Associate Director, Experimental Therapeutics
Research Programs: Immunology and Transplant Biology and Therapy
Professor, Department of Medicine

mille011@tc.umn.edu
612-625-7409 — office
612-626-4217 — lab

Dr. Miller's clinical profile
(University of Minnesota Physicians Web site)

Research Interests

Natural killer cell therapy to treat cancer

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. Clinical trials using allogeneic NK cells in acute leukemia and breast cancer are underway. Laboratory and clinical efforts using novel reagents to activate NK cells through dendritic cell Toll-like receptors have also been initiated as a possible adjunct to this therapy.

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) and Arkadiusz Dudek (Medicine). 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, melanoma and breast cancer will be included in the next generation of these trials. Understanding immune integrity and better immune adjuvants in cancer patients is an integral part of this effort.

Selected Publications

Chiorean EG, DeFor TE, Weisdorf DJ, Blazar BR , McGlave PB, Burns LJ, Charlotte Brown C, Miller JS: Donor chimerism does not predict response to DLI for relapsed CML after allogeneic hematopoietic cell transplantation, Biol Blood Marrow Transplant. 10:171-77, 2004.

Chen W, Chan ASH, Dawson AJ, Liang X, Blazar BR, Miller JS: FLT3-ligand administration after hematopoietic cell transplantation increases circulating dendritic cell precursors that can be activated by CpG oligodeoxynucleotides to enhance T-cell and NK-cell function. Biol Blood Marrow Transplant. 2005 Jan;11:23-34.

Miller, JS Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB: Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in cancer patients. Blood 105:3051-3057, 2005.

Miller JS, Curtsinger J, Berthold M, Malvey K, Bliss RL, Le CT,. Fautsch SK, Dudek AZ, Blazar BR, and Panoskaltsis-Mortari A: 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, 2005.

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