Department of Pediatrics
Center for Cell and Gene Therapy
Texas Children’s Cancer Center
Baylor College of Medicine
Dr. Leonid S. Metelitsa
1102 Bates St., Suite 1760.06
Houston, TX 77030
Dr. Leonid Metelitsa’s research is focused on understanding the role of Vα24-invariant Natural Killer T cells (NKTs) in tumor immunity. Dr. Metelitsa’s laboratory has published a series of high-impact papers that revealed the mechanism of NKT cell localization to the tumor site and their interaction with other cells in the tumor microenvironment. In one of these studies, they identified the mechanism by which aggressive neuroblastomas escape from NKT cell control (L. Song et al., J. Clin. Invest. 2007). In another, they discovered a novel mechanism by which NKT cell attack tumor-associated macrophages and mediate indirect anti-tumor activity in solid tumors (L. Song et al., J. Clin. Invest., 2009). In the next step toward understanding the role of NKT cells in the tumor microenvironment, Metelitsa’s lab discovered a general mechanism by which tumor-induced hypoxia neutralizes NKT-cell function and rescues tumor-supportive macrophages from the NKT-cell attack (D. Liu et al., J. Clin. Invest. 2012).
Dr. Metelitsa’s research spans the spectrum from the basic mechanisms of disease to the development of new therapies for children with cancer. To this end, he and his colleagues have developed a novel immunotherapeutic strategy using ex-vivo expanded NKT cells that are genetically modified with a neuroblastoma-specific chimeric antigen receptor (CAR) for targeting both tumor cells and tumor-supportive macrophages (A. Heczey et al., Blood, 2014). In another project, they developed a novel Salmonella-based cancer vaccine platform with the use of NKT ligands as adjuvants. They demonstrated that such vaccines have potent anti-tumor activity in mice with formation of protective memory (X. Xu et al., Canc. Res., 2014).
Postdoctoral Research Fellowship, Children’s Hospital Los Angeles, University of Southern California (mentor: Robert C. Seeger, MD), Los Angeles, CA
Ph.D. and Clinical Fellowship, N.N. Blokhin Memorial Cancer Research Center of Russian Academy of Medical Sciences, Moscow, Russia
M.D., Tver State Medical Academy, Tver, Russia
Member, American Association of Immunologists (AAI)
Elected Member, American Society of Clinical Investigation (ASCI)
Member, American Society of Gene & Cell Therapy (ASGCT)
Va24-Ja18-invariant Natural Killer T (iNKT) cells
NKT-based immunotherapeutic strategies
Our research is focused on Va24-Ja18-invariant Natural Killer T cells (NKTs). NKTs are an evolutionary conserved sub-lineage of T cells that are characterized by the expression of an invariant TCR œ-chain, Vœ24-Jœ18 and reactivity to self- and microbial-derived glycolipids presented by monomorphic HLA class-I-like molecule CD1d. The emerging concept places the NKT-CD1d system at the bridging point between innate and adaptive immunity that makes them an attractive target for developing new immunotherapeutic strategies in many diseases including cancer.
Despite the fact that the majority of solid tumors including neuroblastoma are CD1d-negative, the antitumor potential of NKTs has been demonstrated in numerous models of cancer. Our group made an original observation that NKT-cell infiltration of primary tumors was associated with good outcome in children with neuroblastoma, a finding that has been since extended to other malignancies. However, the mechanism by which NKTs mediate antitumor responses against CD1d-negative tumors had remained largely unknown. In a recent report we showed that NKTs co-localize with tumor-associated macrophages (TAMs) in primary neuroblastomas and upon recognition of tumor-derived glycolipids specifically kill TAMs in a CD1d-dependent manner (Song et al, J Clin Invest, 2009). Since TAMs provide a critical stromal support for tumor cell growth in neuroblastoma and many other types of cancer, NKT cell-mediated killing or inhibition of TAMs explains how NKTs may indirectly affect tumor growth.
We continue studies on the mechanisms of NKT cell localization and function at the tumor site (e.g. D. Liu et al., J. Clin. Invest. 2012; A. Heczey et al., Blood, 2014). Our hypotheses are largely based on the findings that have been made in primary human tumors, tested in experimental in vitro and in vivo models, and are related to the disease outcome in cancer patients. The results will identify novel molecular targets for the development of effective immunotherapy of neuroblastoma and other types of cancer.
Our research is supported by competitive grants from NIH/NCI, CPRIT , Leukemia & Lymphoma Society, Alex’s Lemonade Stand Foundation, and Cookies for Kids’ Cancer Foundation.
Dr. Leonid Metelitsa is a member of the Center for Cell and Gene Therapy (CAGT) research laboratories.
Leonid Metelitsa, M.D., Ph.D.
Katia Marinova, Ph.D.
Daofeng Liu, Ph.D.
Amy Courtney, Ph.D.
Tynetta Fletcher-Beals, Ph.D.
Wei Huang, Ph.D.
Xin Xu, Ph.D.
Linjie Guo, M.D.
Xiuhua Gao, Ph.D.
Ismail Meraz, Ph.D.
Michael Wood, M.S.
Gengwen Tian, M.D.
Suhrab Kurbanov, B.S.