Skip to main content
Give
Edit Icon - Click to update your profileUpdate Your Profile

Curt I. Civin, MD

Philip A. Zaffere Distinguished Professor of Regenerative Medicine

Academic Title:

Professor

Primary Appointment:

Pediatrics

Secondary Appointment(s):

Physiology

Administrative Title:

Director, Center for Stem Cell Biology & Regenerative Medicine

Email:

ccivin@som.umaryland.edu

Location:

HSF II, S103D

Phone (Primary):

(410) 706-1181

Phone (Secondary):

(410) 706-1198

Education and Training

  • Amherst College, BA, Biology/Independent Study, 1966-70 (magna cum-laude)
  • Harvard Medical School, MD, 1970-74 (cum-laude)
  • Residency in Pediatrics, Boston Children’s Hospital, 1974-76
  • Fellowships, Pediatric Hematology-Oncology & Tumor-Immunology, National Cancer Institute, National Institutes of Health, 1976-79

Biosketch

Dr. Civin is a pioneer in stem cell research and cancer research known internationally for developing a technology to isolate stem cells from other blood cells. The founding director for the University of Maryland’s Center for Stem Cell Biology & Regenerative Medicine, he has received wide recognition for his groundbreaking 1984 discovery of CD34, which has had a major impact on the field of blood research, as well as his mentoring of scientist and physician trainees who have become world leaders.

Dr. Civin’s breakthrough discovery of the CD34 lympho-hematopoietic stem cell antigen and monoclonal antibody (Civin et al., J. Immunology 1984) accelerated basic research in stem cell and leukemia biology and improved stem cell transplantation for thousands of patients. This led to multiple honors, including the 1999 National Inventor of the Year Award and the 2009 Landsteiner Award (Civin et al., Transfusion 2010). Through his laboratory research, Dr. Civin accomplished the rare feat of making discoveries that not only opened entirely new directions and continue to empower stem cell, leukemia, and transplantation research, but that are also valuable in clinical bone marrow stem cell transplantation and leukemia diagnosis.

His work led to the first successful stem cell therapies emanating from basic research, as he proved in his own patients (Civin et al., J. Clinical Oncology 1996). CD34 was the first and is still the best marker for hematopoietic stem-progenitor cells, as well as endothelial cells (Beschorner et al., Am. J. Pathology 1985). CD34 monoclonal antibodies have provided an efficient, robust technology to immunoaffinity-purify these key cells. Tens of thousands of scientific articles involve CD34 (e.g., Loken et al., Blood 1987), and thousands of patients have received CD34+ cell transplants and/or have had their mobilized peripheral blood stem cell harvests assessed for numbers of CD34+ cells.

Dr. Civin’s laboratory has over 4 decades of expertise with comprehensive cell and molecular biologic studies of normal and malignant hematopoiesis using cell lines, primary human CD34+ hematopoietic stem-progenitor cells, mouse cells, and primary human leukemia cells. His own current research focuses on the roles of key molecules (e.g., Creed et al., Development 2020), including microRNAs (e.g., Georgantas et al. PNAS, 2007) and their targets in normal and leukemic stem-progenitor cells, on targeting leukemias (e.g., Moses et al., Blood Advances 2021), and on applying new bioengineering technologies to problems in hematology and oncology (e.g., Campos-González et al., SLAS Technology 2018).

Dr. Civin and colleagues immunophenotypically identified and characterized most of the major stages and lineages of normal human blood and immune cell development, including the CD34+CD38- subset that is highly enriched in engrafting human hematopoietic stem cells (Civin et al., Blood 1996). The direct clinical impact of CD34 and other monoclonal antibodies made by his lab include many thousands of patients whose leukemias have been sub-classified using immunophenotyping panels. They also developed monoclonal antibody panels that define normal lympho-hematopoietic cell subtypes (e.g., Loken et al., Blood 1987), to determine diagnostic and prognostic subtypes of leukemia cases (e.g., Hurwitz et al., Blood 1988), and to detect minimal residual leukemia (Gore et al., Blood 1991).

Civin’s team discovered several key human stem-progenitor cell molecules, such as the human FLT3 receptor (Small et al., PNAS 1994) and the TNK1 tyrosine kinase. They were among the first to find that certain microRNAs were key normal hematopoietic regulators (e.g., Georgantas et al., PNAS 2007), and they continue to use microRNAs to identify novel target molecules and pathways involved in regulation of normal and leukemic human hematopoiesis, including miR144, miR451, RAB14 (Kim et al., British J. Haematology 2015), EYA and SIX (Creed et al., Development 2020).

