Nicholas DeVito

Overview:

I am an instructor of Medical Oncology who primarily treats patients with gastrointestinal malignancies. My laboratory and translational research is focused on tumor immune evasion and immunotherapy, with a specific interest in dendritic cell tolerance.

Positions:

Medical Instructor in the Department of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2012

University of South Florida, College of Medicine

Internal Medicine Internship and Residency

Tufts University School of Medicine

Hematology-Oncology Fellowship, Medicine

Duke University School of Medicine

Grants:

Publications:

A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis.

Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and HER2 amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, HER2 amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.
MLA Citation
DeVito, Nicholas C., et al. “A case report of microsatellite instability (MSI)-high, HER2 amplified pancreatic adenocarcinoma with central nervous system metastasis.Ame Case Rep, vol. 5, 2021, p. 14. Pubmed, doi:10.21037/acr-20-154.
URI
https://scholars.duke.edu/individual/pub1481212
PMID
33912803
Source
pubmed
Published In
Ame Case Rep
Volume
5
Published Date
Start Page
14
DOI
10.21037/acr-20-154

Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy.

While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.
Authors
DeVito, NC; Sturdivant, M; Thievanthiran, B; Xiao, C; Plebanek, MP; Salama, AKS; Beasley, GM; Holtzhausen, A; Novotny-Diermayr, V; Strickler, JH; Hanks, BA
MLA Citation
DeVito, Nicholas C., et al. “Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy.Cell Rep, vol. 35, no. 5, May 2021, p. 109071. Pubmed, doi:10.1016/j.celrep.2021.109071.
URI
https://scholars.duke.edu/individual/pub1470781
PMID
33951424
Source
pubmed
Published In
Cell Reports
Volume
35
Published Date
Start Page
109071
DOI
10.1016/j.celrep.2021.109071

