Research Interests:

Natural killer cell development

Dr. Miller's research team works in two areas that seek to understand fundamental issues regarding innate immune function: 1.) How undifferentiated stem cells develop into functioning NK cell lymphocytes, and 2.) How to manipulate NK cells to treat or prevent cancer relapse. A major emphasis is on natural killer (NK) cell development and the mechanism of commitment to the lymphoid versus myeloid lineages. Recently, receptors on NK cells have been identified that recognize class I MHC molecules. The hypothesis underlying current research efforts is that "self" MHC molecules influence the NK cell receptor repertoire during development. These NK cell receptors may also play a physiologic role in cancer. Laboratory evaluation and human clinical trials will test the hypothesis that a mismatch between NK receptor and class I alleles on recipient tumor will result in greater tumor kill.

Targeted Immunotherapy to Treat Human Cancer

The second major emphasis in Dr. Miller's laboratory is based on pre-clinical and clinical studies to develop effective anti-tumor immunotherapies. Early studies focused on nonspecific immune stimulation using subcutaneous IL-2. Strong evidence suggests that this nonspecific therapy alone will be ineffective and current efforts aim to target effectors specifically to tumor cells. For natural killer cells, current approaches include combined therapy with monoclonal antibodies and interleukin-2 to target therapy through antibody dependent cellular cytotoxicity (ADCC). To target T-cells, we have initiated a study in collaboration with Matthew Mescher (Director, Center for Immunology). These studies focus on the human translation of large multivalent immunogens (LMI) into the clinic. Our first clinical trial was FDA approved and open for accrual in April, 2001. Patients with advanced renal cell carcinoma and melanoma are eligible. Additional trials are planned for breast cancer. Understanding immune integrity in cancer patients is an integral part of this effort.

Selected Recent Publications:

• Miller, J.S. Soignier Y. Panoskaltsis-Mortari A., McNearney S.A., Yun G.H..,
  Fautsch S.K., McKenna D., Le C., Defor T.E., Burns L.J., Orchard P.J., Blazar B.R.,
  Wagner J.E., Slungaard A., Weisdorf D.J., Okazaki I.J., McGlave P.B. 2005. Successful
  adoptive transfer and in vivo expansion of human haploidentical NK cells
  in cancer patients. Blood, 105:3051-3057.

• Miller J.S., Curtsinger J., Berthold M., Malvey K., Bliss R.L., Le C.T., Fautsch
  S.K., Dudek A.Z., Blazar B.R., and Panoskaltsis-Mortari A. 2005. Diminished
  neo-antigen response to keyhole limpet hemocyanin (KLH) vaccines in
  patients after treatment with chemotherapy or hematopoietic cell
  transplantation. Clinical Immunology, 117:144-151.

• Chan H.W., Miller J.S., Moore M.B., Lutz C.T. 2005. Epigenetic Control of Highly
  Homologous Killer Ig-Like Receptor Gene Alleles. Journal of Immunology,
  175: 5966-5974.

• Cooley S., McCullar V., Wangen R., Bergemann, T.L., Spellman S., Weisdorf D.J.,
  and Miller J.S. 2005. KIR reconstitution is altered by T cells in the graft and
  correlates with clinical outcomes after unrelated donor transplantation.
  Blood, 106:4370-4376.

Last modified on August 9, 2006