The Caligiuri laboratory at The Ohio State University pursues basic science discovery with the immediate intent of creating impact in clinical medicine. Our laboratory is especially suited for the physician-scientist in training or the postdoctoral researcher interested in discovery for the sake of clinical application. Our research focuses on natural killer cell biology, the Epstein-Barr virus (EBV), lymphoma and leukemia. Since 1990, more than 100 students have trained in the Caligiuri laboratory and have received more than 70 awards for their research.

About the Lab

The laboratory of Michael A. Caligiuri, MD, began in 1990 at Roswell Park Cancer Institute (RPCI) when Dr. Caligiuri was a newly appointed assistant professor in internal medicine (oncology) and microbiology/immunology at RPCI and the State University of New York (SUNY) at Buffalo.

The Caligiuri laboratory moved to The Ohio State University (OSU) in July 1997. Fifteen members of Dr. Caligiuri's team at RPCI joined him at OSU, and since that time he has recruited additional  members into the laboratory. The laboratory, which is supervised by Donna Bucci, consists of investigators at the technical, undergraduate, graduate, postgraduate and assistant professor level. The laboratory is also the home for one of the world's largest leukemia tissue banks: the Alliance Hematologic Malignancy Biorepository (HEME). The laboratory also houses the OSU Leukemia Tissue Bank Shared Resource, which serves the Leukemia and hematologic malignancy research community both at OSU and at large.

Dr. Caligiuri's laboratory has evolved to investigate three main scientific areas:

  • The development and normal role of the body's large granular lymphocytes called natural killer cells, and to exploit their properties in order to develop effective therapies against cancer and immune deficiency;
  • The development of a vaccine to prevent lymphoma associated with the Epstein-Barr virus;
  • Why we get acute leukemia and how we should treat it. The lab has mouse models of acute leukemia as well as the world's largest bank of human leukemia cells to study the causes of acute leukemia and to develop novel immune therapies to treat acute leukemia. 

Lab Research

Acute Myeloid Leukemia:

In the era of personalized medicine, we are developing targeted drug combinations for acute myeloid leukemia (AML) patients harboring mutations in the H3K4 methyltransferase, MLL (myeloid/lymphoid or mixed lineage leukemia) and the receptor tyrosine kinase FLT3 (FMS-like tyrosine kinase 3).  Preclinical studies utilize a mouse model of acute myeloid leukemia that harbors these two genetic mutations. We are targeting the downstream effects of both mutations by testing the efficacy of epigenetic modifiers as well as tyrosine kinase inhibitors in drug trials. We hope to find a combinatorial effect that gives MLL-PTD (partial tandem duplication); FLT3-ITD patients a potentially better therapeutic outcome. Future experiments will address epigenetic changes that occur in response to the drugs with the goal of finding yet more therapeutic targets to help these patients survive longer and eventually be cured of cancer.

Additional areas of research in AML include studing of the role of the Axl/Gas6 pathway in the pathogenesis of this disease. The Axl/Gas6 pathway is a receptor tyrosine kinase (RTK) known to be involved in a variety of biological functions. As it was previously published, the Axl/Gas6 pathway is crucial for signaling of another RTK c-Kit, which is highly homologous to RTK FLT3.  As FLT3 is the most well-known prognostic marker for AML, my work has been to test the hypothesis that the Axl/Gas6 pathway may contribute to AML through regulating FLT3 and its biological functions. Current data has demonstrated that the Axl/Gas6 pathway promotes the growth and survival of leukemic cells and blocks myeloid differentiation. Furthermore, the Axl/Gas6 pathway is crucial for FLT3 signaling. Ongoing and future studies will test whether inhibiting the Axl/Gas6 pathway can suppress the occurrence of AML in vivo in a mouse leukemia model.

