HANKS LAB


Tumor Immunology and Immunotherapy

Image Credit: Alpine BioVentures

Mission

We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of checkpoint inhibitor and vaccine-based immunotherapies while also developing predictive biomarkers to better guide the management of cancer patients with these immunotherapy agents. While our work is focused on understanding the fundamental biochemical and metabolic pathways within the tumor microenvironment that are critical for driving immune evasion and resistance to our currently available immunotherapies, we constantly strive to translate these concepts into early phase clinical trial testing.

Research

Our work utilizes a variety of techniques and methodologies than span the breadth of basic biological research including qrt-PCR, RNAseq, multi-parameter flow symmetry, a variety of in-cell reporter assays, tandem mass spectrometry secretome analysis, as well as a variety of computational approaches to investigate murine and human genetic databases. Our work also includes a substantial effort in 1) transgenic mouse tumor studies that utilizes bioluminescence imaging with plans to move into micro-CT imaging and 2) patient-derived circulating tumor cell single cell qrt-PCR studies to assess tumor-dependent genetic alterations that occur in patients undergoing active immunotherapy.

Our current projects include:

  1. Elucidating mechanisms of tumor-induced dendritic cell tolerization and immune suppression
    1. Investigating cancer-mediated paracrine signaling pathways and cancer-derived exosome-dependent pathways that functionally tolerize dendritic cells within the tumor microenvironment.
    2. Understanding the metabolic shifts of dendritic cells within the tumor microenvironment that enable the development of regulatory T cells.
    3. Characterizing novel pathways of regulating indoleamine 2,3-dioxygenase enzyme activity in the cancer microenvironment
  2. Investigating mechanisms of immunotherapy resistance in melanoma, non-small cell lung cancer, and colon cancer based on both transgenic model systems as well as clinic specimens derived from ongoing clinical trial protocols.
  3. Understanding the role of cancer-associated fibroblasts in the generation of an immunotolerant tumor microenvironment.
  4. Development of novel dendritic cell-based cancer vaccine and oncolytic virus immunotherapy strategies.




Lab Updates

  • thumb_upThe Hanks Lab receives a two year award from Merck

    The Hanks Lab receives a 2 year award from Merck to investigate novel biomarkers of immunotherapy resistance in advanced melanoma. Please see the following link: http://www.dukecancerinstitute.org/news/hanks-team-awarded-500000-study-immunotherapy-resistance

  • whatshotDr. DeVito has been awarded a 2017 ASCO Conquer Cancer Foundation Young Investigator Award

    Dr. DeVito was awarded the 2017 American Society Clinical Oncology (ASCO) Conquer Cancer Foundation Young Investigator Award for his ongoing work investigating the role of oncogenic signaling pathways in the immune tolerization of the melanoma microenvironment. Dr. DeVito will receive this one year award during a ceremony at the 2017 ASCO Annual Meeting in Chicago in early June.

  • thumb_upThe Hanks Lab receives a two year 2017 Pilot Award from the Melanoma Research Alliance

    The Hanks Lab has been awarded a two year award to continue their investigation into mechanisms of checkpoint inhibitor resistance in pre-clinical transgenic models of melanoma.

  • whatshotDr. DeVito receives the 2017 2nd Year Hem/Onc Fellows Research Presentation Award

    Dr. DeVito was awarded the 2nd Year Fellows Research Presentation Award for his talk ‘Inhibiting Paracrine Wnt-Beta-catenin Signaling to Augment the Efficacy of Anti-PD-1 Antibody Immunotherapy in Melanoma’ at the 2017 Annual Hematology/Oncology Fellows Research Retreat!

  • whatshotDr. Hanks receives Duke Health Scholars Award

    Dr. Hanks was recently awarded the Duke Health Scholars Award from the Duke University Health System for his work in understanding the mechanisms of tumor-mediated immune evasion and immunotherapy resistance.

  • trending_upBala Theivanthiran, Ph.D. joins the Hanks Lab

    Bala recently completed his training at the Baylor Institute for Immunology where he developed expertise in studying signaling pathways involved in innate immunity. He will be working on investigating pathways involved in tumor immunotherapy resistance while also developing novel dendritic cell-based vaccine strategies.

  • trending_upNick DeVito M.D. joins the Hanks Lab

    Nick DeVito recently completed his first year of clinical training in the Duke Hematology/Oncology Fellowship program. He has a longstanding interest in tumor immunology and will be focused on studying Wnt paracrine signaling in the tumor immune microenvironment.

