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Dr. Nadler received his MD from Harvard Medical School in 1973. After residency training at Columbia-Presbyterian Medical Center and training at the National Cancer Institute in tumor immunology, he completed a medical oncology fellowship at DFCI, where he joined the staff in 1980. During his tenure at DFCI, he has served as chief and chair of several departments.
Our laboratory focuses on translational bench-to-bedside and bedside-to-bench research. First, we are investigating the mechanisms of tolerance induction to improve the outcome of allogeneic stem cell transplantation. Second, we are attempting to induce antigen-specific tumor immunity. Our studies of anergy and tolerance are direct extensions of our discovery and characterization of the B7 family of costimulatory molecules. Blockade of the B7 family is both necessary and sufficient to induce alloantigen-specific anergy. We have shown that anergy is an active signaling process. Following extensive preclinical studies, we embarked on a clinical trial. The objective of this study was to induce tolerance of donor T cell antigens specific to host antigen anergy ex vivo through blockade of B7 costimulation. Induction of antigen-specific tolerance would eliminate or sharply curtail the need for nonspecific prophylactic immunosuppression and for the subsequent toxic and often inefficacious treatment of severe acute or chronic graft-versus-host disease (GVHD). Similarly, retention of a mature T cell component in the graft with its residual repertoire intact could facilitate engraftment and eliminate the risks of lymphoproliferative disease and increased relapse after transplant that currently attend global T cell depletion strategies. We have completed two phase I studies using anti-B7 blockade to induce alloantigen-specific anergy in patients undergoing haploidentical human stem cell transplantation. We have demonstrated feasibility, less than expected incidence of GVHD, and fewer than expected infections. Going forward, we are focusing on the retention of pathogen and tumor-specific immunity. Our studies in antigen-specific antitumor immunity have focused on the identification and clinical translational of universal tumor antigens. We have shown that hTERT and CYP1B1 are expressed in most human tumors with limited expression in normal tissues. Human T cells directed against these antigens exist in the T cell repertoire of normal individuals and patients with cancer. T cells directed against these antigens can be generated ex vivo, and these T cells can kill human tumor cells in an HLA-restricted, antigen-restricted fashion. Each of these universal tumor antigens has been taken to the clinic to treat patients with advanced-stage multiply relapsed cancer. A phase I trial of hTERT peptide-pulsed dendritic cells demonstrated feasibility, safety, and the generation of peptide-specific T cells. We are now extending this trial. We have also conducted a DNA vaccine trial of CYP1B1. Again, no significant toxicities were observed and patients generated anti-CYP1B1 specific T cells.
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