Publications by authors named "Zachary Morris"

68 Publications

Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.

Sci Transl Med 2021 Jul;13(602)

Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, USA.

Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8 T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.
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http://dx.doi.org/10.1126/scitranslmed.abb3631DOI Listing
July 2021

Optimizing Flow Cytometric Analysis of Immune Cells in Samples Requiring Cryopreservation from Tumor-Bearing Mice.

J Immunol 2021 Jul 14. Epub 2021 Jul 14.

Department of Human Oncology, Wisconsin Institutes for Medical Research, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI;

Most shared resource flow cytometry facilities do not permit analysis of radioactive samples. We are investigating low-dose molecular targeted radionuclide therapy (MTRT) as an immunomodulator in combination with in situ tumor vaccines and need to analyze radioactive samples from MTRT-treated mice using flow cytometry. Further, the sudden shutdown of core facilities in response to the COVID-19 pandemic has created an unprecedented work stoppage. In these and other research settings, a robust and reliable means of cryopreservation of immune samples is required. We evaluated different fixation and cryopreservation protocols of disaggregated tumor cells with the aim of identifying a protocol for subsequent flow cytometry of the thawed sample, which most accurately reflects the flow cytometric analysis of the tumor immune microenvironment of a freshly disaggregated and analyzed sample. Cohorts of C57BL/6 mice bearing B78 melanoma tumors were evaluated using dual lymphoid and myeloid immunophenotyping panels involving fixation and cryopreservation at three distinct points during the workflow. Results demonstrate that freezing samples after all staining and fixation are completed most accurately matches the results from noncryopreserved equivalent samples. We observed that cryopreservation of living, unfixed cells introduces a nonuniform alteration to PD1 expression. We confirm the utility of our cryopreservation protocol by comparing tumors treated with in situ tumor vaccines, analyzing both fresh and cryopreserved tumor samples with similar results. Last, we use this cryopreservation protocol with radioactive specimens to demonstrate potentially beneficial effector cell changes to the tumor immune microenvironment following administration of a novel MTRT in a dose- and time-dependent manner.
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http://dx.doi.org/10.4049/jimmunol.2000656DOI Listing
July 2021

Quantification and molecular imaging of fatty acid isomers from complex biological samples by mass spectrometry.

Chem Sci 2021 May 4;12(23):8115-8122. Epub 2021 May 4.

School of Pharmacy, University of Wisconsin-Madison Madison WI 53705 USA

Elucidating the isomeric structure of free fatty acids (FAs) in biological samples is essential to comprehend their biological functions in various physiological and pathological processes. Herein, we report a novel approach of using peracetic acid (PAA) induced epoxidation coupled with mass spectrometry (MS) for localization of the C[double bond, length as m-dash]C bond in unsaturated FAs, which enables both quantification and spatial visualization of FA isomers from biological samples. Abundant diagnostic fragment ions indicative of the C[double bond, length as m-dash]C positions were produced upon fragmentation of the FA epoxides derived from either in-solution or on-tissue PAA epoxidation of free FAs. The performance of the proposed approach was evaluated by analysis of FAs in human cell lines as well as mapping the FA isomers from cancer tissue samples with MALDI-TOF/TOF-MS. Merits of the newly developed method include high sensitivity, simplicity, high reaction efficiency, and capability of spatial characterization of FA isomers in tissue samples.
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http://dx.doi.org/10.1039/d1sc01614hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208125PMC
May 2021

Combination of radiation therapy, bempegaldesleukin, and checkpoint blockade eradicates advanced solid tumors and metastases in mice.

J Immunother Cancer 2021 Jun;9(6)

Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA

Background: Current clinical trials are using radiation therapy (RT) to enhance an antitumor response elicited by high-dose interleukin (IL)-2 therapy or immune checkpoint blockade (ICB). Bempegaldesleukin (BEMPEG) is an investigational CD122-preferential IL-2 pathway agonist with prolonged in vivo half-life and preferential intratumoral expansion of T effector cells over T regulatory cells. BEMPEG has shown encouraging safety and efficacy in clinical trials when used in combination with PD-1 checkpoint blockade. In this study, we investigated the antitumor effect of local RT combined with BEMPEG in multiple immunologically 'cold' tumor models. Additionally, we asked if ICB could further enhance the local and distant antitumor effect of RT+BEMPEG in the setting of advanced solid tumors or metastatic disease.

Methods: Mice bearing flank tumors (B78 melanoma, 4T1 breast cancer, or MOC2 head and neck squamous cell carcinoma) were treated with combinations of RT and immunotherapy (including BEMPEG, high-dose IL-2, anti(α)-CTLA-4, and α-PD-L1). Mice bearing B78 flank tumors were injected intravenously with B16 melanoma cells to mimic metastatic disease and were subsequently treated with RT and/or immunotherapy. Tumor growth and survival were monitored. Peripheral T cells and tumor-infiltrating lymphocytes were assessed via flow cytometry.

Results: A cooperative antitumor effect was observed in all models when RT was combined with BEMPEG, and RT increased IL-2 receptor expression on peripheral T cells. This cooperative interaction was associated with increased IL-2 receptor expression on peripheral T cells following RT. In the B78 melanoma model, RT+BEMPEG resulted in complete tumor regression in the majority of mice with a single ~400 mm tumor. This antitumor response was T-cell dependent and supported by long-lasting immune memory. Adding ICB to RT+BEMPEG strengthened the antitumor response and cured the majority of mice with a single ~1000 mm B78 tumor. In models with disseminated metastasis (B78 primary with B16 metastasis, 4T1, and MOC2), the triple combination of RT, BEMPEG, and ICB significantly improved primary tumor response and survival.

Conclusion: The combination of local RT, BEMPEG, and ICB cured mice with advanced, immunologically cold tumors and distant metastasis in a T cell-dependent manner, suggesting this triple combination warrants clinical testing.
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http://dx.doi.org/10.1136/jitc-2021-002715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237721PMC
June 2021

Future Directions in the Use of SAbR for the Treatment of Oligometastatic Cancers.