  • whatshotDr. Hanks receives ACGT Young Investigator Award

    Dr. Hanks was recently awarded the 2016 Alliance for Cancer Gene Therapy Young Investigator Award for his novel approach for re-engineering dendritic cell-based cancer vaccines. This was developed based on Dr. Fei Zhao’s basic research efforts and will be conducted in collaboration with Dr. Smita Nair.

  • whatshotDr. Zhao receives Duke Cancer Institute Award

    Dr. Fei Zhao was selected as one of eight up-and-coming scientists at the recent third annual DCI Scientific Retreat where he presented his work on tumor-mediated reprogramming of dendritic cell metabolism as a mechanism of immune evasion.

  • trending_upChristine Xiao joins the Hanks Lab

    Christine Xiao B.S. joins the lab as a Research Technician II investigating novel combinatorial immunotherapy strategies.

  • local_atmNew Funding

    Brent Hanks was awarded a NIH K08 grant for investigating tumor-mediated immune evasion mechanisms and a grant from Merck for studying immunotherapy resistance.

  • trending_upFei Zhao Ph.D. joins the Hanks Lab

    Dr. Fei Zhao recently completed his graduate work in Dr. Walter Klimecki's lab at the University of Arizona where he investigated arsenite induction of HIF-1A mediated aerobic glycolysis and the role of metabolism shift during malignant transformation in a human lung epithelial model. Fei will be focusing his post-doctoral research on dendritic cell metabolism in the tumor microenvironment.

  • whatshot Dr. Hanks was awarded the Duke-MRA Young Investigator Award

    Dr. Hanks was awarded the Duke-MRA Young Investigator Award in Honor of Frank Courtney. The Melanoma Research Alliance awards grants to promising young faculty in an effort to support early career development.

Lab Members

Brent Hanks, M.D., Ph.D.

Principal Investigator

Kathy Evans, BS

Lab Manager

Fei Zhao, Ph.D.

Post-doctoral Associate

Christine Xiao, BS

Research Technician II

Nicholas DeVito, M.D.

Hematology/Oncology Fellow

Bala Theivanthiran, Ph.D.

Post-doctoral Associate

Nick Jerles

Undergraduate Researcher

Publications

Paracrine Wnt5a-b-catenin Signaling Triggers a Metabolic Program That Drives Dendritic Cell Tolerization.
Zhao, F., Xiao, C., Evans, K., Theivanthiran, T., DeVito, N., Holtzhausen, A., Liu, J., Liu, X., Boczkowski, D., Nair, S., Locasale, J.W., and Hanks, B.A.
Immunity. In press.

Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy.
Gnjatic, S., Bronte, V., Brunet, L.R.; Butler, M.O., Disis, M., Galon, J., Hakansson, L.G., Hanks, B.A., Karanikas, V., Khleif, S., Kirkwood, J.M., Miller, L.D., Schendel, D.J., Tanneau, I., Wigginton, J.M., and Butterfield, L.
(2017) J ImmunoTherapy of Cancer. 5:44 PMID: 28515944

Genetic Risk Analysis of a Patient with Fulminant Autoimmune Type I Diabetes Mellitus Secondary to Combination Ipilimumab/Nivolumab Immunotherapy.
Lowe, J.R., Perry, D.J., Salama, A.K., Mathews, C.E., Moss, L.G. and Hanks, B.A.
(2016) J ImmunoTherapy of Cancer. 4:89. PMID: 28031819.

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated with Ipilimumab.
Qin, R., Olson, A., Singh, B., Thomas, S., Wolf, S., Bhavsar, N.A., Hanks, B.A., Salama, J.K., Salama, A.K.
(2016) Int J Radiat Oncol Biol Phys. 96(1): 72-77. PMID: 27375168.

Immune Evasion Pathways and the Design of Dendritic Cell-based Cancer Vaccines.
Hanks B.A.
(2016) Discov Med. 21(114):135-142. PMID: 27011049.

Melanoma-derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
Holtzhausen A., Zhao F., Evans K., Tsutsui M., Orabona C., Tyler D.S. and Hanks B.A.
(2015) Cancer Immunol. Res. 3(9):1082-95. doi: 10.1158/2326-6066.CIR-14-0167. Epub 2015 Jun 3. PMID: 26041736.

Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis.
Bostwick A., Salama A. and Hanks B.A.
(2015) J Immunother Cancer 3:19. doi: 10.1186/s40425-015-0064-2. eCollection 2015. PMID: 25992290.

