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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.

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.

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 A single treatment planning system (TPS) model for matched linacs provides flexible clinical workflows from patient treatment to intensity‐modulated radiation therapy (IMRT) quality assurance (QA) measurement. Since general guidelines for building a single TPS model and its validation for matched linacs are not well established, we present our RayStation photon TPS modeling strategy for matched Elekta VersaHD linacs. Method The four linacs installed from 2013 to 2020 were matched in terms of Percent Depth Dose (PDD), profile, output factor and wedge factors for 6‐MV, 10‐MV, 15‐MV, and 6‐MV‐FFF, and maintained following TG‐142 recommendations until RayStation commissioning. The RayStation single model was built to represent all four linacs within the tolerance limits recommended by MPPG‐5.a. The comprehensive validation tests were performed for one linac following MPPG‐5.a and TG‐119 guidelines, and spot checks for the other three. Our TPS modeling/validation method was evaluated by re‐analyzing the previous 103 patient‐specific IMRT/volumetric modulated arc therapy (VMAT) QA measurements with the calculated planar doses by the single model in comparison with the analysis results using four individual Pinnacle TPS models. Results For all energies, our single model PDDs were within 1% agreement of the four‐linac commissioning measurements. The MPPG‐5.a validation tests from 5.1 through 7.5 and all TG‐119 measurements passed within the recommended tolerance limits. The IMRT QA results (mean ± standard deviation) for RayStation single model versus Pinnacle individual models were 98.9% ± 1.3% and 98.0% ± 1.4% for 6‐MV, 99.9% ± 0.1% and 99.1% ± 1.9% for 10‐MV, and 98.2% ± 1.3% and 97.9% ± 1.8% for 6‐MV‐FFF, respectively. Conclusion We successfully built and validated a single photon beam model in RayStation for four Elekta Linacs. The proposed new validation methods were proven to be both efficient and effective.

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 .sup.86 Y-NM600 (for PET imaging and subject-specific dosimetry) and IV .sup.90 Y-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 .sup.86 Y-NM600 tumor:bone marrow absorbed-dose differential uptakes [greater than or equal to]2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy .sup.90 Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by .sup.90 Y-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.

Radiotherapy delivering immunomodulatory dose to localized disease has been shown to enhance tumor response to systemic and local immunotherapies. In metastatic disease, where conventional radiotherapy is limited, radiopharmaceutical therapy (RPT) with an alkylphosphocholine analog, 90Y-NM600, can deliver immunomodulatory dose to all sites of disease. In preclinical models, cooperative therapeutic effect between immunotherapy and 90Y-NM600 RPT delivering as little as 2 Gy to tumors has been observed. Work presented here describes the development and clinical translation of prospective theranostic dosimetry using pre-therapy imaging of 86Y-NM600 for delivery of low-dose 90Y-NM600 RPT.Novel methodology for voxel and region level partial volume correction (PVC) of 86Y-based 90Y dosimetry was developed for this framework. Voxel-level PVC improved the recovery of 86Y by up to 17.8% in small 0.5 ml lesions but demonstrated less utility in larger and more heterogeneous cases, necessitating region-based PVC. Region-level PVC increased dosimetry estimates by 45.6% ± 9.8% in preclinical tumors and 23-56% for 16-0.5 ml hot-spheres (10:1) in clinical phantom studies. In application to lung met dosimetry for canine patients, uncorrected dosimetry estimates were 38% ± 8.3% low compared to those with PVC.Locoregional temporal coregistration approaches for multi-timepoint dosimetry were developed, automated, and validated in a deformable anthropomorphic phantom study. Target volume registration improved by 19.8-38.7% as measured by the dice similarity coefficient. With improved registration, the dosimetric impact of target volume definition was reduced by 30.6% to a difference of 4.4% ± 1.9% in D90 across all validation cases.The developed framework was successfully implemented within a clinically reasonable timeframe (7.5 ± 2.3 days) for five canine patients. Low-dose 90Y-NM600 at the ≥2 Gy level was administered as prescribed, with dosimetry indicating the potential for ≥4 Gy to all tumors. Notably, the constitution of canine patient immune function remained intact with little to no adverse events observed.