Semin Radiat Oncol 2021 Jul;31(3):253-262

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI. Electronic address:

The role of local therapy as a sole therapy or part of a combined approach in treating metastatic cancer continues to evolve. The most obvious requirements for prudent implementation of local therapies like stereotactic ablative radiotherapy (SAbR) to become mainstream in treating oligometastases are (1) Clear guidance as to what particular patients might benefit, and (2) Confirmation of improvements in outcome after such treatments via clinical trials. These future directional requirements are non-negotiable. However, innovation and research offer many more opportunities to understand and improve therapy. Identifying candidates and personalizing their therapy can be afforded via proteomic, genomic and epigenomic characterization techniques. Such molecular profiling along with liquid biopsy opportunities will both help select best therapies and facilitate ongoing monitoring of response. Technologies both to find targets and help deliver less-toxic therapy continue to improve and will be available in the marketplace. These technologies include molecular-based imaging (eg, PET-PSMA), FLASH ultra-high dose rate platforms, Grid therapy, PULSAR adaptive dosing, and MRI/PET guided linear accelerators. Importantly, a treatment approach beyond oligometastastic could evolve including a rationale for using SAbR in the oligoprogressive, oligononresponsive, oligobulky and oligolethal settings as well as expansion beyond oligo- toward even plurimetastastic disease. In any case, lessons learned and experiences required by the implementation of using SAbR in oligometastatic cancer will be revisited.
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http://dx.doi.org/10.1016/j.semradonc.2021.03.004DOI Listing
July 2021

Using Radiation Therapy to Prime and Propagate an Anti-tumor Immune Response Against Brain Tumors.

Neuromolecular Med 2021 Jun 3. Epub 2021 Jun 3.

Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.

Immunotherapies have demonstrated efficacy and survival benefits in some patients suffering from brain tumors; however, most do not respond and new approaches to enhance anti-tumor immunotherapeutic responses in the brain are needed. Radiotherapy remains a commonly used cancer treatment modality and can augment immunotherapeutic responses through multiple mechanisms. Recent preclinical studies may provide insight on how to optimally combine radiation and immunotherapies to maximize treatment efficacy. Unique aspects of the brain tumor microenvironment may play a critical role in limiting the successful application of immunotherapies in this location. Emerging studies suggest that such limits may be redressed through combination of immunotherapies with radiation therapy. In these settings, the latter may play a critical role in immunomodulating both tumor cells and the radiated brain tumor microenvironment. This review analyzes recent developments in combining radiation and immunotherapies to prime and better propagate anti-tumor immune response against brain tumors.
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http://dx.doi.org/10.1007/s12017-021-08668-wDOI Listing
June 2021

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

Theranostics 2021 15;11(13):6120-6137. Epub 2021 Apr 15.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.

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.
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http://dx.doi.org/10.7150/thno.54881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120207PMC
July 2021

Combination of Bempegaldesleukin and Anti-CTLA-4 Prevents Metastatic Dissemination After Primary Resection or Radiotherapy in a Preclinical Model of Non-Small Cell Lung Cancer.

Front Oncol 2021 15;11:645352. Epub 2021 Apr 15.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.

Surgical resection or hypo-fractionated radiation therapy (RT) in early-stage non-small cell lung cancer (NSCLC) achieves local tumor control, but metastatic relapse remains a challenge. We hypothesized that immunotherapy with anti-CTLA-4 and bempegaldesleukin (BEMPEG; NKTR-214), a CD122-preferential IL2 pathway agonist, after primary tumor RT or resection would reduce metastases in a syngeneic murine NSCLC model. Mice bearing Lewis Lung Carcinoma (LLC) tumors were treated with combinations of BEMPEG, anti-CTLA-4, and primary tumor treatment (surgical resection or RT). Primary tumor size, mouse survival, and metastatic disease at the time of death were assessed. Flow cytometry, qRT-PCR, and cytokine analyses were performed on tumor specimens. All mice treated with RT or surgical resection of primary tumor alone succumbed to metastatic disease, and all mice treated with BEMPEG and/or anti-CTLA-4 succumbed to primary tumor local progression. The combination of primary tumor RT or resection and BEMPEG and anti-CTLA-4 reduced spontaneous metastasis and improved survival without any noted toxicity. Flow cytometric immunoprofiling of primary tumors revealed increased CD8 T and NK cells and decreased T-regulatory cells with the combination of BEMPEG, anti-CTLA-4, and RT compared to RT alone. Increased expression of genes associated with tumor cell immune susceptibility, immune cell recruitment, and cytotoxic T lymphocyte activation were observed in tumors of mice treated with BEMPEG, anti-CTLA-4, and RT. The combination of BEMPEG and anti-CTLA-4 with primary tumor RT or resection enabled effective control of local and metastatic disease in a preclinical murine NSCLC model. This therapeutic combination has important translational potential for patients with early-stage NSCLC and other cancers.
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http://dx.doi.org/10.3389/fonc.2021.645352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083981PMC
April 2021

Depth of tumor implantation affects response to in situ vaccination in a syngeneic murine melanoma model.

J Immunother Cancer 2021 Apr;9(4)

Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA

An important component of research using animal models is ensuring rigor and reproducibility. This study was prompted after two experimenters performing virtually identical studies obtained different results when syngeneic B78 murine melanoma cells were implanted into the skin overlying the flank and treated with an in situ vaccine (ISV) immunotherapy. Although both experimenters thought they were using identical technique, we determined that one was implanting the tumors intradermally (ID) and the other was implanting them subcutaneously (SC). Though the baseline in vivo immunogenicity of tumors can depend on depth of their implantation, the response to immunotherapy as a function of tumor depth, particularly in immunologically 'cold' tumors, has not been well studied. The goal of this study was to evaluate the difference in growth kinetics and response to immunotherapy between identically sized melanoma tumors following ID versus SC implantation. We injected C57BL/6 mice with syngeneic B78 melanoma cells either ID or SC in the flank. When tumors reached 190-230 mm, they were grouped into a 'wave' and treated with our previously published ISV regimen (12 Gy local external beam radiation and intratumoral hu14.18-IL2 immunocytokine). Physical examination demonstrated that ID-implanted tumors were mobile on palpation, while SC-implanted tumors became fixed to the underlying fascia. Histologic examination identified a critical fascial layer, the panniculus carnosus, which separated ID and SC tumors. SC tumors reached the target tumor volume significantly faster compared with ID tumors. Most ID tumors exhibited either partial or complete response to this immunotherapy, whereas most SC tumors did not. Further, the 'mobile' or 'fixed' phenotype of tumors predicted response to therapy, regardless of intended implantation depth. These findings were then extended to additional immunotherapy regimens in four separate tumor models. These data indicate that the physical 'fixed' versus 'mobile' characterization of the tumors may be one simple method of ensuring homogeneity among implanted tumors prior to initiation of treatment. Overall, this short report demonstrates that small differences in depth of tumor implantation can translate to differences in response to immunotherapy, and proposes a simple physical examination technique to ensure consistent tumor depth when conducting implantable tumor immunotherapy experiments.
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http://dx.doi.org/10.1136/jitc-2020-002107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055108PMC
April 2021

