Dennis M. Klinman, M.D., Ph.D.
Dennis M. Klinman, M.D., Ph.D.
Senior Investigator
Head, Immune Modulation Group

Dr. Klinman co-discovered CpG oligonucleotides (ODN) and demonstrated that they were TLR9 agonists in Man. He pioneered the use of CpG ODN as vaccine adjuvants and immunoprotective agents. He also discovered immunosuppressive ODN and demonstrated their ability to treat/prevent autoimmune and inflammatory diseases. Dr. Klinman’s lab focuses on modifying the innate immune system to alter inflammation and host susceptibility to cancer.

Areas of Expertise
1) immunotherapy, 2) cancer vaccines, 3) innate immunity, 4) TLR agonists

Contact Info

Dennis M. Klinman, M.D., Ph.D.

Center for Cancer Research
National Cancer Institute

Building 567, Room 205
Frederick, MD 21702-1201
301-228-4265

My laboratory is interested in understanding the mechanism by which immunomodulatory DNA alters host susceptibility to cancer, inflammation and infectious diseases. Our research focuses on the ability of immunostimulatory CpG and immunosuppressive TTAGGG oligodeoxynucleotides (ODN) to alter the inflammatory and immune milieu of the host. CpG DNA interacts with toll-like receptor 9 to trigger an innate immune response that improves host resistance to a wide range of infectious microorganisms and tumors. CpG DNA also improves antigen presenting cell function, thereby facilitating the development of an adaptive immune response when co-administered with vaccines encoding pathogen or tumor specific antigens. In contrast, suppressive ODN down-regulate inflammatory responses, delaying the onset and reducing the severity of autoimmune and pro-inflammatory syndromes.

My laboratory has been studying the mechanism of action and therapeutic potential of CpG and suppressive ODN for the past decade. We contributed to the initial discovery of CpG ODN and their immunomodulatory properties, the identification of TLR 9 as the receptor for CpG DNA, the finding that CpG ODN improved host resistance to pathogen and tumor challenge, and the ability of these molecules to act as immune adjuvants, boosting and accelerating the response to therapeutic and prophylactic vaccines. Our studies of suppressive ODN included the discovery of the key TTAGGG motif, the molecular mechanism by which suppressive ODN block T cell responses, and their ability to prevent/treat multiple autoimmune and inflammatory diseases in animal models. We hold numerous licensed patents relating to CpG and suppressive ODN, and our pre-clinical studies examining the immunomodulatory activity and safety of these agents form the basis for a number of ongoing phase I, II and III clinical trials.

Ongoing studies focus on furthering our understanding of the immunomodulatory activity of CpG and suppressive ODN, especially when combined with other immune response modifiers. This includes nalyzing the ability of CpG ODN (alone and in combination with other TLR ligands and small molecule immune potentiators) to accelerate and magnify the protective immune response elicited by vaccines targeting infectious pathogens and tumors. We've identified novel adjuvant combinations/ formulations that significantly improve vaccine-specific immunity, and are pursuing strategies to boost their activity further.

At a more basic level, my lab is interested in the receptors that contribute to the recognition of CpG and suppressive DNA. We will pursue our recent finding that CXCL16 plays a key role in the recognition, uptake, and intracellular localization of 'D' class CpG ODN. We will also evaluate whether other scavenger receptors participate in the recognition of immunomodulatory DNA. To gain a broader perspective on the impact of CpG and suppression ODN on host immunity, we will continue studies using microarray technology to examine the kinetics and magnitude with which genes are activated following exposure to these agents. By correlating the up-regulation of specific genes with the host's subsequent immune responses, we hope to identify genetic markers predictive of clinically effective treatments.

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology, Microbiology and Infectious Diseases, Stem Cell Biology

View Dr. Klinman's PubMed Summary.

Selected Key Publications
  1. Klinman DM, Higgins KW, Conover J.
    J Exp Med. 173: 881, 1991. [ Journal Article ]
  2. Krieg AM, Yi A, Matson S, Waldschmidt TJ, Bishop G, Teasdale R, Koretzky GA, Klinman DM.
    Nature. 374: 546, 1995. [ Journal Article ]
  3. Klinman DM, Yi A, Beaucage SL, Conover J, Krieg AM.
    Proc Natl Acad Sci USA. 93: 2879, 1996. [ Journal Article ]
  4. Verthelyi D, Ishii KJ, Gursel M, Klinman DM.
    J Immunol. 166: 2372, 2001. [ Journal Article ]
  5. Shirota Y, Shirota H, Klinman DM.
    J Immunol. 188: 1592, 2012. [ Journal Article ]

Dr. Klinman received his MD/PhD from the University of Pennsylvania, and completed his fellowship training in Rheumatology at the National Institute of Arthritis, NIH. He headed the Section of Viral Immunology at the Center for Biologics Evaluation and Research of the FDA before joining the Laboratory of Experimental Immunology of the National Cancer Institute as chief of the Immunoregulation Group. He has authored over 300 peer reviewed articles, received of the FDA's 'Outstanding Scientist of the Year' Award, the 'Outstanding Achievement Award In Biology' from the Washington Academy of Science, and 'Meritorious', 'Outstanding' and 'Distinguished' Service Medals from the Public Health Service, among other honors.

