionuclide therapy (TRT), have shown significant potential for treating metastatic prostate cancer. Preclinical studies have demonstrated the ability of external beam radiation therapy (EBRT) to sensitize tumors to T cell checkpoint blockade. Combining TRT approaches with immunotherapy may be more feasible than combining with EBRT to treat widely metastatic disease, however the effects of TRT on the prostate tumor microenvironment alone and in combinfation with checkpoint blockade have not yet been studied.MethodsC57BL/6 mice-bearing TRAMP-C1 tumors and FVB/NJ mice-bearing Myc-CaP tumors were treated with a single intravenous administration of either low-dose or high-dose 90Y-NM600 TRT, and with or without anti-PD-1 therapy. Groups of mice were followed for tumor growth while others were used for tissue collection and immunophenotyping of the tumors via flow cytometry.Results90Y-NM600 TRT was safe at doses that elicited a moderate antitumor response. TRT had multiple effects on the tumor microenvironment including increasing CD8 +T cell infiltration, increasing checkpoint molecule expression on CD8 +T cells, and increasing PD-L1 expression on myeloid cells. However, PD-1 blockade with TRT treatment did not improve antitumor efficacy. Tregs remained functional up to 1 week following TRT, but CD8 +T cells were not, and the suppressive function of Tregs increased when anti-PD-1 was present in in vitro studies. The combination of anti-PD-1 and TRT was only effective in vivo when Tregs were depleted.ConclusionsOur data suggest that the combination of 90Y-NM600 TRT and PD-1 blockade therapy is ineffective in these prostate cancer models due to the activating effect of anti-PD-1 on Tregs. This finding underscores the importance of thorough understanding of the effects of TRT and immunotherapy combinations on the tumor immune microenvironment prior to clinical investigation.

Purpose We investigated the hypothesis that the transmission function of rounded end linearly traveling multileaf collimators (MLCs) is constant with position. This assumption is made by some MLC models used in clinical treatment planning systems (TPSs) and in the Varian MLC calibration convention. If not constant, this would have implications for treatment plan QA results. Methods A two‐dimensional ray‐tracing tool to generate transmission curves as a function of leaf position was created and validated. The curves for clinically available leaf tip positions (−20 to 20 cm) were analyzed to determine the location of the beam edge (half‐attenuation X‐ray [XR]) location, the beam edge broadening (BEB, 80%–20% width), as well as the leaf tip zone width. More generalized scenarios were then simulated to elucidate trends as a function of leaf tip radius. Results In the analysis of the Varian high‐definition MLC, two regions were identified: a quasi‐static inner region centered about central axis (CAX), and an outer one, in which large deviations were observed. A phenomenon was identified where the half‐attenuation ray position, relative to that of the tip or tangential ray, increases dramatically at definitive points from CAX. Similar behavior is seen for BEB. An analysis shows that as the leaf radius parameter value is made smaller, the size of the quasi‐static region is greater (and vice versa). Conclusion The MLC transmission curve properties determined by this study have implications both for MLC position calibrations and modeling within TPSs. Two‐dimensional ray tracing can be utilized to identify where simple behaviors hold, and where they deviate. These results can help clinical physicists engage with vendors to improve MLC models, subsequent fluence calculations, and hence dose calculation accuracy.

Intrafraction imaging‐based motion management systems for external beam radiotherapy can rely on internal surrogate structures when the target is not easily visualized. This work evaluated the validity of using liver vessels as internal surrogates for the estimation of liver tumor motion. Vessel and tumor motion were assessed using ten two‐dimensional sagittal MR cine datasets collected on the ViewRay MRIdian. For each case, a liver tumor and at least one vessel were tracked for 175 s. A tracking approach utilizing block matching and multiple simultaneous templates was applied. Accuracy of the tracked motion was calculated from the error between the tracked centroid position and manually defined ground truth annotations. The patient’s abdomen surface and diaphragm were manually annotated in all frames. The Pearson correlation coefficient (CC) was used to compare the motion of the features and tumor in the anterior–posterior (AP) and superior–inferior (SI) directions. The distance between the centroids of the features and the tumors was calculated to assess if feature proximity affects relative correlation, and the tumor range of motion was determined. Intra‐ and interfraction motion amplitude variabilities were evaluated to further assess the relationship between tumor and feature motion. The mean CC between the motion of the vessel and the tumor were 0.85 ± 0.11 (AP) and 0.92 ± 0.04 (SI), 0.83 ± 0.11 (AP) and −0.89 ± 0.06 (SI) for the surface and tumor, and 0.80 ± 0.17 (AP) and 0.94 ± 0.03 (SI) for the diaphragm and tumor. For intrafraction analysis, the average amplitude variability was 2.47 ± 0.77 mm (AP) and 3.14 ± 1.49 mm (SI) for the vessels, 2.70 ± 1.08 mm (AP) and 3.43 ± 1.73 mm (SI) for the surface, and 2.76 ± 1.41 mm (AP) and 2.91 ± 1.38 mm (SI) for the diaphragm. No relationship between distance and motion correlation was observed. The motion of liver tumors and liver vessels was well correlated, making vessels a suitable surrogate for tumor motion in the liver.