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

J Immunother Cancer 2021 Apr;9(4)

Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis, Bethesda, Maryland, USA

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory 'drug' to provide alternatives to the widely adopted 'one-size-fits-all' strategy of frequently used 8 Gy×3 regimens immunomodulation.
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http://dx.doi.org/10.1136/jitc-2020-002038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031689PMC
April 2021

Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain.

Radiat Res 2021 06;195(6):522-540

Department of a Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Brain metastases develop in over 60% of advanced melanoma patients and negatively impact quality of life and prognosis. In a murine melanoma model, we previously showed that an in situ vaccination (ISV) regimen, combining radiation treatment and intratumoral (IT) injection of immunocytokine (IC: anti-GD2 antibody fused to IL2), along with the immune checkpoint inhibitor anti-CTLA-4, robustly eliminates peripheral flank tumors but only has modest effects on co-occurring intracranial tumors. In this study, we investigated the ability of low-dose radiation to the brain to potentiate anti-tumor immunity against a brain tumor when combined with ISV + anti-CTLA-4. B78 (GD2+, immunologically "cold") melanoma tumor cells were implanted into the flank and the right striatum of the brain in C57BL/6 mice. Flank tumors (50-150 mm3) were treated following a previously optimized ISV regimen [radiation (12 Gy × 1, treatment day 1), IT-IC (50 µg daily, treatment days 6-10), and anti-CTLA-4 (100 µg, treatment days 3, 6, 9)]. Mice that additionally received whole-brain radiation treatment (WBRT, 4 Gy × 1) on day 15 demonstrated significantly increased survival compared to animals that received ISV + anti-CTLA-4 alone, WBRT alone or no treatment (control) (P < 0.001, log-rank test). Timing of WBRT was critical, as WBRT administration on day 1 did not significantly enhance survival compared to ISV + anti-CTLA-4, suggesting that the effect of WBRT on survival might be mediated through immune modulation and not just direct tumor cell cytotoxicity. Modest increases in T cells (CD8+ and CD4+) and monocytes/macrophages (F4/80+) but no changes in FOXP3+ regulatory T cells (Tregs), were observed in brain melanoma tumors with addition of WBRT (on day 15) to ISV + anti-CTLA-4. Cytokine multiplex immunoassay revealed distinct changes in both intracranial melanoma and contralateral normal brain with addition of WBRT (day 15) to ISV + anti-CTLA-4, with notable significant changes in pro-inflammatory (e.g., IFNγ, TNFα and LIX/CXCL5) and suppressive (e.g., IL10, IL13) cytokines as well as chemokines (e.g., IP-10/CXCL10 and MIG/CXCL9). We tested the ability of the alkylphosphocholine analog, NM600, to deliver immunomodulatory radiation to melanoma brain tumors as a targeted radionuclide therapy (TRT). Yttrium-86 (86Y) chelated to NM600 was delivered intravenously by tail vein to mice harboring flank and brain melanoma tumors, and PET imaging demonstrated specific accumulation up to 72 h at each tumor site (∼12:1 brain tumor/brain and ∼8:1 flank tumor/muscle). When NM600 was chelated to therapeutic β-particle-emitting 90Y and administered on treatment day 13, T-cell infiltration and cytokine profiles were altered in melanoma brain tumor, like that observed for WBRT. Overall, our results demonstrate that addition of low-dose radiation, timed appropriately with ISV administration to tumors outside the brain, significantly increases survival in animals co-harboring melanoma brain tumors. This observation has potentially important translational implications as a treatment strategy for increasing the response of tumors in the brain to systemically administered immunotherapies.
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http://dx.doi.org/10.1667/RADE-20-00237.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259713PMC
June 2021

A multipurpose brachytherapy catheter to enable intratumoral injection.

Brachytherapy 2021 Jul-Aug;20(4):900-910. Epub 2021 Mar 27.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.

Purpose: To create and test a multipurpose brachytherapy catheter prototype enabling intratumoral injection and brachytherapy after a single catheter insertion.

Methods And Materials: The design of the prototype consists of an outer tube and an inner syringe tube that can be filled with injectable agent. The outer sheath and inner syringe tube were constructed using polytetrafluoroethylene tubing, and the other components were 3D printed using dental resin and polylactic acid material. To demonstrate functionality, we injected in vitro phantoms with dyed saline. For proof of concept, we demonstrated the potential for the prototype to deliver cell therapy, enhance tumor delineation, deliver tattoo ink for pathology marking, avoid toxicity through local delivery of chemotherapy, and facilitate combination brachytherapy and immunotherapy.

Results: The prototype enables accurate injection in vitro and in vivo without altering dosimetry. To illustrate the potential for delivery of cell therapies, we injected luciferase-expressing splenocytes and confirmed their delivery with bioluminescence imaging. To demonstrate feasibility of radiographically visualizing injected material, we delivered iohexol contrast intratumorally and confirmed tumor retention using Faxitron x-ray imaging. In addition, we show the potential of intratumoral administration to reduce toxicity associated with cyclophosphamide compared with systemic administration. To demonstrate feasibility, we treated tumor-bearing mice with brachytherapy (Ir source, 2 Gy to 5 mm) in combination with intratumoral injection of 375,000 U of interleukin 2 and observed no increased toxicity.

