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:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Assistant Professor in Immunology

Immunology
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

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

Investigating the adaptive immune response to dormant tumor cells

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:

Cancer vaccine strategies using self-replicating RNA viral platforms.

The development and success of RNA-based vaccines targeting SARS-CoV-2 has awakened new interest in utilizing RNA vaccines against cancer, particularly in the emerging use of self-replicating RNA (srRNA) viral vaccine platforms. These vaccines are based on different single-stranded RNA viruses, which encode RNA for target antigens in addition to replication genes that are capable of massively amplifying RNA messages after infection. The encoded replicase genes also stimulate innate immunity, making srRNA vectors ideal candidates for anti-tumor vaccination. In this review, we summarize different types of srRNA platforms that have emerged and review evidence for their efficacy in provoking anti-tumor immunity to different antigens. These srRNA platforms encompass the use of naked RNA, DNA-launched replicons, viral replicon particles (VRP), and most recently, synthetic srRNA replicon particles. Across these platforms, studies have demonstrated srRNA vaccine platforms to be potent inducers of anti-tumor immunity, which can be enhanced by homologous vaccine boosting and combining with chemotherapies, radiation, and immune checkpoint inhibition. As such, while this remains an active area of research, the past and present trajectory of srRNA vaccine development suggests immense potential for this platform in producing effective cancer vaccines.
Authors
Dailey, GP; Crosby, EJ; Hartman, ZC
MLA Citation
Dailey, Gabrielle P., et al. “Cancer vaccine strategies using self-replicating RNA viral platforms.Cancer Gene Ther, July 2022. Pubmed, doi:10.1038/s41417-022-00499-6.
URI
https://scholars.duke.edu/individual/pub1526278
PMID
35821284
Source
pubmed
Published In
Cancer Gene Ther
Published Date
DOI
10.1038/s41417-022-00499-6

Trastuzumab/pertuzumab combination therapy stimulates antitumor responses through complement-dependent cytotoxicity and phagocytosis.

Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.
Authors
Tsao, L-C; Crosby, EJ; Trotter, TN; Wei, J; Wang, T; Yang, X; Summers, AN; Lei, G; Rabiola, CA; Chodosh, LA; Muller, WJ; Lyerly, HK; Hartman, ZC
MLA Citation
Tsao, Li-Chung, et al. “Trastuzumab/pertuzumab combination therapy stimulates antitumor responses through complement-dependent cytotoxicity and phagocytosis.Jci Insight, vol. 7, no. 6, Mar. 2022. Pubmed, doi:10.1172/jci.insight.155636.
URI
https://scholars.duke.edu/individual/pub1510788
PMID
35167491
Source
pubmed
Published In
Jci Insight
Volume
7
Published Date
DOI
10.1172/jci.insight.155636

Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.

BACKGROUND: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. METHODS: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. RESULTS: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. CONCLUSION: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.
Authors
Hwang, B-J; Tsao, L-C; Acharya, CR; Trotter, T; Agarwal, P; Wei, J; Wang, T; Yang, X-Y; Lei, G; Osada, T; Lyerly, HK; Morse, MA; Hartman, ZC
MLA Citation
Hwang, Bin-Jin, et al. “Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.J Immunother Cancer, vol. 10, no. 3, Mar. 2022. Pubmed, doi:10.1136/jitc-2021-003721.
URI
https://scholars.duke.edu/individual/pub1515355
PMID
35361727
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
10
Published Date
DOI
10.1136/jitc-2021-003721

HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.

A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes. In a phase I human study, systemically administered HS196 could be detected in malignant nodules within prostatectomy specimens. Single-cell RNA sequencing identified uptake of HS196 by malignant prostate epithelium from the peripheral zone (AMACR+ERG+EPCAM+ cells), including SYP+ neuroendocrine cells that are associated with therapeutic resistance and metastatic progression. A theranostic version of this molecule is under clinical testing.
Authors
Osada, T; Crosby, EJ; Kaneko, K; Snyder, JC; Ginzel, JD; Acharya, CR; Yang, X-Y; Polascik, TJ; Spasojevic, I; Nelson, RC; Hobeika, A; Hartman, ZC; Neckers, LM; Rogatko, A; Hughes, PF; Huang, J; Morse, MA; Haystead, T; Lyerly, HK
MLA Citation
Osada, Takuya, et al. “HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.Mol Cancer Ther, vol. 21, no. 1, Jan. 2022, pp. 217–26. Pubmed, doi:10.1158/1535-7163.MCT-21-0334.
URI
https://scholars.duke.edu/individual/pub1499234
PMID
34675120
Source
pubmed
Published In
Mol Cancer Ther
Volume
21
Published Date
Start Page
217
End Page
226
DOI
10.1158/1535-7163.MCT-21-0334

How can we create precision immunotherapy as standard in breast cancer?

Authors
MLA Citation
Hartman, Zachary C. “How can we create precision immunotherapy as standard in breast cancer?Expert Rev Anticancer Ther, vol. 21, no. 11, Nov. 2021, pp. 1179–81. Pubmed, doi:10.1080/14737140.2021.1951241.
URI
https://scholars.duke.edu/individual/pub1488189
PMID
34213990
Source
pubmed
Published In
Expert Rev Anticancer Ther
Volume
21
Published Date
Start Page
1179
End Page
1181
DOI
10.1080/14737140.2021.1951241