Early Carcinogenesis Involves the Establishment of Immune Privilege via Intrinsic and Extrinsic Regulation of Indoleamine 2,3-dioxygenase-1: Translational Implications in Cancer Immunotherapy.
Holtzhausen A., Zhao F., Evans K.S. and Hanks B.A.
(2014) Front Immunol. 5:438. doi: 10.3389/fimmu.2014.00438. eCollection 2014. PMID: 25339948.

Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma.
Jiang B.S., Beasley G.M., Speicher P.J., Mosca P.J., Morse M.A., Hanks B.A., Salama A. and Tyler D.S.
(2014) Ann Surg Oncol. doi: 10.1245/s10434-014-3671-0. Epub 2014 Apr 4. PMID: 24700302.

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.
Hanks B.A., Holtzhausen A., Evans K., Jamieson R., Gimpel P., Campbell O.M., Hector-Greene M., Sun L., Tewari A., George A., Starr M., Nixon, Augustine C., Beasley G., Tyler D.S., Osada T., Morse M.A., Ling L., Lyerly H.K., and Blobe G.C.
(2013) J Clin Invest. doi:10.1172/JCI65745. Epub 2013 Aug 8. PMID: 23925295.

Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma.
Morse M.A., Hanks B.A., Suhocki P., Doan P.L., Liu E.A., Frost P., Bernard S.A., Tsai A., Moore D.T., O’Neil B.H.
(2012) Clin Colorectal Cancer. 11(3):185-90. doi: 10.1016/j.clcc.2011.11.003. Epub 2012 Jan 26. PMID: 22280845.

Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response.
Hanks B.A., Morse M.A.
(2010) Curr Opin Investig Drugs. 11(12):1342-53. PMID: 21154116.

Enhanced activation of human dendritic cells by inducible CD40 and Toll-like receptor-4 ligation.
Lapteva N., Seethammagari M.R., Hanks B.A., Jiang J., Levitt J.M., Slawin K.M., Spencer D.M.
(2007) Cancer Res. 67(21):10528-37. PMID: 17974997.

Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo.
Hanks B.A., Jiang J., Singh R.A., Song W., Barry M., Huls M.H., Slawin K.M., Spencer D.M.
(2005) Nat Med. 11(2):130-7. Epub 2005 Jan 23. PMID: 15665830.

Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: implications for cytokine receptor signaling.
Soman K.V., Hanks B.A., Tien H., Chari M.V., O’Neal K.D., Morrisett J.D.
(1997) Protein Sci. 6(5):999-1008. PMID: 9144770.

Comparison of the functional differences for the homologous residues within the carboxy phosphate and carbamate domains of carbamoyl phosphate synthetase.
Javid-Majd F., Stapleton M.A., Harmon M.F., Hanks B.A., Mullins L.S., Raushel F.M.
(1996) Biochemistry. 35(45):14362-9. PMID: 8916923.

Role of conserved residues within the carboxy phosphate domain of carbamoyl phosphate synthetase.
Stapleton M.A., Javid-Majd F., Harmon M.F., Hanks B.A., Grahmann J.L., Mullins L.S., Raushel F.M.
(1996) Biochemistry. 35(45):14352-61. PMID: 8916922.

Meeting Abstracts and Presentations

A HSP-TLR-Wnt5a Paracrine Signaling Axis Drives CXCR2 Ligand Recruitment of Myeloid-derived Suppressor Cells and Represents a Novel Adaptive Resistance Mechanism to Anti-PD-1 Antibody Therapy.
Theivanthiran, B., DeVito, N., Evans, K., Zhao, F., Xiao, C., Goldschmidt, B., Edgar, R., Holtzhausen, A., Salama, A., Lewicki, J., Strickler, J., Viator, J., and Hanks, B.
(2017) Journal for Immunotherapy of Cancer. 5(Suppl 2): P385. In Press. Poster Presentation. Washington, DC.

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.
DeVito, N., Xiao, C., Zhao, F., Evans, K., Theivanthiran, T., Lewicki, J., Hoey, T., Hurwitz, H., Strickler, J., and Hanks, B.
(2017) Journal of Clinical Oncology. 35: (suppl; abstract 3053). Poster Presentation. Chicago, IL.

Utilizing Pre-Clinical Melanoma Models to Design Rational Combinatorial Immunotherapy Regimens Lessons Learned from Targeting the TGF-β Signaling Pathway.
Hanks, B.A.
(2017) Melanoma Research Alliance Annual Meeting. Oral Presentation. Washington, DC.