Conclusions: These results demonstrate that a prototype multipurpose brachytherapy catheter enables accurate intratumoral injection and support the feasibility of combining intratumoral injection with brachytherapy.
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http://dx.doi.org/10.1016/j.brachy.2020.10.012DOI Listing
March 2021

The extra costs associated with a cognitive impairment: Estimates from 15 OECD countries.

Eur J Public Health 2021 Jul;31(3):647-652

University of Tennessee Knoxville, College of Social Work, Knoxville, TN, USA.

Background: The objective of this study is to estimate the additional income required of a household containing an older adult member living with a cognitive impairment (CI) consistent with dementia (CID).

Methods: Secondary analyses were provided of data from the Survey of Health Aging and Retirement in Europe incorporating data of adults' age 65 years old and older across 15 OECD countries in 2013. We also analyzed longitudinal data of a smaller subset of respondents interviewed in a previous survey wave in 2011. We used OLS regression and the Standard of Living (SOL) approach to estimating the extra costs of disability.

Results: Households containing a member experiencing a CID are estimated to require 48% more income to maintain their SOL compared to similar households not including an adult with CID. Those with CI without dementia are estimated to have lower costs (14%). Those with longer-term CID are estimated to incur greater costs than those with a more recent onset of a CI. The extra costs are estimated to be lower in countries with more formalized public long-term care arrangements. We further identified out of pocket costs for home care services as a likely expenditure item driving these cost estimates.

Conclusions: Results suggest that caring for a person living with dementia can lead to considerable expenses. These additional direct costs associated with dementia provide insights for households in anticipating the risks of financial insecurity as they grow older. Future research is needed to identify the consumption items driving these estimates.
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http://dx.doi.org/10.1093/eurpub/ckab011DOI Listing
July 2021

Heading for higher ground: Developmental origins and evolutionary diversification of the amniote face.

Curr Top Dev Biol 2021 25;141:241-277. Epub 2021 Jan 25.

Department of Life Sciences, Imperial College London, Berkshire, United Kingdom; Natural History Museum, London, United Kingdom. Electronic address:

Amniotes, a clade of terrestrial vertebrates, which includes all of the descendants of the last common ancestor of the reptiles (including dinosaurs and birds) and mammals, is one of the most successful group of animals on our planet. In addition to having an egg equipped with an amnion, an adaptation to lay eggs on land, amniotes possess a number of other major morphological characteristics. Chief among them is the amniote skull, which can be classified into several major types distinguished by the presence and number of temporal fenestrae (windows) in the posterior part. Amniotes evolved from ancestors who possessed a skull composed of a complex mosaic of small bones separated by sutures. Changes in skull composition underlie much of the large-scale evolution of amniotes with many lineages showing a trend in reduction of cranial elements known as the "Williston's Law." The skull of amniotes is also arranged into a set of modules of closely co-evolving bones as revealed by modularity and integration tests. One of the most consistently recovered and at the same time most versatile modules is the "face," anatomically defined as the anterior portion of the head. The faces of amniotes display extraordinary amount of variation, with many adaptive radiations showing parallel tendencies in facial scaling, e.g., changes in length or width. This review explores the natural history of the amniote face and discusses how a better understanding of its anatomy and developmental biology helps to explain the outstanding scale of adaptive facial diversity. We propose a model for facial evolution in the amniotes, based on the differential rate of cranial neural crest cell proliferation and the timing of their skeletal differentiation.
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http://dx.doi.org/10.1016/bs.ctdb.2020.12.003DOI Listing
January 2021

Tumor-Specific Antibody, Cetuximab, Enhances the Vaccine Effect of Radiation in Immunologically Cold Head and Neck Squamous Cell Carcinoma.

Front Immunol 2020 12;11:591139. Epub 2020 Nov 12.

Department of Human Oncology, University of Wisconsin, Madison, WI, United States.

In head and neck squamous cell carcinoma (HNSCC) tumors that over-expresses huEGFR, the anti-EGFR antibody, cetuximab, antagonizes tumor cell viability and sensitizes to radiation therapy. However, the immunologic interactions between cetuximab and radiation therapy are not well understood. We transduced two syngeneic murine HNSCC tumor cell lines to express human EGFR (MOC1- and MOC2-huEGFR) in order to facilitate evaluation of the immunologic interactions between radiation and cetuximab. Cetuximab was capable of inducing antibody-dependent cellular cytotoxicity (ADCC) in MOC1- and MOC2-huEGFR cells but showed no effect on the viability or radiosensitivity of these tumor cells, which also express muEGFR that is not targeted by cetuximab. Radiation enhanced the susceptibility of MOC1- and MOC2-huEGFR to ADCC, eliciting a type I interferon response and increasing expression of NKG2D ligands on these tumor cells. Co-culture of splenocytes with cetuximab and MOC2-huEGFR cells resulted in increased expression of IFNγ in not only NK cells but also in CD8+ T cells, and this was dependent upon splenocyte expression of FcγR. In MOC2-huEGFR tumors, combining radiation and cetuximab induced tumor growth delay that required NK cells, EGFR expression, and FcγR on host immune cells. Combination of radiation and cetuximab increased tumor infiltration with NK and CD8+ T cells but not regulatory T cells. Expression of PD-L1 was increased in MOC2-huEGFR tumors following treatment with radiation and cetuximab. Delivering anti-PD-L1 antibody with radiation and cetuximab improved survival and resulted in durable tumor regression in some mice. Notably, these cured mice showed evidence of an adaptive memory response that was not specifically directed against huEGFR. These findings suggest an opportunity to improve the treatment of HNSCC by combining radiation and cetuximab to engage an innate anti-tumor immune response that may prime an effective adaptive immune response when combined with immune checkpoint blockade. It is possible that this approach could be extended to any immunologically cold tumor that does not respond to immune checkpoint blockade alone and for which a tumor-specific antibody exists or could be developed.
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http://dx.doi.org/10.3389/fimmu.2020.591139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689006PMC
June 2021

The Radiobiology of Radiopharmaceuticals.