Natural Killer Cell Biology:

Research efforts are directed to define the molecular mechanisms regulating the immunoregulatory and cytotoxicity functions of natural killer (NK) cells and their subsets. To achieve this, we are currently the activatory and inhibitory pathways that regulate NK cell activity. We’ve discovered that the inositol-phosphatase SHIP-1 and the PP2A inhibitor SET gene are, respectively, a negative and a positive regulator of interferon gamma production, which is induced in NK cells by different monokines. We also have evidence that SET regulates NK cell cytotoxicity by effecting expression of granule components like the Granzyme B. In addition, we also investigated the role of anti-inflammatory cytokines TGF-β in regulating Fc receptor functions. We reported that the anti-inflammatory cytokine TGF-β utilizes SMAD3 to inhibit CD16-mediated IFN-γ production, antibody dependent cytotoxicity, granzyme B and perforin expression in NK cells. Based on these findings we are also investigating the role of microRNAs in the regulation of NK cell activation and/or development. The goal of my studies is to identify activatory and inhibitory molecules that can be used to enhance NK cell anti tumor activity.

EBV-Associated Disease:

EBV-associated post-transplant lymphoproliferative disorder (PTLD) is a common and often fatal malignancy in organ transplant patients. The incidence of PTLD has been shown to be directly related to a low frequency of EBV-specific cytotoxic T lymphocytes (CTLs) in patients receiving immunosuppressive therapy to prevent organ rejection. Using a chimeric mouse-human model of human PTLD and subsequently in PTLD patients, we have identified that the expression of an EBV lytic gene, BZLF1, plays an important role in controlling the development of PTLD.  We hypothesize that at least one component of the increased incidence of PTLD in this patient population is a cellular immune deficiency against EBV lytic and latent antigens. A corollary to this hypothesis is that vaccine-enhanced, EBV-specific immunity will restore the protection from this malignancy. We recently reported a novel strategy for vaccination against the EBV-associated PTLD using a chimeric rAdF35/BZLF1 viral vector or a highly purified EBV BZLF1 protein. Approximately 75 percent of normal human donor cells show a moderate to strong immune response to rAdF35/BZLF1 viral vector stimulation assayed by an IFN- ELISpot. Moreover, rAdF35BZLF1 viral vector-transduced dendritic cell vaccination greatly improves survival rates in a Hu-PBL-SCID animal model. We have cloned the lytic EBV BZLF1 protein into a prokaryotic vector expression cassette name pET26b+ system, expressed in E. Coli BL26 cells. From this system, large quantities of highly purified and endotoxin-free BZLF1 protein (>95 percent by SDS-PAGE) have been obtained by ion exchange and subsequent size column chromatography. We’ve shown that the highly purified BZLF1-loaded human antigen-presenting cells (APCs) can promote the expansion of the EBV BZLF1 specific memory CD8+ CTLs in vitro. We are evaluating the efficacy of highly purified BZLF1 protein-mediated vaccination in a chimeric mouse-human model of human PTLD.

Lab Mentoring

The Caligiuri lab is strongly committed to the mentoring of MD, MD-PhD and PhD students interested in basic discovery and translation into the clinic. We believe this theme of basic discovery and "translational" research is our strength, and we seek students and postdoctoral fellows interested in the career track.

Mentoring is at the heart of the Caligiuri laboratory. We judge our success by the quality and quantity of student publications, the success with grant applications, and the subsequent training and job opportunities that we are able to create for our students. We have worked very hard to place our students in the best clinical training programs. Students train in the laboratory for at least one year, and no graduate or postdoctoral student leaves our laboratory without having competed for a peer-reviewed federal grant. Many of these students are continuing their training at highly reputable institutions, while others are assistant or associate professors at institutions throughout the world. 

We gratefully acknowledge the kind and generous support of Mr. and Mrs. Richard Wells. Each summer since 1998, the Wells family has provided support for student research positions in our lab. The interns are undergraduate students, from universities across the United States, with a strong interest in pursuing graduate study in medicine or the biomedical sciences.

CCC Members

William Carson, III, MD

Dr. Carson is a surgical oncologist with clinical interests in breast cancer, melanoma and general cancer surgery. His primary research focus is the immunotherapy of tumors, which can be thought of as using drugs and other treatments to boost the human immune system's innate ability to fight tumor.

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Robert Wesolowski, MD

Dr. Wesolowski's research interests include breast cancer immunology, in particular myeloid-derived suppressor cells (MDSC) and early phase trials of experimental therapeutics. MDSC are important inhibitors of anti-tumor immune response.