Name Position
Defne Bayik Postdoctoral Fellow (Visiting)
Christian Bode Special Volunteer
Stanislaw Kaczmarczyk Ph.D. Special Volunteer
Luis Rodriguez Special Volunteer
Julia Scheiermann Postdoctoral Fellow (Visiting)
Isaac Soltz Special Volunteer
Folkert Steinhagen MD Guest Researcher
Debra Tross-Currie Research Biologist
Jing Wang Guest Researcher

Research

My laboratory is interested in understanding the mechanism by which immunomodulatory DNA alters host susceptibility to cancer, inflammation and infectious diseases. Our research focuses on the ability of immunostimulatory CpG and immunosuppressive TTAGGG oligodeoxynucleotides (ODN) to alter the inflammatory and immune milieu of the host. CpG DNA interacts with toll-like receptor 9 to trigger an innate immune response that improves host resistance to a wide range of infectious microorganisms and tumors. CpG DNA also improves antigen presenting cell function, thereby facilitating the development of an adaptive immune response when co-administered with vaccines encoding pathogen or tumor specific antigens. In contrast, suppressive ODN down-regulate inflammatory responses, delaying the onset and reducing the severity of autoimmune and pro-inflammatory syndromes.

My laboratory has been studying the mechanism of action and therapeutic potential of CpG and suppressive ODN for the past decade. We contributed to the initial discovery of CpG ODN and their immunomodulatory properties, the identification of TLR 9 as the receptor for CpG DNA, the finding that CpG ODN improved host resistance to pathogen and tumor challenge, and the ability of these molecules to act as immune adjuvants, boosting and accelerating the response to therapeutic and prophylactic vaccines. Our studies of suppressive ODN included the discovery of the key TTAGGG motif, the molecular mechanism by which suppressive ODN block T cell responses, and their ability to prevent/treat multiple autoimmune and inflammatory diseases in animal models. We hold numerous licensed patents relating to CpG and suppressive ODN, and our pre-clinical studies examining the immunomodulatory activity and safety of these agents form the basis for a number of ongoing phase I, II and III clinical trials.

Ongoing studies focus on furthering our understanding of the immunomodulatory activity of CpG and suppressive ODN, especially when combined with other immune response modifiers. This includes nalyzing the ability of CpG ODN (alone and in combination with other TLR ligands and small molecule immune potentiators) to accelerate and magnify the protective immune response elicited by vaccines targeting infectious pathogens and tumors. We've identified novel adjuvant combinations/ formulations that significantly improve vaccine-specific immunity, and are pursuing strategies to boost their activity further.

At a more basic level, my lab is interested in the receptors that contribute to the recognition of CpG and suppressive DNA. We will pursue our recent finding that CXCL16 plays a key role in the recognition, uptake, and intracellular localization of 'D' class CpG ODN. We will also evaluate whether other scavenger receptors participate in the recognition of immunomodulatory DNA. To gain a broader perspective on the impact of CpG and suppression ODN on host immunity, we will continue studies using microarray technology to examine the kinetics and magnitude with which genes are activated following exposure to these agents. By correlating the up-regulation of specific genes with the host's subsequent immune responses, we hope to identify genetic markers predictive of clinically effective treatments.

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology, Microbiology and Infectious Diseases, Stem Cell Biology

Publications

View Dr. Klinman's PubMed Summary.

Selected Key Publications
  1. Klinman DM, Higgins KW, Conover J.
    J Exp Med. 173: 881, 1991. [ Journal Article ]
  2. Krieg AM, Yi A, Matson S, Waldschmidt TJ, Bishop G, Teasdale R, Koretzky GA, Klinman DM.
    Nature. 374: 546, 1995. [ Journal Article ]
  3. Klinman DM, Yi A, Beaucage SL, Conover J, Krieg AM.
    Proc Natl Acad Sci USA. 93: 2879, 1996. [ Journal Article ]
  4. Verthelyi D, Ishii KJ, Gursel M, Klinman DM.
    J Immunol. 166: 2372, 2001. [ Journal Article ]
  5. Shirota Y, Shirota H, Klinman DM.
    J Immunol. 188: 1592, 2012. [ Journal Article ]

Biography

Dr. Klinman received his MD/PhD from the University of Pennsylvania, and completed his fellowship training in Rheumatology at the National Institute of Arthritis, NIH. He headed the Section of Viral Immunology at the Center for Biologics Evaluation and Research of the FDA before joining the Laboratory of Experimental Immunology of the National Cancer Institute as chief of the Immunoregulation Group. He has authored over 300 peer reviewed articles, received of the FDA's 'Outstanding Scientist of the Year' Award, the 'Outstanding Achievement Award In Biology' from the Washington Academy of Science, and 'Meritorious', 'Outstanding' and 'Distinguished' Service Medals from the Public Health Service, among other honors.

Team

Name Position
Defne Bayik Postdoctoral Fellow (Visiting)
Christian Bode Special Volunteer
Stanislaw Kaczmarczyk Ph.D. Special Volunteer
Luis Rodriguez Special Volunteer
Julia Scheiermann Postdoctoral Fellow (Visiting)
Isaac Soltz Special Volunteer
Folkert Steinhagen MD Guest Researcher
Debra Tross-Currie Research Biologist
Jing Wang Guest Researcher