Semin Radiat Oncol 2021 Jan;31(1):20-27

Department of Radiation Oncology, Stanford University, Palo Alto, CA. Electronic address:

Radiopharmaceutical therapy or targeted radionuclide therapy (TRT) is a well-established class of cancer therapeutics that includes a growing number of FDA-approved drugs and a promising pipeline of experimental therapeutics. Radiobiology is fundamental to a mechanistic understanding of the therapeutic capacity of these agents and their potential toxicities. However, the field of radiobiology has historically focused on external beam radiation. Critical differences exist between TRT and external beam radiotherapy with respect to dosimetry, dose rate, linear energy transfer, duration of treatment delivery, fractionation, range, and target volume. These distinctions simultaneously make it difficult to extrapolate from the radiobiology of external beam radiation to that of TRT and pose considerable challenges for preclinical and clinical studies investigating TRT. Here, we discuss these challenges and explore the current understanding of the radiobiology of radiopharmaceuticals.
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http://dx.doi.org/10.1016/j.semradonc.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990047PMC
January 2021

Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model.

J Immunother Cancer 2020 10;8(2)

Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA

Background: Some patients with cancer treated with anticancer monoclonal antibodies (mAbs) develop antidrug antibodies (ADAs) that recognize and bind the therapeutic antibody. This response may neutralize the therapeutic mAb, interfere with mAb effector function or cause toxicities. We investigated the potential influence of ADA to modify the tumor-binding capability of a tumor-reactive 'immunocytokine' (IC), namely, a fusion protein (hu14.18-IL2) consisting of a humanized, tumor-reactive, anti-GD2 mAb genetically linked to interleukin 2. We characterize the role of treatment delivery of IC (intravenous vs intratumoral) on the impact of ADA on therapeutic outcome following IC treatments in an established antimelanoma (MEL) regimen involving radiotherapy (RT) +IC.

Methods: C57BL/6 mice were injected with human IgG or the hu14.18-IL2 IC to develop a mouse anti-human antibody (MAHA) response (MAHA). In vitro assays were performed to assess ADA binding to IC using sera from MAHA and MAHA mice. In vivo experiments assessed the levels of IC bound to tumor in MAHA and MAHA mice, and the influence of IC route of delivery on its ability to bind to B78 (GD2+) MEL tumors.

Results: MAHA is inducible in C57BL/6 mice. In vitro assays show that MAHA is capable of inhibiting the binding of IC to GD2 antigen on B78 cells, resulting in impaired ADCC mediated by IC. When B78-bearing mice are injected intravenously with IC, less IC binds to B78-MEL tumors in MAHA mice than in MAHA mice. In contrast, when IC is injected intratumorally in tumor-bearing mice, the presence of MAHA does not detectibly impact IC binding to the tumor. Combination therapy with RT+IT-IC showed improved tumor regression compared with RT alone in MAHA mice. If given intratumorally, IC could be safely readministered in tumor-bearing MAHA mice, while intravenous injections of IC in MAHA mice caused severe toxicity. Histamine levels were elevated in MAHA mice compared with MAHA mice after reintroduction of IC.

Conclusions: Intratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.
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http://dx.doi.org/10.1136/jitc-2020-001262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594540PMC
October 2020

Vaccine Plus Checkpoint Blockade Induces Memory Humoral Response.

Front Immunol 2020 24;11:1610. Epub 2020 Jul 24.

Department of Human Oncology, University of Wisconsin, Madison, WI, United States.

In a syngeneic murine melanoma (MEL) model, we recently reported an vaccination response to combined radiation (RT) and intra-tumoral (IT) injection of anti-GD2 hu14. 18-IL2 immunocytokine (IC). This combined treatment resulted in 71% complete and durable regression of 5-week tumors, a tumor-specific memory T cell response, and augmented response to systemic anti-CTLA-4 antibody checkpoint blockade. While the ability of radiation to diversify anti-tumor T cell response has been reported, we hypothesize that mice rendered disease-free (DF) by a RT-based ISV might also exhibit a heightened B cell response. C57BL/6 mice were engrafted with 2 × 10 GD2+ B78 MEL and treated at a target tumor size of ~200 mm with 12 Gy RT, IT-IC on day (D)6-D10, and anti-CTLA-4 on D3, 6, and 9. Serum was collected via facial vein before tumor injection, before treatment, during treatment, after becoming DF, and following rejection of subcutaneous 2 × 10 B78 MEL re-challenge on D90. Flow cytometry demonstrated the presence of tumor-specific IgG in sera from mice rendered DF and rejecting re-challenge with B78 MEL at D90 after starting treatment. Consistent with an adaptive endogenous anti-tumor humoral memory response, these anti-tumor antibodies bound to B78 cells and parental B16 cells (GD2-), but not to the unrelated syngeneic Panc02 or Panc02 GD2+ cell lines. We evaluated the kinetics of this response and observed that tumor-specific IgG was consistently detected by D22 after initiation of treatment, corresponding to a time of rapid tumor regression. The amount of tumor-specific antibody binding to tumor cells (as measured by flow MFI) did not correlate with host animal prognosis. Incubation of B16 MEL cells in DF serum, vs. naïve serum, prior to IV injection, did not delay engraftment of B16 metastases and showed similar overall survival rates. B cell depletion using anti-CD20 or anti-CD19 and anti-B220 did not impact the efficacy of ISV treatment. Thus, treatment with RT + IC + anti-CTLA-4 results in adaptive anti-tumor humoral memory response. This endogenous tumor-specific antibody response does not appear to have therapeutic efficacy but may serve as a biomarker for an anti-tumor T cell response.
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http://dx.doi.org/10.3389/fimmu.2020.01610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396490PMC
April 2021

In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases.

J Immunother Cancer 2020 07;8(2)

Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA

Background: Immune checkpoint inhibition (ICI) alone is not efficacious for a large number of patients with melanoma brain metastases. We previously established an in situ vaccination (ISV) regimen combining radiation and immunocytokine to enhance response to ICIs. Here, we tested whether ISV inhibits the development of brain metastases in a murine melanoma model.