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Researchers

Zhiwei Hu

Zhiwei Hu, MD/PhD

Zhiwei is a Research Associate Professor in Surgical Oncology at Ohio State. Dr. Hu is one of first few scientists who proposed to target both the tumor cells and tumor neovasculature.

Nicholas Latchana

Nicholas Latchana, MD

Nicholas is a part of the Masters of Medical Science Program, Surgical Resident, in the Carson lab. His research focus is on the role of MicroRNAs in melanoma.

Kala Levine

Kala Levine, BS

Kala is the laboratory manager and research assistant in the Carson lab. She enjoyed conducting biochemistry research during college and joined the Carson Lab to get back into academic research. She believes that Dr. Carson’s translational research is fascinating and necessary.

Joseph Markowitz

Joseph Markowitz, MD/PhD

Joseph is a Pelotonia Postdoctoral Fellow in the Carson lab. His research focus is on inhibiting immune suppressor cells in pancreatic cancer.

Prashant Trikha

Prashant Trikha, PhD

Prashant is a Senior Research Scientist in the Carson lab. The focus of his research is to investigate the role of signaling pathways that contribute to the expansion of immune cells in tumor microenvironment. Currently, he is investigating the role of signaling pathways that contribute to the expansion of immunosuppressive myeloid cells (MDSC) in the tumor stroma and understanding the molecular mechanisms that contribute to suppression of natural killer cell (NK) functions in cancer patients. Furthermore, he is conducting pre-clinical studies using immunotherapeutic agents (antibodies and cytokines) that can attenuate tumor growth by augmenting NK cell activity.

Students

Lakhvir Atwal

Lakhvir Atwal

Lakhvir is an Undergraduate Research Assistant is the Carson lab.

Megan Duggan

Megan Duggan, BS

Megan is part of the Biomedical Sciences Graduate Program at the Carson lab. Her current research involves the GTPase NRAS, its signaling pathways and its potential role in BRAF inhibitor-resistant melanoma.

Amanda Harper

Amanda Harper, BS

Amanda is part of the Medical Scientist Training Program in the Carson lab. As a MD/PhD trainee in the Carson laboratory, she is studying the role of natural killer (NK) cells in the immune response to cancer. In particular, she is interested in developing therapeutic strategies to promote NK cell activity in the setting of melanoma and triple negative breast cancer.

Vince Hsu

Vincent (Jyh-Haur) Hsu

Vincent is an Undergraduate Research Assistant is the Carson lab.

Liz McMichael

Elizabeth McMichael, BS

Elizabeth is a part of the Biomedical Sciences Graduate Program at the Carson lab. She is currently investigating the role of combination immunotherapy for the treatment of pancreatic cancer, the upregulation of the IL-21 receptor on natural killer (NK) cells following FcR stimulation, the role of MDSCs in melanoma, the creation of novel conjugate antibodies for the treatment of folate receptor positive cancers, looking at correlative studies for several clinical trials ongoing at Ohio State, and the role of “super” cytokines in combination with mAb therapy.

Tiffany Noel

Tiffany is an Undergraduate Research Assistant is the Carson lab.

Kallan Opheim

Kallan Opheim

Kallan is an Undergraduate Research Assistant is the Carson lab.

Nico Salavaggione

Nico Salavaggione

Nico is an Undergraduate Research Assistant is the Carson lab.

Andrew Stiff

Andrew Stiff, BS

Andrew is part of the Medical Scientist Training Program in the Carson lab. He is currently investigating cancer immunology with an emphasis on understanding mechanisms of tumor induced immune suppression. Through better understanding of these mechanisms, the goal is to be able to design more optimal immune based therapies for patients.

Sarvani Uppati

Sarvani Uppati

Sarvani is an Undergraduate Research Assistant is the Carson lab.


Publications

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Michael Caligiuri, MD

Michael Caligiuri

 

Michael A. Caligiuri, MD, is director of The Ohio State University Comprehensive Cancer Center, chief executive officer of Ohio State’s James Cancer Hospital and Solove Research Institute, and holder of the John L. Marakas Nationwide Insurance Enterprise Foundation Chair in Cancer Research. He also is a professor in the Department of Internal Medicine and in the Department of Molecular Virology, Immunology and Medical Genetics in Ohio State’s College of Medicine.

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