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Jeffrey J. Molldrem, MD

Research Summary (up to 350 words): Help

The primary interest of my laboratory is to understand how T cells recognize and attack hematopoietic progenitor cells. This important question is relevant to certain autoimmune disorders and bone marrow failure states, such as aplastic anemia and myelodysplastic syndrome, and to the graft-versus-leukemia (GVL) effect that accompanies allogeneic bone marrow transplantation. To understand these T-cell interactions better, we have studied 2 different model systems.
In the first approach, we studied overexpressed myeloid-restricted proteins as potential targets of GVL. One such protein, an azurophil granule protein called proteinase 3, contains an HLA-A2-restricted 9-amino-acid peptide we named PR1 that can be used in vitro to elicit cytotoxic T lymphocytes (CTLs) from normal donors that preferentially lyse myeloid leukemia cells but not normal myeloid progenitors. Using PR1/HLA-A2 tetramers, we found CTLs with PR1 specificity are increased in patients in cytogenetic remission after IFN or allogeneic bone marrow transplant. This peptide is therefore the first potential tumor antigen for myeloid leukemia. The synthetically produced PR1 peptide is now being used in a clinical vaccine trial with incomplete Freund's adjuvant and GM-CSF to vaccinate patients with myeloid leukemia.

We have developed methods for rapid ex vivo expansion of PR1-specific CTLs, as well as CTLs with other tumor specificities. In the future, these PR1-specific CTLs could be adoptively transferred to patients with myeloid leukemia who have a relapse after allogeneic bone marrow transplantation to convey a potent GVL effect without graft-versus-host disease. In the long term, we are working to identify other potential tissue-restricted tumor antigens for use as selective targets in immunotherapy for leukemia, and we are investigating immune tolerance mechanisms toward PR1.

In the second approach, we have studied autologous T-cell inhibition of hematopoietic precursors in patients with myelodysplastic syndrome. In a phase II trial using antithymocyte globulin (ATG) as treatment for patients with myelodysplastic syndrome and significant cytopenia, we found that effective hematopoiesis was reestablished in 34% of the patients after 1 course of treatment. The response to ATG correlated with the reversal of CTL-mediated suppression of marrow progenitor cells and the disappearance of large numbers of CTL clones that were present prior to ATG treatment. We are performing a clinical trial using fludarabine and cyclosporine with ATG to increase the response rate, and we are working to identify the CTL target antigens in hematopoietic issues.