Zachary Hartman

Overview:

My research interests encompass studies of immunity and inflammation in the context of developing and established cancers. These research interests involve studies of inflammation in the genesis and maintenance of specific cancer types (principally breast and ovarian), as well as the impact of inflammation on tumor metastasis and the tumor microenvironment.  My group is also involved in strategies to modulate the immune response to tumors, which involves the use of novel immunotherapeutic strategies and development of vaccines to specific oncogenic targets.  The major focus of my lab is in uncovering strategies to modulate tumor-derived inflammation and tumor-specific immunity that will translate into clinically efficacious therapies in patients.

Positions:

Assistant Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2006

Duke University

Post-Doctoral Fellow

Duke University

Post Doctoral Fellow, Md Anderson Cancer Center

University of Texas Medical School, Houston

Grants:

A Neoepitope Subunit Vaccine Targeting the Mutated Estrogen Receptor Ligand Binding Domain to Treat and Prevent Endocrine Resistant ER+ Breast Cancer

Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Study of LAMP Vaccines in HER2+ Breast Cancer

Awarded By
Immunomic Therapeutics, Inc.
Role
Principal Investigator
Start Date
End Date

Investigation of stimulating stress response mechanisms to enhance antibody dependent cellular phagocytosis

Awarded By
Bantam Pharmaceutical, LLC
Role
Principal Investigator
Start Date
End Date

Publications:

Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.

PURPOSE:Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. EXPERIMENTAL DESIGN:Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination. RESULTS:We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. CONCLUSIONS:Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
Authors
Crosby, EJ; Acharya, CR; Haddad, A-F; Rabiola, CA; Lei, G; Wei, J-P; Yang, X-Y; Wang, T; Liu, C-X; Wagner, KU; Muller, WJ; Chodosh, LA; Broadwater, G; Hyslop, T; Shepherd, JH; Hollern, DP; He, X; Perou, CM; Chai, S; Ashby, BK; Vincent, BG; Snyder, JC; Force, J; Morse, MA; Lyerly, HK; Hartman, ZC
MLA Citation
Crosby, Erika J., et al. “Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, July 2020. Epmc, doi:10.1158/1078-0432.ccr-20-0389.
URI
https://scholars.duke.edu/individual/pub1453955
PMID
32732224
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Published Date
DOI
10.1158/1078-0432.ccr-20-0389

HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression.

BACKGROUND: The advent of immune checkpoint blockade antibodies has demonstrated that effective mobilization of T cell responses can cause tumor regression of metastatic cancers, although these responses are heterogeneous and restricted to certain histologic types of cancer. To enhance these responses, there has been renewed emphasis in developing effective cancer-specific vaccines to stimulate and direct T cell immunity to important oncologic targets, such as the oncogene human epidermal growth factor receptor 2 (HER2), expressed in ~20% of breast cancers (BCs). METHODS: In our study, we explored the use of alternative antigen trafficking through use of a lysosome-associated membrane protein 1 (LAMP) domain to enhance vaccine efficacy against HER2 and other model antigens in both in vitro and in vivo studies. RESULTS: We found that inclusion of this domain in plasmid vaccines effectively trafficked antigens to endolysosomal compartments, resulting in enhanced major histocompatibility complex (MHC) class I and II presentation. Additionally, this augmented the expansion/activation of antigen-specific CD4+ and CD8+ T cells and also led to elevated levels of antigen-specific polyfunctional CD8+ T cells. Significantly, vaccination with HER2-LAMP produced tumor regression in ~30% of vaccinated mice with established tumors in an endogenous model of metastatic HER2+ BC, compared with 0% of HER2-WT vaccinated mice. This therapeutic benefit is associated with enhanced tumor infiltration of activated CD4+ and CD8+ T cells. CONCLUSIONS: These data demonstrate the potential of using LAMP-based endolysosomal trafficking as a means to augment the generation of polyfunctional, antigen-specific T cells in order to improve antitumor therapeutic responses using cancer antigen vaccines.
Authors
Chen, AC; Xu, R; Wang, T; Wei, J; Yang, X-Y; Liu, C-X; Lei, G; Lyerly, HK; Heiland, T; Hartman, ZC
MLA Citation
Chen, Alan Chen, et al. “HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression.J Immunother Cancer, vol. 8, no. 1, June 2020. Pubmed, doi:10.1136/jitc-2019-000258.
URI
https://scholars.duke.edu/individual/pub1447972
PMID
32532838
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
8
Published Date
DOI
10.1136/jitc-2019-000258

Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.

Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells.
Authors
Mazumdar, A; Poage, GM; Shepherd, J; Tsimelzon, A; Hartman, ZC; Den Hollander, P; Hill, J; Zhang, Y; Chang, J; Hilsenbeck, SG; Fuqua, S; Kent Osborne, C; Mills, GB; Brown, PH
MLA Citation
Mazumdar, Abhijit, et al. “Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.Breast Cancer Res Treat, vol. 158, no. 3, Aug. 2016, pp. 441–54. Pubmed, doi:10.1007/s10549-016-3892-y.
URI
https://scholars.duke.edu/individual/pub1167171
PMID
27393618
Source
pubmed
Published In
Breast Cancer Res Treat
Volume
158
Published Date
Start Page
441
End Page
454
DOI
10.1007/s10549-016-3892-y

Death-associated protein kinase 1 promotes growth of p53-mutant cancers.

Estrogen receptor-negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor-negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs. Specifically, we found that death-associated protein kinase 1 (DAPK1) is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs. Depletion or inhibition of DAPK1 suppressed growth of p53-mutant but not p53-WT breast cancer cells. Moreover, DAPK1 inhibition limited growth of other p53-mutant cancers, including pancreatic and ovarian cancers. DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mTOR/S6K pathway; evaluation of multiple breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers. Together, our data support targeting DAPK1 as a potential therapeutic strategy for p53-mutant cancers.
Authors
Zhao, J; Zhao, D; Poage, GM; Mazumdar, A; Zhang, Y; Hill, JL; Hartman, ZC; Savage, MI; Mills, GB; Brown, PH
MLA Citation
Zhao, Jing, et al. “Death-associated protein kinase 1 promotes growth of p53-mutant cancers.J Clin Invest, vol. 125, no. 7, July 2015, pp. 2707–20. Pubmed, doi:10.1172/JCI70805.
URI
https://scholars.duke.edu/individual/pub1081781
PMID
26075823
Source
pubmed
Published In
J Clin Invest
Volume
125
Published Date
Start Page
2707
End Page
2720
DOI
10.1172/JCI70805

Novel adenovirus vectors 'capsid-displaying' a human complement inhibitor.

Adenovirus (Ad) vectors are currently the most commonly utilized gene transfer vectors in humans worldwide. Unfortunately, upon contact with the circulatory system, Ads induce several, innate, complement-dependent toxicities that limit the full potential for Ad-based gene transfer applications. Therefore, we have constructed several novel Ad5-based vectors, 'capsid-displaying' as fiber or pIX fusion proteins, a complement-regulatory peptide (COMPinh). These novel Ads dramatically minimize Ad-dependent activation of the human and non-human primate complement systems, as determined by several assays. In summary, our work has shown that a novel COMPinh-displaying Ad5 has the potential for broadening the safe use of Ad vectors in future human applications.
Authors
Seregin, SS; Hartman, ZC; Appledorn, DM; Godbehere, S; Jiang, H; Frank, MM; Amalfitano, A
MLA Citation
Seregin, Sergey S., et al. “Novel adenovirus vectors 'capsid-displaying' a human complement inhibitor.J Innate Immun, vol. 2, no. 4, 2010, pp. 353–59. Pubmed, doi:10.1159/000284368.
URI
https://scholars.duke.edu/individual/pub771738
PMID
20375551
Source
pubmed
Published In
J Innate Immun
Volume
2
Published Date
Start Page
353
End Page
359
DOI
10.1159/000284368