Via screens of a repurposing library of 4000 clinical drugs, Dr. Civin and colleagues discovered that artemisinins, which have low/absent clinical toxicity in worldwide use as antimalarials, are active against human leukemia cell lines and primary acute leukemia patient samples in vitro and in mouse xenograft models in vivo. They identified a highly potent analog dimeric analog with prolonged in vivo half-life, artemisinin-derived trioxane diphenylphosphate 838 (ART838) (Mott et al., Bioorg. Med. Chem. 2013). Because multiagent combination regimens are necessary to cure fully evolved leukemias, they sought to identify synergies of artemisinin analogs with established and emerging low toxicity antileukemic drugs. In addition to standard acute myeloid leukemia drugs, tyrosine kinase inhibitors and B-cell lymphoma 2 (BCL2) inhibitors synergized strongly with artemisinins (Fox et al., Oncotarget 2016). Validation assays confirmed that the selective BCL2 inhibitor, venetoclax, and the broad kinase inhibitor, sorafenib, both synergized strongly with artemisinin analogs to inhibit growth and induce apoptotic cell death of multiple acute leukemia cell lines and primary patient samples in vitro. An oral 3-drug “SAV” regimen (sorafenib plus the potent ART838 analog plus venetoclax) efficiently killed leukemia cell lines and primary leukemia cells from patients in vitro but spared normal human hematopoietic progenitor cells. Leukemia cells cultured in ART838 had decreased induced myeloid leukemia cell differentiation protein (MCL1) levels and increased levels of DNA damage-inducible transcript 3 (DDIT3; GADD153) messenger RNA and its encoded CCATT/enhancer-binding protein homologous protein (CHOP), a key component of the integrated stress response. Thus, synergy of the SAV combination may involve combined targeting of MCL1 and BCL2 via discrete, tolerable mechanisms, and cellular levels of MCL1 and DDIT3/CHOP may serve as biomarkers for the mechanism of action of artemisinins and SAV. Finally, SAV treatment was tolerable and resulted in deep responses with extended survival in 2 acute myeloid leukemia cell line xenograft models, both harboring a mixed lineage leukemia gene rearrangement and an FMS-like receptor tyrosine kinase-3 internal tandem duplication, and SAV treatment also inhibited growth in 2 AML primagraft models (Moses et al., Blood Advances 2021). They are currently working to further develop patented novel artemisinin analogs for clinical trials and commercialization, and to elucidate the full molecular mechanism of the unique antileukemic activity of artemisinins (Kagan et al., Frontiers Oncol. 2023; Cancer Chemother. Pharmacol. 2023)

Colleagues at Princeton University and GPB Scientific Inc. had previously developed a deterministic lateral displacement (DLD) microfluidic method to separate cells of various sizes from blood. With NIH STTR grant support, the Civin lab collaborated with them to reduce this technology to practice via a commercially produced, high-precision plastic microfluidic chip-based device designed for automated preparation of human leukocytes for flow cytometry. After a human blood sample was incubated with fluorochrome-conjugated monoclonal antibodies, the mixture was input to a DLD microfluidic chip where it was driven through a micropost array designed to deflect leukocytes purely on the basis of size from the input flow stream into a buffer stream, thus separating leukocytes from smaller cells and particles and washing them simultaneously. They developed a microfluidic cell processing protocol that recovered ~90% of input leukocytes and removed >99.9% of input erythrocytes and >99% of unbound antibody in <20 minutes. Flow cytometric evaluation of the microchip-processed cell product revealed excellent forward and side light scattering and fluorescence characteristics of immunolabeled leukocytes.

These results indicate that cost-effective plastic DLD microchips can speed and automate leukocyte processing for high-quality flow cytometry analysis, and potentially multiple other research and diagnostic applications (Civin et al., Cytometry A 2016). Subsequently, they extended this work toward therapeutic application via a novel DLD device for processing of large-volume apheresis blood products. Supported by a second NIH STTR grant, they demonstrated efficient leukocyte recovery and erythrocyte/platelet depletion, and the recovered T lymphocytes expanded extensively in culture.

Thus, DLD leukocyte processing provides a path to develop a simple closed and automated system, and simultaneously accomplishes multiple steps that involve potential for human error, microbial contamination, and other current technical challenges associated with manufacture of therapeutic cells such as CAR T-cells. As a result of this collaborative research developing bioengineering tools for blood cell separation, Dr. Civin is an inventor on multiple patents with Princeton and GPB colleagues. Recently, the collaborative team has begun to develop DLD processing of mobilized blood apheresis samples for hematopoietic stem cell therapies, and GPB Scientific Inc. has grown and receives substantial venture capital funding (Campos-González et al., SLAS Technology 2018).

Dr. Civin holds dozens of biomedical patents and is currently a principal or collaborating investigator on multiple peer-reviewed research projects funded by the National Institutes of Health, the State of Maryland, and private foundations. Dr. Civin taught and led research and clinical pediatric oncology at Johns Hopkins University School of Medicine for 30 years before becoming founding director for the University of Maryland’s Center for Stem Cell Biology & Regenerative Medicine and Associate Dean for Research in 2009.

He has lectured around the world, published more than 250 scientific articles and many book chapters, received many awards, and served in leadership positions of multiple distinguished committees and editorial boards. Throughout his career, he has mentored a large number of talented scientists and physician-scientists to pursue field-leading academic careers in translational research.

Research/Clinical Keywords

Stem Cell Biology, Hematopoiesis, Regenerative Medicine, Oncology, Pediatric Oncology, Gene Therapy, Hematology, Cancer, Leukemia, Bone Marrow Transplantation, Hematopoietic Stem Cells, CD34

Highlighted Publications

Civin CI. CD34 stem cell stories and lessons from the CD34 wars: the Landsteiner Lecture 2009. Transfusion. 2010 Sep;50(9):2046-56. PubMed ID: 20561292; NIHMSID: NIHMS668003.

Civin CI, Trischmann T, Kadan NS, Davis J, Noga S, Cohen K, Duffy B, Groenewegen I, Wiley J, Law P, Hardwick A, Oldham F, Gee A. Highly purified CD34-positive cells reconstitute hematopoiesis. J Clin Oncol. 1996 Aug;14(8):2224-33. PubMed PMID: 8708711.

Loken MR, Shah VO, Dattilio KL, Civin CI. Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development. Blood. 1987 Nov;70(5):1316-24. PubMed PMID: 3117132.

Beschorner WE, Civin CI, Strauss LC. Localization of hematopoietic progenitor cells in tissue with the anti-My-10 monoclonal antibody. Am J Pathol. 1985 Apr;119(1):1-4. PubMed Central PMCID: PMC1888077.

Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH. Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol. 1984 Jul;133(1):157-65. PubMed PMID: 6586833.

Additional Publication Citations

Research Interests

Awards and Affiliations

Previous Positions

Edit Icon - Click to update your profileUpdate Your Profile
×