How to Integrate Immunotherapy into Your Clinical Practice. The Immune System and Cancer: Mechanisms of Immune Suppression.
Hanks, B.A.
(2017) ASCO-SITC Joint Conference. Oral Presentation. Chicago, IL.

Paracrine Wnt5a-β-catenin Signaling Triggers a Metabolic Switch that Drives Dendritic Cell Tolerization and Indoleamine 2,3-dioxygenase Enzymatic Activity in the Melanoma Microenvironment.
Zhao, F., Xiao, C., Evans, K., Holtzhausen, A., Boczkowski, D., Nair, S., and Hanks, B.
(2016) Journal for ImmunoTherapy of Cancer. 4(Suppl 1): O11. Oral Presentation. Washington, DC.

Increased immune responses in melanoma patients pre-treated with CDX-301, a recombinant human Flt3 ligand, prior to vaccination with CDX-1401, a dendritic cell targeting NY-ESO-1 vaccine, in a phase II study.
Bhardwaj, N., Friedlander, P., Pavlick, A., Ernstoff, M., Gastman, B., Hanks, B.A., Albertini, M., Luke, J., Keler, T., Davis, T., Vitale, L.A., Sharon, S., Danaher, P., Morishima, C., Cheever, M., and Fling, S.
(2016) Journal for ImmunoTherapy of Cancer. 4(Suppl 1):P166. Poster Presentation. Washington, DC.

Stromal fibroblasts promote Wnt5a expression and suppress responses to anti-PD-1 antibody therapy in an autochthonous melanoma model.
Zhao, F., Evans, K., Xiao, C., Holtzhausen, A., and Hanks, B.A.
(2016) Journal for ImmunoTherapy of Cancer. 4(Suppl 1):P383. Poster Presentation. Washington, DC.

A Phase II Randomized Study of CDX-1401, a Dendritic Cell Targeting NY-ESO-1 Vaccine, in Patients with Malignant Melanoma Pre-Treated with Recombinant CDX-301, a Recombinant Human Flt3 Ligand.
Bhardwaj, N., Pavlick, A., Ernstoff, M., Curti, B., Hanks, B., Albertini, M., Luke, J., Yellin, M., Keler, T., Davis, T., Vitale, L., Crocker, A., Friedlander, P., Morishima, C., Cheever, M., and Fling, S.
(2016) Journal of Clinical Oncology. 34: (suppl; abstr 9589). Poster Presentation. Chicago, IL.

Tumor-mediated Metabolic Re-Programing of Dendritic Cells as a Fundamental Mechanism of Immune Tolerance and Immunotherapy Resistance.
Zhao, F., Evans, K., Xiao, C. and Hanks, B.A.
(2016) Keystone Symposium: Immunometabolism. Banff, Alberta, Canada.

Targeting the Wnt5a-β-catenin pathway in the melanoma microenvironment to augment checkpoint inhibitor immunotherapy.
Zhao, F., Evans, K., Holtzhausen, A. Tsutsui, M. Tyler, D.S., and Hanks, B.A.
(2015) Journal of Clinical Oncology. 33 (suppl; abstr 3054).

Melanoma-derived Wnt5a conditions dendritic cells to promote regulatory T cell differentiation via the upregulation of indoleamine 2,3-dioxygenase: novel pharmacological strategies for augmenting immunotherapy efficacy.
Holtzhausen, A., Zhao, F. Evans, K., Orabona, C., Hanks, B.
(2014) Journal for ImmunoTherapy of Cancer. 2(Suppl 3):P209 (6 November 2014).

Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma.
Holtzhausen, A., Evans, K., Siska, P., Rathmell, J., and Hanks, B.
(2014) Journal of Clinical Oncology. 32:5s. (suppl; abstr 3011).

Role of the Wnt-β-catenin Signaling Pathway in Melanoma-mediated Dendritic Cell Tolerization.
Holtzhausen, A., Evans, K., and Hanks, B.
(2013) Journal for ImmunoTherapy of Cancer.1: 153. (suppl 1).

Effect of the loss of the type III TGFβ receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ-related biomarkers to enhance immunotherapy efficacy.
Hanks, B.A., Holtzhausen, A., Gimpel, P, Jamieson, P. Campbell, O., Sun, L., Augustine, C.K., Tyler, T.S., Osada, T., Morse, M., Ling, L.E., Lyerly, H.K. and Blobe, G.C.;
(2012) Journal of Clinical Oncology. 30. (suppl; abstr 10563).