Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy

Jagodinsky, Justin C.; Jin, Won Jong; Bates, Amber M.; Hernandez, Reinier; Grudzinski, Joseph; Marsh, Ian; Chakravarty, Ishan; Arthur, Ian S.; Zangl, Luke; Brown, Ryan; Nystuen, Erin J.; Emma, Sarah E.; Kerr, Caroline P.; Carlson, Peter M.; Sriramaneni, Raghava N.; Engle, Jonathan W.; Aluicio‐Sarduy, Eduardo; Barnhart, Todd; Lе, Trаng; Kim, KyungMann; Bednarz, Bryan; Weichert, Jamey P.; Patel, Ravi B.; Morris, Zachary S.

doi:10.7150/thno.54881

Cited by 48 publications

(66 citation statements)

References 60 publications

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“…43 In addition, Jagodinsky et al demonstrated a STING-dependent type I interferon activation in melanomas, head and neck cancer murine models following TRNT. 33 Despite the expression of CS1 on T-cells, we did not observe any detrimental effect on the T cell population, in contrast we found a significant increase in the percentage CD8 + T-cells after TRNT. All these data point to the immune-stimulating properties of TRNT and its therapeutic potential in combination with current immunotherapeutic approaches including immune checkpoint inhibitors.…”

Section: Discussioncontrasting

confidence: 69%

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

et al. 2021

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Section: Discussioncontrasting

confidence: 69%

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

et al. 2021

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“…Similar to gene-signature cell type profiling, relative increases in CD3, CD8 and FoxP3 TILs were observed by IHC in primary tumors, although this was maximal at 13 days by IHC assessment. The timing of increased relative abundance of TIL cell profile expression signatures and IHC TIL numbers (i.e., peak at day 6–13) mimics observations we have reported in murine melanoma models for tumor immune susceptibility gene expression changes with EBRT [ 61 ] and with TRT [ 62 ] and cellular infiltrate changes with EBRT + IT-IC [ 27 , 28 ].…”

Section: Discussionsupporting

confidence: 68%

Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting

et al. 2021

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Rationale 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. Methods 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. Results 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. Conclusions 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.

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“…One example is their combined effect on the immune system. EBRT induces a plethora of immune-activating mechanisms and emerging evidence shows that MRT can also increase sensitivity to cytotoxic immune cells and promote lymphocyte recruitment and activation [18,19]. Early reports indicate that the timing of changes in the immune landscape may differ for the two treatments; it is plausible that these differences could be harnessed for therapeutic gain [19,20].…”

Section: Enhancement Of Tumour Responsementioning

confidence: 99%

“…EBRT induces a plethora of immune-activating mechanisms and emerging evidence shows that MRT can also increase sensitivity to cytotoxic immune cells and promote lymphocyte recruitment and activation [18,19]. Early reports indicate that the timing of changes in the immune landscape may differ for the two treatments; it is plausible that these differences could be harnessed for therapeutic gain [19,20]. Another exploitable interaction is the increase in blood flow and vessel permeability after exposure to EBRT which, when immediately preceded or followed by MRT, can enhance intra-tumoural accumulation of radioactivity [21,22].…”

Section: Enhancement Of Tumour Responsementioning

confidence: 99%

Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks

et al. 2021

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The emergence of effective radionuclide therapeutics, such as radium-223 dichloride, [ 177 Lu]Lu-DOTA-TATE and [ 177 Lu]Lu-PSMA ligands, over the last 10 years is driving a rapid expansion in molecular radiotherapy (MRT) research. Clinical trials that are underway will help to define optimal dosing protocols and identify groups of patients who are likely to benefit from this form of treatment. Clinical investigations are also being conducted to combine new MRT agents with other anticancer drugs, with particular emphasis on DNA repair inhibitors and immunotherapeutics. In this review, the case is presented for combining MRT with external beam radiotherapy (EBRT). The technical and dosimetric challenges of combining two radiotherapeutic modalities have impeded progress in the past. However, the need for research into the specific radiobiological effects of radionuclide therapy, which has lagged behind that for EBRT, has been recognised. This, together with innovations in imaging technology, MRT dosimetry tools and EBRT hardware, will facilitate the future use of this important combination of treatments.

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Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy

Cited by 48 publications

References 60 publications

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma

Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting

Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks

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