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 in 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

Administered By
Surgery, Surgical Sciences
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

Administered By
Surgery, Surgical Sciences
Awarded By
Bantam Pharmaceutical, LLC
Role
Principal Investigator
Start Date
End Date

Investigating the adaptive immune response to dormant tumor cells

Administered By
Surgery, Surgical Sciences
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Investigation of LAMP anti-tumor vaccines

Administered By
Surgery, Surgical Sciences
Awarded By
Immunomic Therapeutics, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

Progesterone promotes immunomodulation and tumor development in the murine mammary gland.

BACKGROUND: Clinical studies have linked usage of progestins (synthetic progesterone [P4]) to breast cancer risk. However, little is understood regarding the role of native P4, signaling through the progesterone receptor (PR), in breast tumor formation. Recently, we reported a link between PR and immune signaling pathways, showing that P4/PR can repress type I interferon signaling pathways. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland and promote tumor formation. METHODS: To determine the effect of P4 on immune cell populations in the murine mammary gland, mice were treated with P4 or placebo pellets for 21 days. Immune cell populations in the mammary gland, spleen, and inguinal lymph nodes were subsequently analyzed by flow cytometry. To assess the effect of PR overexpression on mammary gland tumor development as well as immune cell populations in the mammary gland, a transgenic mouse model was used in which PR was overexpressed throughout the entire mouse. Immune cell populations were assessed in the mammary glands, spleens, and inguinal lymph nodes of 6-month-old transgenic and control mice by flow cytometry. Transgenic mice were also monitored for mammary gland tumor development over a 2-year time span. Following development of mammary gland tumors, immune cell populations in the tumors and spleens of transgenic and control mice were analyzed by flow cytometry. RESULTS: We found that mice treated with P4 exhibited changes in the mammary gland indicative of an inhibited immune response compared with placebo-treated mice. Furthermore, transgenic mice with PR overexpression demonstrated decreased numbers of immune cell populations in their mammary glands, lymph nodes, and spleens. On long-term monitoring, we determined that multiparous PR-overexpressing mice developed significantly more mammary gland tumors than control mice. Additionally, tumors from PR-overexpressing mice contained fewer infiltrating immune cells. Finally, RNA sequencing analysis of tumor samples revealed that immune-related gene signatures were lower in tumors from PR-overexpressing mice as compared with control mice. CONCLUSION: Together, these findings offer a novel mechanism of P4-driven mammary gland tumor development and provide rationale in investigating the usage of antiprogestin therapies to promote immune-mediated elimination of mammary gland tumors.
Authors
Werner, LR; Gibson, KA; Goodman, ML; Helm, DE; Walter, KR; Holloran, SM; Trinca, GM; Hastings, RC; Yang, HH; Hu, Y; Wei, J; Lei, G; Yang, X-Y; Madan, R; Molinolo, AA; Markiewicz, MA; Chalise, P; Axelrod, ML; Balko, JM; Hunter, KW; Hartman, ZC; Lange, CA; Hagan, CR
MLA Citation
Werner, Lauryn R., et al. “Progesterone promotes immunomodulation and tumor development in the murine mammary gland.J Immunother Cancer, vol. 9, no. 5, May 2021. Pubmed, doi:10.1136/jitc-2020-001710.
URI
https://scholars.duke.edu/individual/pub1482287
PMID
33958486
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
9
Published Date
DOI
10.1136/jitc-2020-001710

Abstract 904: Stimulation and expansion of oncogene-reactive tumor infiltrating T cells through combined Ad-HER2Δ16 vaccination and anti-PD1 enable anti-tumor responses against established HER2 BC

Authors
Crosby, EJ; Acharya, C; Rabiola, C; Muller, WJ; Chodosh, LA; Broadwater, G; Shepherd, J; Hollern, D; He, X; Perou, CM; Ashby, BK; Vincent, BG; Morse, MA; Lyerly, HK; Hartman, ZC
MLA Citation
Crosby, Erika J., et al. “Abstract 904: Stimulation and expansion of oncogene-reactive tumor infiltrating T cells through combined Ad-HER2Δ16 vaccination and anti-PD1 enable anti-tumor responses against established HER2 BC.” Immunology, American Association for Cancer Research, 2020. Crossref, doi:10.1158/1538-7445.am2020-904.
URI
https://scholars.duke.edu/individual/pub1475565
Source
crossref
Published In
Immunology
Published Date
DOI
10.1158/1538-7445.am2020-904

Cancer vaccines: the importance of targeting oncogenic drivers and the utility of combinations with immune checkpoint inhibitors.

Authors
Crosby, EJ; Lyerly, HK; Hartman, ZC
MLA Citation
Crosby, Erika J., et al. “Cancer vaccines: the importance of targeting oncogenic drivers and the utility of combinations with immune checkpoint inhibitors.Oncotarget, vol. 12, no. 1, Jan. 2021, pp. 1–3. Pubmed, doi:10.18632/oncotarget.27861.
URI
https://scholars.duke.edu/individual/pub1472581
PMID
33456706
Source
pubmed
Published In
Oncotarget
Volume
12
Published Date
Start Page
1
End Page
3
DOI
10.18632/oncotarget.27861

Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.

BACKGROUND: There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer. METHODS: OS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity. RESULTS: Among the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9-7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +TEM (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+TCM cells were increased. CONCLUSIONS: VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.
Authors
Crosby, EJ; Hobeika, AC; Niedzwiecki, D; Rushing, C; Hsu, D; Berglund, P; Smith, J; Osada, T; Gwin Iii, WR; Hartman, ZC; Morse, MA; Lyerly, HK
MLA Citation
Crosby, Erika J., et al. “Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.J Immunother Cancer, vol. 8, no. 2, Nov. 2020. Pubmed, doi:10.1136/jitc-2020-001662.
URI
https://scholars.duke.edu/individual/pub1464810
PMID
33177177
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
8
Published Date
DOI
10.1136/jitc-2020-001662

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.Clin Cancer Res, vol. 26, no. 17, Sept. 2020, pp. 4670–81. Pubmed, doi:10.1158/1078-0432.CCR-20-0389.
URI
https://scholars.duke.edu/individual/pub1453955
PMID
32732224
Source
pubmed
Published In
Clinical Cancer Research
Volume
26
Published Date
Start Page
4670
End Page
4681
DOI
10.1158/1078-0432.CCR-20-0389