Methods: B78 (GD2) melanoma 'primary' tumors were engrafted on the right flank of C57BL/6 mice. After 3-4 weeks, primary tumors were treated with ISV (radiation (12 Gy, day 1), α-GD2 immunocytokine (hu14.18-IL2, days 6-10)) and ICI (α-CTLA-4, days 3, 6, 9). Complete response (CR) was defined as no residual tumor observed at treatment day 90. Mice with CR were tested for immune memory by re-engraftment with B78 in the left flank and then the brain. To test ISV efficacy against metastases, tumors were also engrafted in the left flank and brain of previously untreated mice. Tumors were analyzed by quantitative reverse transcription-PCR, immunohistochemistry, flow cytometry and multiplex cytokine assay.

Results: ISV+α-CTLA-4 resulted in immune memory and rejection of B78 engraftment in the brain in 11 of 12 mice. When B78 was engrafted in brain prior to treatment, ISV+α-CTLA-4 increased survival compared with ICI alone. ISV+α-CTLA-4 eradicated left flank tumors but did not elicit CR at brain sites when tumor cells were engrafted in brain prior to ISV. ISV+α-CTLA-4 increased CD8 and CD4 T cells in flank and brain tumors compared with untreated mice. Among ISV + α-CTLA-4 treated mice, left flank tumors showed increased CD8 infiltration and CD8:FOXP3 ratio compared with brain tumors. Flank and brain tumors showed minimal differences in expression of immune checkpoint receptors/ligands or . Cytokine productions were similar in left flank and brain tumors in untreated mice. Following ISV+α-CTLA-4, production of immune-stimulatory cytokines was greater in left flank compared with brain tumor grafts.

Conclusion: ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+α-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases.
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http://dx.doi.org/10.1136/jitc-2020-000809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371368PMC
July 2020

Cancer Moonshot Immuno-Oncology Translational Network (IOTN): accelerating the clinical translation of basic discoveries for improving immunotherapy and immunoprevention of cancer.

J Immunother Cancer 2020 06;8(1)

Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches.
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http://dx.doi.org/10.1136/jitc-2020-000796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304845PMC
June 2020

Priming and Propagating Anti-tumor Immunity: Focal Hypofractionated Radiation for in Situ Vaccination and Systemic Targeted Radionuclide Theranostics for Immunomodulation of Tumor Microenvironments.

Semin Radiat Oncol 2020 Apr;30(2):181-186

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI. Electronic address:

Recent preclinical and clinical studies have elucidated mechanisms whereby radiation therapy influences the anti-tumor immune response. Immunogenic cell death and phenotypic changes in tumor cells surviving radiation may underlie this effect and contribute to the capacity of radiation to elicit an in situ tumor vaccine effect. In situ vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a source of enhanced antigen recognition for the purpose of augmenting a systemic anti-tumor immune response. Capitalizing on the in situ vaccine effect of radiation, several groups have demonstrated anti-tumor efficacy in preclinical models by combining radiation with immune checkpoint blockade. Local delivery of immune adjuvants and/or immune stimulatory cytokines via direct injection into the radiated tumor microenvironment may further increase the in situ vaccine capacity of radiation therapy. However, recent studies suggest that in some contexts this effect is antagonized by the presence of distant untreated sites of disease that may dampen the systemic immune response generated by in situ vaccination through a phenomenon termed concomitant immune tolerance. Concomitant immune tolerance may be overcome by delivering radiation to all sites of metastatic disease, however this is often not possible to safely achieve using external beam radiation therapy without considerable risk of lymphopenia that would negate the immune effects of in situ vaccination. For patients with widespread metastatic disease, alternative strategies may include systemic treatment with targeted radionuclide therapies alone or in combination with an external beam radiation therapy-based in situ vaccine approach.
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http://dx.doi.org/10.1016/j.semradonc.2019.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286051PMC
April 2020

The Promise of Combining Radiation Therapy With Immunotherapy.

Int J Radiat Oncol Biol Phys 2020 09 23;108(1):6-16. Epub 2020 Apr 23.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Electronic address:

The development of immunotherapy in oncology builds upon many years of scientific investigation into the cellular mechanics underlying interactions between tumor cells and immune cell populations. The past decade has brought an accelerating pace to the clinical investigation of new immunotherapy agents, particularly in the setting of metastatic disease. The integration of immunotherapy into phase 3 clinical trial design has lagged in settings of advanced locoregional disease, where combination with radiation therapy may be critical. Yet, such may be the settings where immunotherapies have their greatest potential to affect patient survival and achieve curative outcomes. In this review, we discuss the interaction of radiation with the immune system and the potential to augment antitumor immunity through combined-modality approaches that integrate radiation and immunotherapies. The dynamics of cellular and tumor response to radiation offer unique opportunities for beneficial interplay with immunotherapy that may go unrecognized with conventional screening and monotherapy clinical testing of novel pharmaceutical agents. Using immune checkpoint blockade as a primary example, we discuss recent preclinical and clinical studies that illustrate the potential synergy of such therapies in combination with radiation, and we highlight the potential clinical value of such interactions. For various immunotherapy agents, their greatest clinical effect may rest in combination with radiation, and efforts to facilitate systematic investigation of this approach are highly warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442714PMC
September 2020

Outcome-Related Signatures Identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated after Starting Hu14.18-IL2.

Clin Cancer Res 2020 07 9;26(13):3296-3306. Epub 2020 Mar 9.

Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin.

Purpose: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in patients with melanoma at high risk for recurrence.

Experimental Design: Patients were randomly assigned to receive the first of three monthly courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known diseases. Tumors were evaluated by histology and whole transcriptome sequencing.

Results: Tumor-infiltrating lymphocyte (TIL) levels directly associated with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature, which associated with RFS and OS, particularly in Group A tumors. In Group A tumors, there were decreased cell-cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors.

Conclusions: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNA-sequencing analyses detected shortly after initiation of hu14.18-IL2 therapy, are associated with long-term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334053PMC
July 2020

Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition.

