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:

Immune Checkpoint Combinations with Inflammatory Pathway Modulators

Immune checkpoint inhibition of program death protein-1 (PD-1) and its ligands PD-L1 and PD-L2 is an established therapeutic modality in melanoma, non-small cell lung cancer, renal cell carcinoma, and other tumor types. Unfortunately, 60 to 80% of all patients experience disease progression and become refractory to immune checkpoint therapies. Broadly, mechanisms of immune checkpoint inhibitor resistance can be categorized as presence of oncogenic driver mutations, severe T cell exhaustion, neoantigen burden, epigenetic alterations, or mutations involved in critical pathways including PTEN, JAK, or Wnt signaling. The dysregulation of inflammatory signaling pathways (namely, genes involved in angiogenesis, chemotaxis, matrix remodeling, wound healing, and mesenchymal transition) is of critical importance to response to immune checkpoint therapies. Inflammatory cytokine signaling pathways exert downstream effects on immunosuppressive elements such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) which inhibit the function of effector T cells, NK cells, and dendritic cells, promoting immune tolerance and tumor growth. We herein review three targets for inflammatory pathway modulation: indoleamine 2,3-dioxygenase (IDO), transforming growth factor β (TGFβ), and adenosine. Targeting these pathways may address the unmet need to develop novel therapeutic approaches to increase response rates to immune checkpoint inhibitors and improve clinical outcomes.
MLA Citation
DeVito, N., et al. “Immune Checkpoint Combinations with Inflammatory Pathway Modulators.” Current Cancer Research, 2018, pp. 219–41. Scopus, doi:10.1007/978-3-319-63757-0_8.
URI
https://scholars.duke.edu/individual/pub1494214
Source
scopus
Published Date
Start Page
219
End Page
241
DOI
10.1007/978-3-319-63757-0_8

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.

The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.
Authors
Theivanthiran, B; Haykal, T; Cao, L; Holtzhausen, A; Plebanek, M; DeVito, NC; Hanks, BA
MLA Citation
Theivanthiran, Balamayooran, et al. “Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.Cancers (Basel), vol. 13, no. 19, Sept. 2021. Pubmed, doi:10.3390/cancers13194753.
URI
https://scholars.duke.edu/individual/pub1497259
PMID
34638239
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13194753

A case report of microsatellite instability (MSI)-high, <i>HER2</i> 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 <i>HER2</i> 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, <i>HER2</i> 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 Reports, vol. 5, Jan. 2021, p. 14. Epmc, doi:10.21037/acr-20-154.
URI
https://scholars.duke.edu/individual/pub1481212
PMID
33912803
Source
epmc
Published In
Ame Case Reports
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 Reports, vol. 35, no. 5, May 2021, p. 109071. Epmc, doi:10.1016/j.celrep.2021.109071.
URI
https://scholars.duke.edu/individual/pub1470781
PMID
33951424
Source
epmc
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