Polyamines and polyamine conjugates display a diverse range of important biological functions, ranging from antibiotics to immunosuppressants and glutamate receptor antagonists. For these reasons, polyamines provide an excellent template/scaffold for combinatorial chemistry. In this paper we present methods for the solid-phase immobilisation of polyamines for use in synthetic and combinatorial chemistry and describe how they have been employed in the preparation of a number of important polyamine conjugates and polyamine libraries. Thus, we have designed, synthesised and utilised a number of polyamine linkers for both solution and resin screening combinatorial application.

Purpose: In this study, we present the creation of an anthropomorphic, head and neck, nuclear medicine phantom and its characterization for the validation of a Monte Carlo, SPECT image based, Iodine-131 RPT dosimetry workflow. Methods: 3D printing techniques were used to create the anthropomorphic phantom from a patient CT dataset. Three Iodine-131 SPECT/CT imaging studies were performed using a homogeneous, Jaszczak, and an anthropomorphic phantom to quantify the SPECT images. The impact of collimator detector response (CDR) modeling and volume-based partial volume corrections (PVC) upon the absorbed dose was calculated using an image based, Geant4 Monte Carlo RPT dosimetry workflow and compared against a ground truth scenario. Finally, uncertainties were quantified in accordance with recent EANM guidelines. Results: The 3D printed anthropomorphic phantom was an accurate re-creation of patient anatomy including bone. The extrapolated Jaszczak recovery coefficients were greater than that of the 3D printed insert (~22.8 ml) for both the CDR and non-CDR cases. Utilizing Jaszczak phantom PVCs, the absorbed dose was underpredicted by 0.7% and 4.9% without and with CDR, respectively. Utilizing anthropomorphic phantom RCs overpredicted the absorbed dose by 3% both with and without CDR. All dosimetry scenarios that incorporated PVC were within the calculated uncertainty of the activity. The uncertainties in the cumulative activity ranged from 25.6% to 113% for Jaszczak spheres ranging in volume from 0.5 ml to 16 ml. Conclusion: The accuracy of Monte Carlo-based dosimetry for Iodine-131 RPT in head and neck cancer was validated with an anthropomorphic phantom. Future applications of the phantom could involve 3D printing and characterizing patient specific volumes for more personalized RPT dosimetry estimates.

Combination radiopharmaceutical and external beam radiotherapy offers the potential to diminish locoregional toxicity that remains dose-limiting in the conventional treatment paradigm for recurrent head and neck cancer (HNC). In this study, we investigated the tumor targeting capacity of 131I-CLR1404 (CLR 131) in various HNC xenograft mouse models and the impact of partial volume correction on theranostic dosimetry based on 124I-CLR1404 (CLR 124) PET/CT imaging. Methods: Mice bearing flank tumor xenograft models of HNC (6 murine cell line- and 6 human patient-derived) were intravenously administered 6.5-9.1 MBq of CLR 124 and imaged five times over the course of six days using microPET/CT. In vivo tumor uptake of CLR 124 was assessed and partial volume corrections (PVC) for 124I were applied using a novel preclinical phantom. Using subject-specific theranostic dosimetry estimations for CLR 131 based on CLR 124 imaging, a discrete radiation dose escalation study was performed to evaluate tumor growth response to CLR 131 relative to a single fraction of XRT. Results: PET imaging demonstrated consistent tumor selective uptake and retention of CLR 124 across all HNC xenograft models. Peak uptake of 4.4 +/- 0.8% and 4.2 +/- 0.4% was observed in SCC-22B and UW-13, respectively. PVC application increased uptake measures by 47-188% and reduced absolute differences between in vivo and ex vivo uptake measurements from 3.3 to 1.0 %IA/g. Tumor dosimetry averaged over all HNC models was 0.85 +/- 0.27 Gy/MBq (1.58 +/- 0.46 Gy/MBq with PVC). Therapeutic CLR 131 studies demonstrated a variable, but linear relationship between CLR 131 radiation dose and tumor growth delay (p < 0.05). Conclusion: CLR 131 demonstrated tumoricidal capacity in preclinical HNC tumor models and the theranostic pairing of CLR 124/131 presents a promising new treatment approach for personalizing administration of CLR 131.