J Immunother Cancer 2019 12 6;7(1):344. Epub 2019 Dec 6.

Department of Pediatrics, University of Wisconsin, 4159 WIMR Bldg., UWCCC, 1111 Highland Ave, Madison, WI, 53711, USA.

Background: Unlike some adult cancers, most pediatric cancers are considered immunologically cold and generally less responsive to immunotherapy. While immunotherapy has already been incorporated into standard of care treatment for pediatric patients with high-risk neuroblastoma, overall survival remains poor. In a mouse melanoma model, we found that radiation and tumor-specific immunocytokine generate an in situ vaccination response in syngeneic mice bearing large tumors. Here, we tested whether a novel immunotherapeutic approach utilizing radiation and immunocytokine together with innate immune stimulation could generate a potent antitumor response with immunologic memory against syngeneic murine neuroblastoma.

Methods: Mice bearing disialoganglioside (GD2)-expressing neuroblastoma tumors (either NXS2 or 9464D-GD2) were treated with radiation and immunotherapy (including anti-GD2 immunocytokine with or without anti-CTLA-4, CpG and anti-CD40 monoclonal antibody). Tumor growth, animal survival and immune cell infiltrate were analyzed in the tumor microenvironment in response to various treatment regimens.

Results: NXS2 had a moderate tumor mutation burden (TMB) while N-MYC driven 9464D-GD2 had a low TMB, therefore the latter served as a better model for high-risk neuroblastoma (an immunologically cold tumor). Radiation and immunocytokine induced a potent in situ vaccination response against NXS2 tumors, but not in the 9464D-GD2 tumor model. Addition of checkpoint blockade with anti-CTLA-4 was not effective alone against 9464D-GD2 tumors; inclusion of CpG and anti-CD40 achieved a potent antitumor response with decreased T regulatory cells within the tumors and induction of immunologic memory.

Conclusions: These data suggest that a combined innate and adaptive immunotherapeutic approach can be effective against immunologically cold syngeneic murine neuroblastoma. Further testing is needed to determine how these concepts might translate into development of more effective immunotherapeutic approaches for the treatment of clinically high-risk neuroblastoma.
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http://dx.doi.org/10.1186/s40425-019-0823-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898936PMC
December 2019

Development of an In Situ Cancer Vaccine via Combinational Radiation and Bacterial-Membrane-Coated Nanoparticles.

Adv Mater 2019 Oct 16;31(43):e1902626. Epub 2019 Sep 16.

Department of Human Oncology, University of Wisconsin, WIMR-I, Room 3131, 1111 Highland Ave, Madison, WI, 53705, USA.

Neoantigens induced by random mutations and specific to an individual's cancer are the most important tumor antigens recognized by T cells. Among immunologically "cold" tumors, limited recognition of tumor neoantigens results in the absence of a de novo antitumor immune response. These "cold" tumors present a clinical challenge as they are poorly responsive to most immunotherapies, including immune checkpoint inhibitors (ICIs). Radiation therapy (RT) can enhance immune recognition of "cold" tumors, resulting in a more diversified antitumor T-cell response, yet RT alone rarely results in a systemic antitumor immune response. Therefore, a multifunctional bacterial membrane-coated nanoparticle (BNP) composed of an immune activating PC7A/CpG polyplex core coated with bacterial membrane and imide groups to enhance antigen retrieval is developed. This BNP can capture cancer neoantigens following RT, enhance their uptake in dendritic cells (DCs), and facilitate their cross presentation to stimulate an antitumor T-cell response. In mice bearing syngeneic melanoma or neuroblastoma, treatment with BNP+RT results in activation of DCs and effector T cells, marked tumor regression, and tumor-specific antitumor immune memory. This BNP facilitates in situ immune recognition of a radiated tumor, enabling a novel personalized approach to cancer immunotherapy using off-the-shelf therapeutics.
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http://dx.doi.org/10.1002/adma.201902626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810793PMC
October 2019

Fission yeast TRP channel Pkd2p localizes to the cleavage furrow and regulates cell separation during cytokinesis.

Mol Biol Cell 2019 07 22;30(15):1791-1804. Epub 2019 May 22.

Department of Biological Sciences, University of Toledo, Toledo, OH 43606.

Force plays a central role in separating daughter cells during cytokinesis, the last stage of cell division. However, the mechanism of force sensing during cytokinesis remains unknown. Here we discovered that Pkd2p, a putative force-sensing transient receptor potential channel, localizes to the cleavage furrow during cytokinesis of the fission yeast, . Pkd2p, whose human homologues are associated with autosomal polycystic kidney disease, is an essential protein whose localization depends on the contractile ring and the secretory pathway. We identified and characterized a novel mutant . The mutant cells show signs of osmotic stress, including temporary shrinking, paused turnover of the cytoskeletal structures, and hyperactivated mitogen-activated protein kinase signaling. During cytokinesis, although the contractile ring constricts more rapidly in the mutant than the wild-type cells (50% higher), the cell separation in the mutant is slower and often incomplete. These cytokinesis defects are also consistent with misregulated turgor pressure. Finally, the mutant exhibits strong genetic interactions with two mutants of the septation initiation network pathway, a signaling cascade essential for cytokinesis. We propose that Pkd2p modulates osmotic homeostasis and is potentially a novel regulator of cytokinesis.
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http://dx.doi.org/10.1091/mbc.E18-04-0270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727746PMC
July 2019

Examining the relevance of employment integration policies on disability benefit receipt: a multilevel analysis of older working age adults in 16 countries.

Authors:
Zachary A Morris

Disabil Rehabil 2020 11 21;42(23):3339-3347. Epub 2019 Apr 21.

School of Social Welfare, Stony Brook University, Stony Brook, NY, USA.