425 Investigation of Wnt ligand signaling regulators as a predictor of Anti-PD-1 response in metastatic melanoma

<jats:sec><jats:title>Background</jats:title><jats:p>Responses to anti-PD-1 antibodies (aPD1) have changed the therapeutic landscape of metastatic melanoma, however predictive biomarkers of resistance are lacking. Beta-catenin pathway activation has been inversely correlated with tumor-infiltrating T lymphocytes in melanoma as well as several other solid tumors.<jats:sup>1</jats:sup> However, activating mutations involving this pathway are rare, implying that the modulation of upstream Wnt ligand/Fzd receptor (Wnt/Fzd) signaling could be a critical regulator of anti-tumor immunity. Indeed, expression of certain Wnt ligands has been associated with inferior responses to checkpoint inhibitor immunotherapy in metastatic melanoma patients.<jats:sup>2</jats:sup> In addition, we have further found tumor-derived paracrine and autocrine Wnt ligand signaling to drive dendritic cell tolerization and to be associated with escape from aPD1 therapy in transgenic mouse models.<jats:sup>3 4</jats:sup> No studies to date have focused on the impact of the various regulators and components of proximal Wnt/Fzd receptor signaling on resistance to aPD1 therapy in melanoma patients. We therefore developed a unique Wnt/Fzd pathway panel using Nanostring technology to examine alterations in Wnt ligands, their receptors, and regulators as a predictor of aPD1 resistance.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To test whether this panel could identify aPD1 resistant patients, Nanostring analysis was performed on archival FFPE tissue specimens of 12 responding (R) and 12 nonresponding (NR) metastatic melanoma patients (pts) taken prior to aPD1 monotherapy. Response was assessed radiographically by week 12 RECIST criteria.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Several components of both canonical and non-canonical Wnt ligand signaling, including regulators of autocrine/paracrine signaling, were upregulated in aPD1 NR pts compared to R pts (figure 1, table 1). GZMB, CD8, and IFNG were among cytotoxic T cell related genes upregulated in Rs. Upregulation of SFRP2 and DKK2 in NR pts, classically negative feedback regulators of Wnt ligands, are a reflection of enhanced Wnt ligand signaling activity.</jats:p><jats:table-wrap id="T1" position="float" orientation="portrait"><jats:label>Abstract 425 Table 1</jats:label><jats:caption><jats:p>Most significantly upregulated Wnt ligands, receptors, and pathway components in patients that do not respond to aPD1</jats:p></jats:caption><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="ABS_425_T001" position="float" orientation="portrait" /></jats:table-wrap><jats:fig id="F1" position="float" orientation="portrait"><jats:label>Abstract 425 Figure 1</jats:label><jats:caption><jats:p>Volcano plot of the top 30 genes from the nanostring panel comparing responders (red) and nonresponders (blue)</jats:p></jats:caption><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="ABS_425_F001" position="float" orientation="portrait" /></jats:fig></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This study supports the importance of paracrine and autocrine Wnt ligand signaling in the regulation of effector T cell responses and aPD1 resistance in cancer. In addition to predicting response to aPD1 checkpoint inhibitor immunotherapy, these findings further suggest that this Wnt signaling panel could serve as a predictive marker of immunologic response to Wnt ligand inhibitors, such as the PORCN inhibitors, which are currently under development. We continue to accrue additional pts to further validate these findings. Future studies will include a comparison of pre-treatment and on-treatment biopsies to evaluate these markers as predictors of adaptive aPD1 resistance.</jats:p></jats:sec><jats:sec><jats:title>Acknowledgements</jats:title><jats:p>Holly Dressman, PhD of the Duke Center for Genomic and Computational Biology for her assistance with the Nanostring samples; Jenna Goodwin, Carol Ann Wiggs, and Jennifer Nixon of the Duke Clinical Melanoma Research Team for their assistance with the melanoma tissue acquisition protocol; Tadas Rimkus of Nanostring for his assistance with analysis</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>NCT02694965</jats:p></jats:sec><jats:sec><jats:title>Ethics Approval</jats:title><jats:p>This study was approved by Duke University’s Institutional Review Board, protocol number Pro00059349</jats:p></jats:sec><jats:sec><jats:title>Consent</jats:title><jats:p>Not applicable</jats:p></jats:sec><jats:sec><jats:title>References</jats:title><jats:list list-type="order"><jats:list-item><jats:p>Luke JJ, B.R., Spranger S, Sweis RF, Lingen MW, Lengyel E, Zha Y, Gajewski TF. Wnt/Beta-catenin pathway activation correlates with immune exclusion across most human cancers. <jats:italic>Journal of Clinical Oncology</jats:italic> 2016;34(15).</jats:p></jats:list-item><jats:list-item><jats:p>Hugo W, et al. Genomic and transcriptomic features of response to anti-pd-1 therapy in metastatic melanoma. <jats:italic>Cell</jats:italic> 2016;165(1): p. 35–44.</jats:p></jats:list-item><jats:list-item><jats:p>DeVito NC, X.C., Zhao F, Evans KS, Theivanthiran B, Lewicki J, Hoey T, Hurwitz H, Strickler JH, Hanks BA. Paracrine wnt-β-catenin signaling inhibition as a strategy to enhance the efficacy of anti-PD-1 antibody (Ab) therapy in a transgenic model of melanoma. <jats:italic>Journal of Clinical Oncology</jats:italic>, 2017. 35(no. 15_suppl).</jats:p></jats:list-item><jats:list-item><jats:p>Zhao F, et al. Paracrine Wnt5a-beta-Catenin signaling triggers a metabolic program that drives dendritic cell tolerization. <jats:italic>Immunity</jats:italic> 2018;48(1): p. 147–160 e7.</jats:p></jats:list-item></jats:list></jats:sec>
Authors
DeVito, N; Sturdivant, M; Wachsmuth, L; Strickler, J; Beasley, G; Al-Rohil, R; Salama, A; Hanks, B
MLA Citation
DeVito, Nicholas, et al. “425 Investigation of Wnt ligand signaling regulators as a predictor of Anti-PD-1 response in metastatic melanoma.” Journal for Immunotherapy of Cancer, vol. 8, no. Suppl 3, BMJ, 2020, pp. A450–A450. Crossref, doi:10.1136/jitc-2020-sitc2020.0425.
URI
https://scholars.duke.edu/individual/pub1475621
Source
crossref
Published In
Journal for Immunotherapy of Cancer
Volume
8
Published Date
Start Page
A450
End Page
A450
DOI
10.1136/jitc-2020-sitc2020.0425

Role of dendritic cell metabolic reprogramming in tumor immune evasion.

The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.
Authors
Plebanek, MP; Sturdivant, M; DeVito, NC; Hanks, BA
MLA Citation
Plebanek, Michael P., et al. “Role of dendritic cell metabolic reprogramming in tumor immune evasion.Int Immunol, vol. 32, no. 7, June 2020, pp. 485–91. Pubmed, doi:10.1093/intimm/dxaa036.
URI
https://scholars.duke.edu/individual/pub1442098
PMID
32449776
Source
pubmed
Published In
Int Immunol
Volume
32
Published Date
Start Page
485
End Page
491
DOI
10.1093/intimm/dxaa036

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Authors
Theivanthiran, B; Evans, KS; DeVito, NC; Plebanek, M; Sturdivant, M; Wachsmuth, LP; Salama, AK; Kang, Y; Hsu, D; Balko, JM; Johnson, DB; Starr, M; Nixon, AB; Holtzhausen, A; Hanks, BA
MLA Citation
Theivanthiran, Balamayoora, et al. “A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.J Clin Invest, vol. 130, no. 5, May 2020, pp. 2570–86. Pubmed, doi:10.1172/JCI133055.
URI
https://scholars.duke.edu/individual/pub1431106
PMID
32017708
Source
pubmed
Published In
J Clin Invest
Volume
130
Published Date
Start Page
2570
End Page
2586
DOI
10.1172/JCI133055