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University of Texas, MD Anderson Cancer Center
To Collect Peripheral Blood and Bone Marrow Samples from Donors and Recipients of Blood and Marrow Transplants for Laboratory Research
In his ongoing studies of anti-leukemia immunity and CTL antigens, Dr. Molldrem has studied myeloid-restricted normal proteins that are highly expressed leukemia. Myeloid leukemias express a number of differentiation antigens associated with granule formation. He chose to study Pr3, a 26,000 dalton neutral serine protease that is stored in primary azurophil granules and is maximally expressed at the promyelocyte stage of myeloid differentiation. The human gene contains 5 exons, is localized on chromosome 19p and has recently been cloned. Pr3 is over expressed in a variety of myeloid leukemia cells including 75% of CML patients, approximately 50% of acute myeloid leukemia patients, and approximately 30% of the cases of myelodysplastic syndrome patients. Dr. Molldrem has found that PR1, a 9 aa peptide derived from Pr3 that binds to HLA_A2.1, can be used to elicit CTL in vitro from an HLA-A2.1+ normal donor. These PR1-specific CTL show preferential cytotoxicity toward allogeneic HLA-A2.1 myeloid leukemia cells over HLA-identical normal donor marrow. PR1 is therefore the first peptide antigen identified that can elicit specific CTL lysis of fresh human myeloid leukemia cells. More recently, he has identified PR1-specific CTL in the peripheral blood of CML patients using PR1/HLA-A2 tetramers, and detection of these CTL correlates with a cytogenetic response to either interferon or allogeneic BMT (p = 0.002), thus establishing PR1 as the first human leukemia-associated tumor antigen. By FAC sorting CML patients' PR1-specific CTL to high purity, he showed that PR1-specific CTL could specifically lyse CML but not normal marrow cells, and that they were HLA-A2 restricted. Dr. Molldrem proposes to improve his methods to efficiently grow PR1-specific lymphocytes in the lab. He will also investigate a new laboratory method to isolate only the PR1-specific lymphocytes from peripheral blood using microbeads that are conjugated to the HLA-A2 molecule plus PR1 peptide. These PR1-spcific lymphocytes will then be expanded to high enough numbers to be transferred to patients with relapsed myeloid leukemia after allogeneic transplant in order to induce GVL without GVHD.