Nearly all advanced economic countries have adopted employment integration policies to improve the labor market outcomes of workers with disabilities and to reduce enrollment on disability benefits. To date, research has yet to investigate whether the adoption of integration policies is associated with a reduced likelihood of an older working age adult receiving disability benefits. This study, drawing on data of older working-age adults from the Survey of Health Ageing and Retirement in Europe, the English Longitudinal Study of Ageing, and the Health and Retirement Study, applies multilevel logistic regression to investigate the relationship between country-level integration policies and the likelihood of disability benefit receipt in 16 OECD countries. No clear association was identified between the adoption of major integration policies (comprehensiveness of vocational rehabilitation systems, employer obligation policies, work-incentive rules, benefit suspension options, and early intervention efforts) and an individual's likelihood of receiving disability benefits. The minimum level of disability required to receive benefits was, however, identified as a significant country-level factor. The findings of this study may prove useful for policy makers who must weigh the costs and benefits of expanding integration measures targeted at those nearing the state pension age.Implications for RehabilitationMany countries have adopted integration policies to improve employment outcomes of adults with work-disabilities.No clear association is identified between the adoption of integration policies and a reduced likelihood of receiving disability benefits among older adults in 16 countries.The strictness of the definition of disability used to determine eligibility is identified as a significant country-level predictor.Policy makers should carefully weigh the costs and benefits of expanding integration measures targeted at those nearing the state pension age.
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http://dx.doi.org/10.1080/09638288.2019.1593521DOI Listing
November 2020

Loneliness as a Predictor of Work Disability Onset Among Nondisabled, Working Older Adults in 14 Countries.

Authors:
Zachary A Morris

J Aging Health 2020 Aug-Sep;32(7-8):554-563. Epub 2019 Apr 9.

Stony Brook University, NY, USA.

The objective of this study is to examine the relationship between loneliness and work disability and whether depression mediates the hypothesized relationship. We draw on data from the 2013 and 2015 waves of the Survey of Health, Aging, and Retirement in Europe. We limited the sample to adults between the ages of 50 and 65 who were working and without work limitations in 2013, which consisted of 10,154 adults from 14 countries. We apply multivariate logistic regression and a binary mediation analysis with logistic regression to examine predictors of the onset of work disability in 2015. Loneliness was predictive of future work disability onset when adjusting for other factors in the disablement process. Depression partly mediated the longitudinal relationship between loneliness and work disability. The results indicate that addressing loneliness could mitigate the risk of depression and, in turn, work disability onset.
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http://dx.doi.org/10.1177/0898264319836549DOI Listing
March 2021

Heterochronic shifts and conserved embryonic shape underlie crocodylian craniofacial disparity and convergence.

Proc Biol Sci 2019 02;286(1897):20182389

1 Museum of Comparative Zoology and Department of Organismic and Evolutionary Biology, Harvard University , 26 Oxford Street, Cambridge, MA 02138 , USA.

The distinctive anatomy of the crocodylian skull is intimately linked with dietary ecology, resulting in repeated convergence on blunt- and slender-snouted ecomorphs. These evolutionary shifts depend upon modifications of the developmental processes which direct growth and morphogenesis. Here we examine the evolution of cranial ontogenetic trajectories to shed light on the mechanisms underlying convergent snout evolution. We use geometric morphometrics to quantify skeletogenesis in an evolutionary context and reconstruct ancestral patterns of ontogenetic allometry to understand the developmental drivers of craniofacial diversity within Crocodylia. Our analyses uncovered a conserved embryonic region of morphospace (CER) shared by all non-gavialid crocodylians regardless of their eventual adult ecomorph. This observation suggests the presence of conserved developmental processes during early development (before Ferguson stage 20) across most of Crocodylia. Ancestral state reconstruction of ontogenetic trajectories revealed heterochrony, developmental constraint, and developmental systems drift have all played essential roles in the evolution of ecomorphs. Based on these observations, we conclude that two separate, but interconnected, developmental programmes controlling craniofacial morphogenesis and growth enabled the evolutionary plasticity of skull shape in crocodylians.
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http://dx.doi.org/10.1098/rspb.2018.2389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408887PMC
February 2019

Preclinical Characterization of Y-NM600 in a Variety of Murine and Human Cancer Tumor Models.

J Nucl Med 2019 11 6;60(11):1622-1628. Epub 2019 Apr 6.

Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.

We characterize the in vivo biodistribution and tumor selectivity of Y-NM600, a theranostic alkylphosphocholine radiometal chelate with broad tumor selectivity, in a variety of preclinical cancer models. Mice bearing flank tumors (representative of lung, pancreatic, prostate, liver, skin, and lymphoid cancers) were injected intravenously with 9.25 MBq of Y-NM600 and imaged longitudinally over 4-5 d using small-animal PET/CT. Percentage injected activity per gram (%IA/g) for each volume of interest was measured at each time point for the organs of interest. Mice were euthanized after the final time point, and the tumor and organs of interest were counted with an automatic γ-counter. Absorbed doses delivered by Y-NM600 per injected activity (Gy/MBq) were estimated. Mice bearing B78 flank tumors were injected with a prescription of Y-NM600 that delivered 2.5 Gy of absorbed tumor dose and was compared with an equivalent absorbed dose delivered via external-beam radiotherapy using tumor volume as a measure of response. Histology and complete blood counts were analyzed in naïve C57BL/6 mice that were injected with 9.25 MBq of Y-NM600 at 5, 10, and 28 d after injection. PET imaging showed consistent tumor accumulation and retention across all tumor models investigated, with little off-target retention of NM600 except in the liver, as is characteristic of hepatobiliary metabolism. The tumor uptake was highest in the pancreatic and lymphoid cancer models, reaching peak concentrations of 9.34 ± 2.66 %IA/g ( = 3) and 9.10 ± 0.13 %IA/g ( = 3), respectively, at approximately 40-48 h after injection. These corresponded to tumor dose estimates of 2.72 ± 0.33 Gy/MBq and 2.67 ± 0.32 Gy/MBq, respectively. In the toxicity study, there were no visible signs of acute toxicity by histology, and perturbation of hematologic parameters was transient when observed, returning to pretherapy levels after 28 d. NM600 is a theranostic agent with a unique ability to selectively target a variety of cancer types, presenting a unique opportunity for PET image-guided targeted radionuclide therapy and combination with immunotherapies.
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http://dx.doi.org/10.2967/jnumed.118.224808DOI Listing
November 2019
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